28579691	The role of prediction error (PE) in driving learning is well-established in fields such as classical and instrumental conditioning, reward learning and procedural memory; however, its role in human one-shot declarative encoding is less clear. According to one recent hypothesis, PE reflects the divergence between two probability distributions: one reflecting the prior probability (from previous experiences) and the other reflecting the sensory evidence (from the current experience). Assuming unimodal probability distributions, PE can be manipulated in three ways: (1) the distance between the mode of the prior and evidence, (2) the precision of the prior, and (3) the precision of the evidence. We tested these three manipulations across five experiments, in terms of peoples' ability to encode a single presentation of a scene-item pairing as a function of previous exposures to that scene and/or item. Memory was probed by presenting the scene together with three choices for the previously paired item, in which the two foil items were from other pairings within the same condition as the target item. In Experiment 1, we manipulated the evidence to be either consistent or inconsistent with prior expectations, predicting PE to be larger, and hence memory better, when the new pairing was inconsistent. In Experiments 2a-c, we manipulated the precision of the priors, predicting better memory for a new pairing when the (inconsistent) priors were more precise. In Experiment 3, we manipulated both visual noise and prior exposure for unfamiliar faces, before pairing them with scenes, predicting better memory when the sensory evidence was more precise. In all experiments, the PE hypotheses were supported. We discuss alternative explanations of individual experiments, and conclude the Predictive Interactive Multiple Memory Signals (PIMMS) framework provides the most parsimonious account of the full pattern of results.
28575862	Most patients with mild cognitive impairment and Alzheimer's disease can initially present memory loss. The medial temporal lobes are the brain regions most associated with declarative memory function. As sub-components of the MTL, the perirhinal cortex, parahippocampal cortex and hippocampus have also been identified as playing important roles in memory. The functional connectivity between hippocampus subfields and perirhnial cortices as well as parahippocampal cortices among normal cognition controls (NC group, n=33), mild cognitive impairment (MCI group, n=31) and Alzheimer's disease (AD group, n=27) was investigated in this study. The result shows significant differences of functional connectivity in 3 pairs of regions among NC group, MCI group and AD group: right perirhinal cortex with right hippocampus tail, left perirhinal cortex with right hippocampus tail, and right parahippocampal cortex with right hippocampus head. Clustering methods were used to classify NC group, MCI group and AD group (accuracy=100%) as well as different subtypes of mild cognitive impairment patients based on functional alterations. Functional connectivity disrupted between perirhinal and parahippocampal cortex with hippocampal subfields, which may provide a better understanding of the neurodegenerative progress of MCI and AD.
28554357	Children's declarative memories of medical procedures can influence their responses to subsequent events. No previous study has examined the accuracy of children's declarative memories after surgery. We tested the memory of 34 anesthesia-naïve five- to nine-year-old children undergoing ambulatory surgery for accuracy of contextual details, pain, and fear two weeks postoperatively. Parents were not present during induction, and we did not use sedative premedication. Children had a mean contextual recall accuracy of 64.5%. Most children (60.6%) remembered a prompt that was given one minute after receiving nitrous oxide. Children's memories of pain and fear were similar to their reported pain and fear on the day of surgery. Of 29 children, 6 (20.7%) exaggerated their memory of fear, and 8 of 22 children (36.4%) exaggerated their memory of pain. Although a small proportion of children had exaggerated memories, there was no evidence of consistent bias in their memory of fear or pain.
28527215	Episodic memory impairment is the core feature of typical Alzheimer's disease.To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimer's disease (MCI-AD) and to predict progression to Alzheimer's disease dementia (AD-d).	Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimer's disease (CERAD-WL). Cerebrospinal fluid (CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/Aβ1-42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model.	A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9-65.3% and 59.4-62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test.	The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.	
28490858	The objective of the present study was to examine relations between social network size and three cognitive abilities (episodic memory, semantic memory, visuospatial ability) in middle-aged adults. We analyzed cross-sectional data on social network size and cognitive functioning that were available for 804 participants aged 40-60 years. In addition, we examined 5- and 10-year follow-up measurements of cognitive functioning that were available for 604 and 255 participants, respectively. Cross-sectional analyses revealed a positive association between social network size and each of the three cognitive abilities. Baseline network size was positively related to 5-year changes in semantic memory, and to 10-year changes in semantic as well as episodic memory, but was unrelated to changes in visuospatial performance. A minor portion of the sample (n = 131) had 10-year follow-up data on network size. Cross-lagged panel correlations revealed that baseline network size was associated with follow-up measurement in cognitive functioning (episodic memory, semantic memory), whereas baseline cognitive performance was unrelated to future network size. Together, the results demonstrate a small but positive relation between network size and declarative memory abilities, in line with models proposing a cognitive reserve built up by factors such as the increased cognitive stimulation associated with a more extensive social network.
28482463	Lutein is a xanthophyll carotenoid widely known by its biological properties and low toxicity. When located in the brain, lutein may inhibit damage mechanisms, acting in neural cells maintenance. However, this carotenoid is very sensitive to external agents such as heat, light, pH and oxidation, besides presenting low absorption in gastrointestinal tract due its low solubility in water. Encapsulation procedures have shown promising results to increase lutein stability and bioavailability. In this work, lutein was encapsulated in polyvinylpyrrolidone (PVP) matrix by the dissolution in common solvent method. Nanoparticles were characterized in respect to morphology, water solubility, and interactions between PVP and lutein. In vivo tests were carried out in order to investigate the influence of lutein encapsulation on mice's declarative memory. Ex vivo tests were also carried out to determine if nanoparticles may cause any inflammatory process per se. Results indicated that lutein was successfully encapsulated in PVP while nanoparticles presented spherical shape and uniform size. Encapsulation was able to increase water solubility of lutein by more than 43 times, which may be attributed to the formation of soluble complexes trough hydrogen bonds between lutein hydroxyl group and PVP carbonyl group. In vivo studies showed that the administration of free lutein at 100mg·kg-1 and lutein-loaded PVP nanoparticles at 10 and 1.5mg·kg-1 significantly increased mice's object recognition index, meaning that significant lower doses of lutein were needed to achieve the same effect when lutein was encapsulated. Ex vivo studies showed that lutein-loaded nanoparticles administration did not alter inflammatory parameters in plasma, liver and brain of mice. In this sense, lutein-loaded PVP nanocapsules showed to be an advantageous alternative to increase water solubility and to improve the memory of mice without causing inflammatory damage per se.
28475942	Adolescence is a crucial period for neurodevelopment, but few studies have investigated the impact of early cocaine use on cognitive performance and patterns of substance use.We evaluated 103 cocaine dependent inpatients divided in two groups: early-onset users (EOG; n=52), late-onset users (LOG; n=51), and 63 healthy controls. Neuropsychological functioning was evaluated using Digits Forward (DF) and Backward (DB), Trail Making Test (TMT), Stroop Color Word Test (SCWT), Controlled Oral Word Association Test (COWAT), Wisconsin Card Sorting Test (WCST), Rey Osterrieth Complex Figure Test (ROCFT), Frontal Assessment Battery (FAB), and Iowa Gambling Test (IGT). Use of alcohol and other drugs was assessed with the Addiction Severity Index (ASI-6).	Analyses of covariance controlling for age, IQ and years of education showed that EOG presented worse performance in attention span (DF, p=0.020), working memory (DB, p=0.001), sustained attention (WCST, p=0.030), declarative memory (ROCFT, p=0.031) and general executive functioning (FAB, p=0.003) when compared with the control group. LOG presented impairments on divided attention (TMT, p=0.003) and general executive functioning (FAB, p=0.001) in relation to the control group. EOG presented higher use of cannabis and alcohol than LOG (p≤0.001).	Early-onset cocaine users display more pronounced neuropsychological alterations than controls, as well as a greater frequency of polydrug consumption than LOG. The prominent cognitive deficits in EOG probably reflect the deleterious interference of cocaine use with early stages of neurodevelopment. This may be related to more severe clinical characteristics of substance disorder in this subgroup, including polysubstance abuse.	
28475603	Evidence suggests obesity exerts a negative impact on cognition. Major Depressive Disorder (MDD) is also linked to problems in cognitive functioning. Obesity is highly prevalent in individuals with MDD and is linked to a failure to return to a full level of functioning. The study's objective was to investigate the effect of obesity on cognitive impairment in participants with MDD.This study compared cognitive performance in obese individuals with MDD and two control populations (obese individuals without a psychiatric illness and non-obese controls). A standardized battery of neuropsychological tests specifically designed to assess performance in declarative memory, executive functioning, processing speed and attention was administered. Mood ratings, physical measurements, nutritional and health questionnaires were also completed.	We observed a consistent pattern across measures of memory, executive functioning, attention and processing speed. Whereas healthy controls performed better than both bariatric groups across the majority of measures administered, bariatric controls tended to outperform bariatric MDD patients.	The overall sample size of our study was small and thus largely explorative in nature. However, it provides compelling results (while controlling for extraneous variables such as medication load, nutritional status and common metabolic comordidities) that strongly urges for further investigation and study replication with larger sample sizes.	We found obesity has a subtle impact on cognition in obese individuals, and when obesity is present in individuals with MDD, this impact may be significant. It is important to minimize all modifiable variables that can add to cognitive burden in this population.	
28465166	For the past two decades, it has generally been accepted that sleep benefits motor memory consolidation processes. This notion, however, has been challenged by recent studies and thus the sleep and motor memory story is equivocal. Currently, and in contrast to the declarative memory domain, a comprehensive overview and synthesis of the effects of post-learning sleep on the behavioral and neural correlates of motor memory consolidation is not available. We therefore provide an extensive review of the literature in order to highlight that sleep-dependent motor memory consolidation depends upon multiple boundary conditions, including particular features of the motor task, the recruitment of relevant neural substrates (and the hippocampus in particular), as well as the specific architecture of the intervening sleep period (specifically, sleep spindle and slow wave activity). For our field to continue to advance, future research must consider the multifaceted nature of sleep-related motor memory consolidation.
28465069	Syntactic priming, the phenomenon in which participants adopt the linguistic behaviour of their partner, is widely used in psycholinguistics to investigate syntactic operations. Although the phenomenon of syntactic priming is well documented, the memory system that supports the retention of this syntactic information long enough to influence future utterances, is not as widely investigated. We aim to shed light on this issue by assessing patients with Korsakoff's amnesia on an active-passive syntactic priming task and compare their performance to controls matched in age, education, and premorbid intelligence. Patients with Korsakoff's syndrome display deficits in all subdomains of declarative memory, yet their nondeclarative memory remains intact, making them an ideal patient group to determine which memory system supports syntactic priming. In line with the hypothesis that syntactic priming relies on nondeclarative memory, the patient group shows strong priming tendencies (12.6% passive structure repetition). Our healthy control group did not show a priming tendency, presumably due to cognitive interference between declarative and nondeclarative memory. We discuss the results in relation to amnesia, aging, and compensatory mechanisms.
28445741	Electrical brain stimulations (EBS) sometimes induce reminiscences, but it is largely unknown what type of memories they can trigger. We reviewed 80 years of literature on reminiscences induced by EBS and added our own database. We classified them according to modern conceptions of memory. We observed a surprisingly large variety of reminiscences covering all aspects of declarative memory. However, most were poorly detailed and only a few were episodic. This result does not support theories of a highly stable and detailed memory, as initially postulated, and still widely believed as true by the general public. Moreover, memory networks could only be activated by some of their nodes: 94.1% of EBS were temporal, although the parietal and frontal lobes, also involved in memory networks, were stimulated. The qualitative nature of memories largely depended on the site of stimulation: EBS to rhinal cortex mostly induced personal semantic reminiscences, while only hippocampal EBS induced episodic memories. This result supports the view that EBS can activate memory in predictable ways in humans.
28412502	Since Ebbinghaus' classical work on oblivion and saving effects, we know that declarative memories may become at first spontaneously irretrievable and only subsequently completely extinguished. Recently, this time-dependent path toward memory-trace loss has been shown to correlate with different patterns of brain activation. Environmental enrichment (EE) enhances learning and memory and affects system memory consolidation. However, there is no evidence on whether and how EE could affect the time-dependent path toward oblivion. We used Object Recognition Test (ORT) to assess in adult mice put in EE for 40days (EE mice) or left in standard condition (SC mice) memory retrieval of the familiar objects 9 and 21days after learning with or without a brief retraining performed the day before. We found that SC mice show preferential exploration of new object at day 9 only with retraining, while EE mice do it even without. At day 21 SC mice do not show preferential exploration of novel object, irrespective of the retraining, while EE mice are still capable to benefit from retraining, even if they were not able to spontaneously recover the trace. Analysis of c-fos expression 20days after learning shows a different pattern of active brain areas in response to the retraining session in EE and SC mice, with SC mice recruiting the same brain network as naïve SC or EE mice following de novo learning. This suggests that EE promotes formation of longer lasting object recognition memory, allowing a longer time window during which saving is present.
28392406	Lesions of the reuniens and rhomboid (ReRh) thalamic nuclei in rats do not alter spatial learning but shorten the period of memory persistence (Loureiro et al. 2012). Such persistence requires a hippocampo-cortical (prefrontal) dialog leading to memory consolidation at the systems level. Evidence for reciprocal connections with the hippocampus and the medial prefrontal cortex (mPFC) makes the ReRh a potential hub for regulating hippocampo-cortical interactions. As environmental enrichment (EE) fosters recovery of declarative-like memory functions after diencephalic lesions (e.g., anterior thalamus), we studied the possibility of triggering recovery of systems-level consolidation in ReRh lesioned rats using a 40-day postsurgical EE. Remote memory was tested 25days post-acquisition in a Morris water maze. The functional activity associated with retrieval was quantified using c-Fos imaging in the dorsal hippocampus, mPFC, intralaminar thalamic nuclei, and amygdala. EE enhanced remote memory in ReRh rats. Conversely, ReRh rats housed in standard conditions were impaired. C-Fos immunohistochemistry showed a higher recruitment of the mPFC in enriched vs. standard rats with ReRh lesions during retrieval. ReRh rats raised in standard conditions showed weaker c-Fos expression than their sham-operated counterparts. The reinstatement of memory capacity implicated an EE-triggered modification of functional connectivity: EE reduced a marked lesion-induced increase in baseline c-Fos expression in the amygdala. Thus, enriched housing conditions counteracted the negative impact of ReRh lesions on spatial memory persistence. These effects could be the EE-triggered consequence of an enhanced neuronal activation in the mPFC, along with an attenuation of a lesion-induced hyperactivity in the amygdala.
28390295	Previous research has suggested that a deficit in working memory might underlie the difficulty of obsessive-compulsive disorder (OCD) patients to control their thoughts and actions. However, a recent meta-analyses found only small effect sizes for working memory deficits in OCD. Recently, a distinction has been made between declarative and procedural working memory. Working memory in OCD was tested mostly using declarative measurements. However, OCD symptoms typically concerns actions, making procedural working-memory more relevant. Here, we tested the operation of procedural working memory in OCD. Participants with OCD and healthy controls performed a battery of choice reaction tasks under high and low procedural working memory demands. Reaction-times (RT) were estimated using ex-Gaussian distribution fitting, revealing no group differences in the size of the RT distribution tail (i.e., τ parameter), known to be sensitive to procedural working memory manipulations. Group differences, unrelated to working memory manipulations, were found in the leading-edge of the RT distribution and analyzed using a two-stage evidence accumulation model. Modeling results suggested that perceptual difficulties might underlie the current group differences. In conclusion, our results suggest that procedural working-memory processing is most likely intact in OCD, and raise a novel, yet untested assumption regarding perceptual deficits in OCD.
28383953	Successful completion of any cognitive task requires selecting a particular action and the object the action is applied to. Oberauer (2009) suggested a working memory (WM) model comprising a declarative and a procedural part with analogous structures. One important assumption of this model is that both parts work independently of each other, and previous work has indeed reported evidence for the independent selection of memory lists and tasks, for example. The present study focused on the selection of single items in declarative and single responses in procedural WM. To this end, WM updating tasks were implemented as Task 2 in a Psychological Refractory Period setup in 3 experiments. The prediction based on the locus of slack logic is that item switch costs are present with a long but not with a short stimulus onset asynchrony. Contrary to this prediction, item switch costs were neither absent nor at least smaller at the short stimulus onset asynchrony. These results help to further constrain the WM model and thus to refine its computational implementation. (PsycINFO Database Record
28375761	Word-list learning tasks are among the most important and frequently used tests for declarative memory evaluation. For example, the California Verbal Learning Test-Children's Version (CVLT-C) and Rey Auditory Verbal Learning Test provide important information about different cognitive-neuropsychological processes. However, the impact of test length (i.e., number of words) and semantic organization (i.e., type of words) on children's and adolescents' memory performance remains to be clarified, especially during this developmental stage. To explore whether a medium-length non-semantically organized test can produce the typical curvilinear performance that semantically organized tests produce, reflecting executive control, we studied and compared the cognitive performance of normal children and adolescents by utilizing mathematical modeling. The model is based on the first-order system transfer function and has been successfully applied to learning curves for the CVLT-C (15 words, semantically organized paradigm). Results indicate that learning nine semantically unrelated words produces typical curvilinear (executive function) performance in children and younger adolescents and that performance could be effectively analyzed with the mathematical model. This indicates that the exponential increase (curvilinear performance) of correctly learned words does not solely depend on semantic and/or length features. This type of test controls semantic and length effects and may represent complementary tools for executive function evaluation in clinical populations in which semantic and/or length processing are affected.
28373127	Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5-HT)1A, and 5-HT2A receptors (Rs), full agonism at α4β2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT2B, 5-HT6, and 5-HT7Rs. Most atypical APDs are 5-HT2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)-as well as amphetamine-induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP-induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co-administration of a sub-effective dose (SED) of RP5063 with SEDs of a 5-HT7R antagonist, a 5-HT1BR antagonist, a 5-HT2AR inverse agonist, or an α4β2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre-treatment with a 5-HT1AR, a D4R, antagonist, but not an α4β2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co-administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP-treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia.
28359883	The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with individual differences in brain structure and function, and cognition. Research on BDNF's influence on brain and cognition has largely been limited to adults, and little is known about the association of this gene, and specifically the Val66Met polymorphism, with developing brain structure and emerging cognitive functions in children. We performed a targeted genetic association analysis on cortical thickness, surface area, and subcortical volume in 78 children (ages 6-10) who were Val homozygotes (homozygous Val/Val carriers) or Met carriers (Val/Met, Met/Met) for the Val66Met locus using Atlas-based brain segmentation. We observed greater cortical thickness for Val homozygotes in regions supporting declarative memory systems (anterior temporal pole/entorhinal cortex), consistent with adult findings. Met carriers had greater surface area in the prefrontal and parietal cortices and greater cortical thickness in lateral occipital/parietal cortex in contrast to prior adult findings that may relate to performance on cognitive tasks supported by these regions in Met carriers. Finally, we found larger right hippocampal volume in Met carriers, although inconsistent with adult findings (generally reports larger volumes for Val homozygotes), is consistent with a recent finding in children. Gene expression levels vary across different brain regions and across development and our findings highlight the need to consider this developmental change in explorations of BDNF-brain relationships. The impact of the BDNF Val66Met polymorphism on the structure of the developing brain therefore reflects regionally-specific developmental changes in BDNF expression and cortical maturation trajectories.
28358551	Cognitive impairment is prevalent and related to functional outcome in schizophrenia, but a significant minority of the patient population overlaps with healthy controls on many performance measures, including declarative-verbal-memory tasks. In this study, we assessed the validity, clinical, and functional implications of normal-range (NR), verbal-declarative memory in schizophrenia.Performance normality was defined using normative data for 8 basic California Verbal Learning Test (CVLT-II; Delis, Kramer, Kaplan, & Ober, 2000) recall and recognition trials. Schizophrenia patients (n = 155) and healthy control participants (n = 74) were assessed for performance normality, defined as scores within 1 SD of the normative mean on all 8 trials, and assigned to normal- and below-NR memory groups.	NR schizophrenia patients (n = 26) and control participants (n = 51) did not differ in general verbal ability, on a reading-based estimate of premorbid ability, across all 8 CVLT-II-score comparisons or in terms of intrusion and false-positive errors and auditory working memory. NR memory patients did not differ from memory-impaired patients (n = 129) in symptom severity, and both patient groups were significantly and similarly disabled in terms of functional status in the community.	These results confirm a subpopulation of schizophrenia patients with normal, verbal-declarative-memory performance and no evidence of decline from higher premorbid ability levels. However, NR patients did not experience less severe psychopathology, nor did they show advantage in community adjustment relative to impaired patients. (PsycINFO Database Record	
28350252	Anoxia can result in selective hippocampal damage with associated impairments in declarative memory. Whilst memory impairments and brain structures are thought to be stable, there are little data regarding the effects of ageing or change over time in patients with amnesia from anoxic brain injury.To assess change over time, we compared structural magnetic resonance imaging (MRI) with data obtained over ten years previously in two well-characterized patients with amnesia (JRW and RS) who experienced an anoxic brain injury. Six healthy, age-matched control participants were recruited to compare brain volumes with the patients at Time 2. Wechsler adult intelligence scale-revised and Wechsler memory scale-revised scores were compared to scores on the same tests administered 13 and 19 years prior.	Patients with amnesia had significantly smaller hippocampal volumes than controls, but comparable medial temporal lobe and ventricular volumes. Memory, intellectual function and brain volumes were stable over time.	Patients with an amnesia due to anoxia have memory impairments and smaller hippocampal volumes compared to controls; however, memory, intelligence and structural volumes remain stable over time. At ages 50 and 57, they do not appear to have early age-associated cognitive decline that is sometimes observed in patients with traumatic brain injury.	
28347877	Consolidated memory can be again destabilized by the presentation of a memory cue (reminder) of the previously acquired information. During this process of labilization/restabilization memory traces can be either impaired, strengthened or updated in content. Here, we study if a consolidated memory can be updated by linking one original cue to two different outcomes and whether this process was modulated by the GABAergic system. To aim that, we designed two experiments carried out in three consecutive days. All participants learned a list of non-sense syllable pairs on day 1. On day 2 the new information was introduced after the reminder or no-reminder presentation. Participants were tested on day 3 for the updated or original list (Exp. 1). In Exp. 2 we tested whether this new information was incorporated by an inhibitory process mediated by the GABAergic system. For that, participants retrieved the original information before being taken Clonazepam 0.25mg (GABAA agonist) or Placebo pill. We found that the groups that received the reminder correctly recalled the old and new information. However, the no reminder groups only correctly recalled the original information. Furthermore, when testing occurred in the presence of Clonazepam, the group that received the reminder plus the new information showed an impaired original memory performance compared to the group that received only Clonazepam (without reminder) or the reminder plus Placebo pill. These results show that new information can be added to a reactivated declarative memory in humans by linking one cue to two different outcomes. Furthermore, we shed light on the mechanisms of memory updating being the GABAergic system involved in the modulation of the old and new information expression.
28340966	Exposure to alcohol in utero can induce a variety of physical and mental impairments, collectively known as fetal alcohol spectrum disorders (FASD). This study explores the persistent cognitive consequences of ethanol administration in rat pups over postnatal days (PD) 4-9, modeling human third trimester consumption. Between PD65-70, ethanol-exposed (5E) and control rats were evaluated in two variants of recognition memory, the spontaneous novel object recognition (NOR) task, using 20 and 240 min sample-to-test delays, and the associative object-in-context (OIC) task, using a 20 min delay. No treatment group differences were observed in object exploration during the sample session for any task. In the 20 min NOR test session the 5E rats explored the novel object significantly less than controls, relative to the total time exploring both objects. Postnatal ethanol exposure is hypothesized to impede object memory consolidation in the perirhinal cortex of 5E rats, hindering their ability to discriminate between familiar and novel objects at short delays. The 5E rats performed as well or better than control rats in the 240 min NOR and the 20 min OIC tasks, indicating developmental ethanol exposure selectively impairs the retention and expression of recognition memories in young adult rats.
28337134	Acoustic stimulation methods applied during sleep in young adults can increase slow wave activity (SWA) and improve sleep-dependent memory retention. It is unknown whether this approach enhances SWA and memory in older adults, who generally have reduced SWA compared to younger adults. Additionally, older adults are at risk for age-related cognitive impairment and therefore may benefit from non-invasive interventions. The aim of this study was to determine if acoustic stimulation can increase SWA and improve declarative memory in healthy older adults. Thirteen participants 60-84 years old completed one night of acoustic stimulation and one night of sham stimulation in random order. During sleep, a real-time algorithm using an adaptive phase-locked loop modeled the phase of endogenous slow waves in midline frontopolar electroencephalographic recordings. Pulses of pink noise were delivered when the upstate of the slow wave was predicted. Each interval of five pulses ("ON interval") was followed by a pause of approximately equal length ("OFF interval"). SWA during the entire sleep period was similar between stimulation and sham conditions, whereas SWA and spindle activity were increased during ON intervals compared to matched periods during the sham night. The increases in SWA and spindle activity were sustained across almost the entire five-pulse ON interval compared to matched sham periods. Verbal paired-associate memory was tested before and after sleep. Overnight improvement in word recall was significantly greater with acoustic stimulation compared to sham and was correlated with changes in SWA between ON and OFF intervals. Using the phase-locked-loop method to precisely target acoustic stimulation to the upstate of sleep slow oscillations, we were able to enhance SWA and improve sleep-dependent memory storage in older adults, which strengthens the theoretical link between sleep and age-related memory integrity.
28330650	This study investigated the effect of green tea (GT) on short and long term declarative memory and oxidative damage induced by transient ischemia-reperfusion (IR) and intracerebral hemorrhage (ICH) in rats. Male Wistar rats were divided into 8 groups of 10 according the stroke type induced: Sham IR, Sham IR+GT, IR, IR+GT, Sham ICH, Sham ICH+GT, ICH, ICH+GT. Supplementation with GT was initiated 10days before stroke surgery and continuous for 6days after (GT dose 400mg/kg). Short (STM) and long term memory (LTM) we evaluated with object recognition task (OR) and hippocampus were used to evaluate parameters related to oxidative stress (ROS, lipid peroxidation and total antioxidant capacity). The rats subjected to IR and ICH showed STM and LTM deficits and GT intervention prevented it in both stroke models. IR and ICH induced increase on ROS levels in hippocampus. ICH increased the lipid peroxidation in hippocampus and the GT supplementation avoided it. IR induced decrease on total antioxidant capacity and GT prevented it. These results reveal that GT supplementation presents a neuroprotective role, attenuates redox imbalance and might have a beneficial impact on cognitive function after stroke.
28316271	Korsakoff's syndrome (KS) is a neuropsychiatric disorder characterised by severe amnesia. Although the presence of impairments in memory has long been acknowledged, there is a lack of knowledge about the precise characteristics of declarative memory capacities in order to implement memory rehabilitation. In this study, we investigated the extent to which patients diagnosed with KS have preserved declarative memory capacities in working memory, long-term memory encoding or long-term memory recall operations, and whether these capacities are most preserved for verbal or visuospatial content. The results of this study demonstrate that patients with KS have compromised declarative memory functioning on all memory indices. Performance was lowest for the encoding operation compared to the working memory and delayed recall operation. With respect to the content, visuospatial memory was relatively better preserved than verbal memory. All memory operations functioned suboptimally, although the most pronounced disturbance was found in verbal memory encoding. Based on the preserved declarative memory capacities in patients, visuospatial memory can form a more promising target for compensatory memory rehabilitation than verbal memory. It is therefore relevant to increase the number of spatial cues in memory rehabilitation for KS patients.
28285131	Acute stress impairs memory retrieval of several types of memories. An increase in glucocorticoids, several minutes after stressful events, is described as essential to the impairing retrieval-effects of stressors. Moreover, memory retrieval under stress can have long-term consequences. Through what process does the reactivated memory under stress, despite the disrupting retrieval effects, modify long-term memories? The reconsolidation hypothesis proposes that a previously consolidated memory reactivated by a reminder enters a vulnerability phase (labilization) during which it is transiently sensitive to modulation, followed by a re-stabilization phase. However, previous studies show that the expression of memories during reminder sessions is not a condition to trigger the reconsolidation process since unexpressed memories can be reactivated and labilized. Here we evaluate whether it is possible to reactivate-labilize a memory under the impairing-effects of a mild stressor. We used a paradigm of human declarative memory whose reminder structure allows us to differentiate between a reactivated-labile memory state and a reactivated but non-labile state. Subjects memorized a list of five cue-syllables associated with their respective response-syllables. Seventy-two hours later, results showed that the retrieval of the paired-associate memory was impaired when tested 20min after a mild stressor (cold pressor stress (CPS)) administration, coincident with cortisol levels increase. Then, we investigated the long-term effects of CPS administration prior to the reminder session. Under conditions where the reminder initiates the reconsolidation process, CPS impaired the long-term memory expression tested 24h later. In contrast, CPS did not show effects when administered before a reminder session that does not trigger reconsolidation. Results showed that memory reactivation-labilization occurs even when retrieval was impaired. Memory reactivation under stress could hinder -via reconsolidation- the probability of the traces to be expressed in the long term.
28281317	Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi-structured interview (E-AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2-3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.
28269774	The medial temporal lobe (MTL), and in particular the hippocampal formation, is essential in the processing and consolidation of declarative memory. The 3D environment of the anatomical structures contained in the MTL is an important issue.Our aim was to explore the spatial relationship of the anatomical structures of the MTL and changes in aging and/or Alzheimer's disease (AD).	MTL anatomical landmarks are identified and registered to create a 3D network. The brain network is quantitatively described as a plane, rostrocaudally-oriented, and presenting Euclidean/real distances. Correspondence between 1.5T RM, 3T RM, and histological sections were assessed to determine the most important recognizable changes in AD, based on statistical significance.	In both 1.5T and 3T RM images and histology, inter-rater reliability was high. Sex and hemisphere had no influence on network pattern. Minor changes were found in relation to aging. Distances from the temporal pole to the dentate gyrus showed the most significant differences when comparing control and AD groups. The best discriminative distance between control and AD cases was found in the temporal pole/dentate gyrus rostrocaudal length in histological sections. Moreover, more distances between landmarks were required to obtain 100% discrimination between control (divided into <65 years or >65 years) and AD cases.	Changes in the distance between MTL anatomical landmarks can successfully be detected by using measurements of 3D network patterns in control and AD cases.	
28268901	The hippocampus is crucial to the formation of long-term memory and declarative memory. It is divided into three sub-fields the CA1, the CA3 and the DG. To understand the neuronal circuitry within the hippocampus and to study the role of the hippocampus in memory function requires the collection of neural activities from multiple subregions of the hippocampus simultaneously. Micro-wire electrode arrays are commonly used as an interface with neural systems. However, recording from multiple deep brain regions with curved anatomical structures such as the thin cell body layers of the hippocampus requires the micro-wires to be arranged into a highly accurate, complex layout that is difficult to fabricated manually. In this work, we designed and developed a flexible parylene-C based neural probe which can be easily micro-machined to the desired dimensions. Sixty-four electrical recording sites are micromachined on to 8 parylene shanks and spaced according to the distribution of hippocampal principal neurons in different hippocampus subregions. Together with our collaborators, we developed and optimized the implantation procedure of the flexible parylene probe and tested the insertion method both in brain tissue phantom and in vivo with a sham device. Immunohistochemistry (IHC) staining post-implantation of the sham probe was used to verify the location of the probe and to evaluate immune responses to the probe. Fully functional devices were fabricated and, in future studies, functional probes will be chronically implanted into the rat hippocampus, and neural activities will be recorded and compared with signals obtained with micro-wire arrays.
28251722	Effectiveness of memory consolidation is determined by multiple factors, including sleep after learning, emotional valence, arousal and novelty. Few studies investigated how the effect of sleep compares with (and interacts with) these other factors, of which virtually none are in children. The present study did so by repeated assessment of declarative memory in 386 children (45% boys) aged 9-11 years through an online word-pair task. Children were randomly assigned to either a morning or evening learning session of 30 unrelated word-pairs with positive, neutral or negative valenced cues and neutral targets. After immediately assessing baseline recognition, delayed recognition was recorded either 12 or 24 h later, resulting in four different assessment schedules. One week later, the procedure was repeated with exactly the same word-pairs to evaluate whether effects differed for relearning versus original novel learning. Mixed-effect logistic regression models were used to evaluate how the probability of correct recognition was affected by sleep, valence, arousal, novelty and their interactions. Both immediate and delayed recognition were worse for pairs with negatively valenced or less arousing cue words. Relearning improved immediate and delayed word-pair recognition. In contrast to these effects, sleep did not affect recognition, nor did sleep moderate the effects of arousal, valence and novelty. The findings suggest a robust inclination of children to specifically forget the pairing of words to negatively valenced cue words. In agreement with a recent meta-analysis, children seem to depend less on sleep for the consolidation of information than has been reported for adults, irrespective of the emotional valence, arousal and novelty of word-pairs.
28246641	Rodents sleep in bouts lasting minutes; humans sleep for hours. What are the universal needs served by sleep given such variability? In sleeping mice and humans, through monitoring neural and cardiac activity (combined with assessment of arousability and overnight memory consolidation, respectively), we find a previously unrecognized hallmark of sleep that balances two fundamental yet opposing needs: to maintain sensory reactivity to the environment while promoting recovery and memory consolidation. Coordinated 0.02-Hz oscillations of the sleep spindle band, hippocampal ripple activity, and heart rate sequentially divide non-rapid eye movement (non-REM) sleep into offline phases and phases of high susceptibility to external stimulation. A noise stimulus chosen such that sleeping mice woke up or slept through at comparable rates revealed that offline periods correspond to raising, whereas fragility periods correspond to declining portions of the 0.02-Hz oscillation in spindle activity. Oscillations were present throughout non-REM sleep in mice, yet confined to light non-REM sleep (stage 2) in humans. In both species, the 0.02-Hz oscillation predominated over posterior cortex. The strength of the 0.02-Hz oscillation predicted superior memory recall after sleep in a declarative memory task in humans. These oscillations point to a conserved function of mammalian non-REM sleep that cycles between environmental alertness and internal memory processing in 20- to 25-s intervals. Perturbed 0.02-Hz oscillations may cause memory impairment and ill-timed arousals in sleep disorders.
28245989	Detection of awareness in patients with consciousness disorders is a challenge that can be facilitated by functional neuroimaging. We elaborated a functional magnetic resonance imaging (fMRI) protocol to detect covert activity in altered states of consciousness. We hypothesized that passive listening to narratives with graduated emotional charge triggers graduated cerebral activations. The fMRI protocol was designed in healthy subjects for further clinical applications. The emotional charge was graduated using voice familiarity and long-term declarative memory content: low emotional charge, unknown person telling general semantic memory; mean emotional charge, relative telling the same narratives; high emotional charge, same relative telling autobiographical memory. Autobiographical memory was subdivided into semantic autobiographical memory and episodic autobiographical memory. The protocol proved efficient at triggering graduated cerebral activations: low emotional charge, superior temporal gyri and sulci; mean emotional charge, same as low emotional charge plus bilateral premotor cortices and left inferior frontal gyrus; high emotional charge, cingulate, temporal, frontal, prefrontal and angular areas, thalamus and cerebellum. Semantic autobiographical memory revealed larger activations than episodic autobiographical memory. Independent ROI analysis confirmed the preponderant contribution of narratives with autobiographical memory content in triggering cerebral activation, not only in autobiographical memory-sensitive areas, but also in voice-sensitive, language-sensitive and semantic memory-sensitive areas.
28243162	Numerous studies have implicated the hippocampus in the encoding and storage of declarative and spatial memories. Several models have considered the hippocampus and its distinct subfields to contain homogeneous pyramidal cell populations. Yet, recent studies have led to a consensus that the dorso-ventral and proximo-distal axes have different connectivities and physiologies. The remaining deep-superficial axis of the pyramidal layer, however, remains relatively unexplored due to a lack of techniques that can record from neurons simultaneously at different depths. Recent advances in transgenic mice, two-photon imaging and dense multisite recording have revealed extensive disparities between the pyramidal cells located in the deep and the superficial layers. Here, we summarize differences between the two populations in terms of gene expression and connectivity with other intra-hippocampal subregions and local interneurons that underlie distinct learning processes and spatial representations. A unified picture will emerge to describe how such local segregations can increase the capacity of the hippocampus to compute and process numerous tasks in parallel.
28239364	Though there is an extensive literature investigating the ability of younger adults to learn non-native phonology, including investigations into individual differences in younger adults' lexical tone learning, very little is known about older adults' ability to learn non-native phonology, including lexical tone. There are several reasons to suspect that older adults would use different learning mechanisms when learning lexical tone than younger adults, including poorer perception of dynamic pitch, greater reliance on working memory capacity in second language learning, and poorer category learning in older adulthood. The present study examined the relationships among older adults' baseline sensitivity for pitch patterns, working memory capacity, and declarative memory capacity with their ability to learn to associate tone with lexical meaning. In older adults, baseline pitch pattern sensitivity was not associated with generalization performance. Rather, older adults' learning performance was best predicted by declarative memory capacity. These data suggest that training paradigms will need to be modified to optimize older adults' non-native speech sound learning success.
28235729	Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. Periods of sub- and supra- physiological cortisol levels experienced by patients with AD likely induce disrupted sleep. Given that healthy sleep plays an important role in memory consolidation, the novelty of the current study was to characterise, using objective measures, the relationship between sleep and memory in patients with AD, and to examine the hypothesis that poor sleep is a biological mechanism underlying memory impairment in those patients.We used a within-subjects design. Ten patients with AD and 10 matched healthy controls completed standardised neuropsychological tests assessing declarative memory (Rey Auditory Verbal Learning Test) and procedural memory (Finger Tapping Task) before and after a period of actigraphy-measured sleep, and before and after a period of waking.	Relative to healthy controls, patients with AD experienced disrupted sleep characterised by poorer sleep efficiency and more time spent awake. Patients also showed impaired verbal learning and memory relative to healthy controls (p=0.007). Furthermore, whereas healthy controls' declarative memory performance benefited from a period of sleep compared to waking (p=0.032), patients with AD derived no such benefit from sleep (p=0.448). Regarding the procedural memory task, analyses detected no significant between-group differences (all p's<0.065), and neither group showed significant sleep-enhanced performance.	We demonstrated, using actigraphy and standardized measures of memory performance, an association between sleep disturbances and cognitive deficits in patients with AD. These results suggest that, in patients with AD, the source of memory deficits is, at least to some extent, disrupted sleep patterns that interfere with optimal consolidation of previously-learned declarative information. Hence, treating the sleep disturbances that are frequently experienced by patients with AD may improve their cognitive functioning.	
28228742	Children suffering from attention-deficit hyperactivity disorder (ADHD) often also display impaired learning and memory. Previous research has documented aberrant reward processing in ADHD as well as impaired sleep-dependent consolidation of declarative memory. We investigated whether sleep also fosters the consolidation of behavior learned by probabilistic reward and whether ADHD patients with a comorbid disorder of social behavior show deficits in this memory domain, too. A group of 17 ADHD patients with comorbid disorders of social behavior aged 8-12 years and healthy controls matched for age, IQ, and handedness took part in the experiment. During the encoding task, children worked on a probabilistic learning task acquiring behavioral preferences for stimuli rewarded most often. After a 12-hr retention interval of either sleep at night or wakefulness during the day, a reversal task was presented where the contingencies were reversed. Consolidation of rewarded behavior is indicated by greater resistance to reversal learning. We found that healthy children consolidate rewarded behavior better during a night of sleep than during a day awake and that the sleep-dependent consolidation of rewarded behavior by trend correlates with non-REM sleep but not with REM sleep. In contrast, children with ADHD and comorbid disorders of social behavior do not show sleep-dependent consolidation of rewarded behavior. Moreover, their consolidation of rewarded behavior does not correlate with sleep. The results indicate that dysfunctional sleep in children suffering from ADHD and disorders of social behavior might be a crucial factor in the consolidation of behavior learned by reward.
28213812	We are called upon to make decisions, large and small, many times a day. Whether in the voting booth, the stock exchange, or the cafeteria line, we identify potential options, estimate and compare their subjective values, and make a choice. Decision-making has only recently become a focus for cognitive neuroscience. The last two decades have seen rapid progress in our understanding of the brain basis of at least some aspects of this rather complex aspect of cognition. This work has provided fresh perspectives on poorly understood brain regions, such as orbitofrontal cortex and ventral striatum. It has led to interesting interdisciplinary exchanges with diverse fields, notably economics, but also ecology and political science, among others. The novel perspectives arising from these exchanges have begun to be related to better understood aspects of cognition. In particular, it is increasingly clear that decision-making is tightly interlinked with learning and memory. Key early insights in decision neuroscience came from what were essentially reinforcement learning tasks. Recent work has made similar links to aspects of declarative memory. Indeed, decision-making can be seen as the link between memory of the past and future actions. This chapter reviews selected topics in decision neuroscience, with a particular focus on the links to learning and memory, and a particular emphasis on regions within prefrontal cortex.
28213114	Substantial evidence suggests that human category learning is governed by the interaction of multiple qualitatively distinct neural systems. In this view, procedural memory is used to learn stimulus-response associations, and declarative memory is used to apply explicit rules and test hypotheses about category membership. However, much less is known about the interaction between these systems: how is control passed between systems as they interact to influence motor resources? Here, we used fMRI to elucidate the neural correlates of switching between procedural and declarative categorization systems. We identified a key region of the cerebellum (left Crus I) whose activity was bidirectionally modulated depending on switch direction. We also identified regions of the default mode network (DMN) that were selectively connected to left Crus I during switching. We propose that the cerebellum-in coordination with the DMN-serves a critical role in passing control between procedural and declarative memory systems.
28195521	Damage to the medial temporal lobe (MTL) has long been known to impair declarative memory, and recent evidence suggests that it also impairs visual perception. A theory termed the representational-hierarchical account explains such impairments by assuming that MTL stores conjunctive representations of items and events, and that individuals with MTL damage must rely upon representations of simple visual features in posterior visual cortex, which are inadequate to support memory and perception under certain circumstances. One recent study of visual discrimination behavior revealed a surprising antiperceptual learning effect in MTL-damaged individuals: With exposure to a set of visual stimuli, discrimination performance worsened rather than improved [Barense, M. D., Groen, I. I. A., Lee, A. C. H., Yeung, L. K., Brady, S. M., Gregori, M., et al. Intact memory for irrelevant information impairs perception in amnesia. Neuron, 75, 157-167, 2012]. We extend the representational-hierarchical account to explain this paradox by assuming that difficult visual discriminations are performed by comparing the relative "representational tunedness"-or familiarity-of the to-be-discriminated items. Exposure to a set of highly similar stimuli entails repeated presentation of simple visual features, eventually rendering all feature representations maximally and, thus, equally familiar; hence, they are inutile for solving the task. Discrimination performance in patients with MTL lesions is therefore impaired by stimulus exposure. Because the unique conjunctions represented in MTL do not occur repeatedly, healthy individuals are shielded from this perceptual interference. We simulate this mechanism with a neural network previously used to explain recognition memory, thereby providing a model that accounts for both mnemonic and perceptual deficits caused by MTL damage with a unified architecture and mechanism.
28193522	The intracerebroventricular injection of beta-amyloid (Aβ) in mice allows the investigation of acute effects on cognitive function and cellular pathology. The aim of this investigation was to further characterize the time course of Aβ-induced cognitive and behavioural changes and to detect potential molecular mechanisms.Cannulas were implanted in the lateral cerebral ventricle. 14days after surgery the mice were injected with Aβ1-42 or phosphate buffered saline (PBS). Starting 2, 4 or 8 (PBS only 4) days after injection we evaluated cognitive and behavioural performance using the modified hole board test (mHBT). We determined tumour-necrosis factor alpha (TNF alpha) and caspase 3 by western blotting, on days 10, 12 and 16. Data were analysed using general linear modelling, Kruskall-Wallis and Mann-Whitney-U test.	Aβ induced a decline in cognitive performance represented as an increased total number of wrong choices during the testing period from day 2-15 (p<0.05). Behavioural parameters were comparable between mice treated with Aβ and PBS. There was no difference regarding TNF alpha levels between the groups. Compared to day 16 Caspase 3 levels were increased on day 10 (p=0.004).	Application of Aβ in the lateral ventricle of mice is associated with cognitive impairment of declarative memory in the mHBT. There is no interference caused by altered behaviour. Therefore, it represents a valid model for acute Aβ-mediated neurotoxic effects. Although the exact mechanisms remain unclear, changes in levels of Caspase 3 suggest apoptosis as an important factor for the development of cognitive dysfunction.	

28188665	A central idea about the organization of declarative memory and the function of the hippocampus is that the hippocampus provides for the coding of relationships between items. A question arises whether this idea refers to the process of forming long-term memory or whether, as some studies have suggested, memory for relations might depend on the hippocampus even at short retention intervals and even when the task falls within the province of short-term (working) memory. The latter formulation appears to place the operation of relational memory into conflict with the idea that working memory is independent of medial temporal lobe (MTL) structures. In this report, the concepts of relational memory and working memory are discussed in the light of a simple demonstration experiment. Patients with MTL lesions successfully learned and recalled two word pairs when tested directly after learning but failed altogether when tested after a delay. The results do not contradict the idea that the hippocampus has a fundamental role in relational memory. However, there is a need for further elaboration and specification of the idea in order to explain why patients with MTL lesions can establish relational memory in the short term but not in long-term memory. © 2017 Wiley Periodicals, Inc.
28161367	A period of post-learning sleep benefits memory consolidation compared with an equal-length wake interval. However, whether this sleep-based memory consolidation changes as a function of age remains controversial. Here we report a meta-analysis that investigates the age differences in the sleep-based memory consolidation in two types of memory: declarative memory and procedural memory. The meta-analysis included 22 comparisons of the performance between young adults (N =640) and older adults (N =529) on behavioral tasks measuring sleep-based memory consolidation. Our results showed a significant overall sleep-based beneficial effect in young adults but not in older adults. However, further analyses suggested that the age differences were mainly manifested in sleep-based declarative memory consolidation but not in procedural memory consolidation. We discussed the possible underlying mechanisms for the age-related degradation in sleep-based memory consolidation. Further research is needed to determine the crucial components for sleep-related memory consolidation in older adults such as age-related changes in neurobiological and cardiovascular functions, which may play an important role in this context and have the potential to delineate the interrelationships between age-related changes in sleep and memory.
28123666	Sleep is well known to have a significant impact on learning and memory. Specifically, studies adopting an experimentally induced sleep loss protocol in healthy individuals have provided evidence that the consolidation of spatial memories, as acquired through navigating and orienteering in spatial surroundings, is negatively affected by total sleep loss. Here, we used both objective and subjective measures to characterize individuals' quality of sleep, and grouped participants into either a poor (insomnia-like) or normal (control) sleep quality group. We asked participants to solve a wayfinding task in a virtual environment, and scored their performance by measuring the time spent to reach a target location and the number of wayfinding errors made while navigating. We found that participants with poor sleep quality were slower and more error-prone than controls in solving the task. These findings provide novel evidence that pre-existing sleep deficiencies in otherwise healthy individuals affects negatively the ability to learn novel routes, and suggest that sleep quality should be accounted for among healthy individuals performing experimental spatial orientation tasks in virtual environments.
28111250	Previous research has shown that individuals with Parkinson's disease (PD) show preserved learning of tool-related motor skills, while retention was impaired after a three-week delay, possibly as a result of striatal dysfunction. The goal of the current study was to identify if shorter delays and more extensive practice might reduce retention deficits related to complex tool use in PD. PD participants and healthy age and education-matched controls were trained to use novel tools across four sessions, spaced one-day, one-week, and three-weeks apart. Recall of tool attributes (e.g., function) and skilled motor performance using tools was investigated by examining patterns of learning and forgetting over time. Results showed that tool attribute recall was unimpaired in PD participants relative to controls. For motor skill performance, PD participants were unimpaired in motor skill learning within sessions, but they did not retain these skills across one-week and three-week delays between sessions. This dissociation suggests that the striatum plays a critical role in retention of motor skills needed in skilled tool use performance. Finally, in spite of forgetting, individuals with PD still demonstrated improvement across sessions with additional training, suggesting that people with PD may benefit from extensive practice when learning motor skills.
28104188	Brain and cognitive development during the first 1000 days from conception are affected by multiple biomedical and socioenvironmental determinants including nutrition, health, nurturing, and stimulation. An improved understanding of the long-term influence of these factors is needed to prioritise public health investments to optimise human development.We did a follow-up study of the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind, cluster-randomised trial of maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA) in Indonesia. Of 27 356 live infants from birth to 3 months of age in 2001-04, we re-enrolled 19 274 (70%) children at age 9-12 years, and randomly selected 2879 from the 18 230 who were attending school at a known location. Of these, 574 children were oversampled from mothers who were anaemic or malnourished at SUMMIT enrolment. We assessed the effects of MMN and associations of biomedical (ie, maternal and child anthropometry and haemoglobin and preterm birth) and socioenvironmental determinants (ie, parental education, socioeconomic status, home environment, and maternal depression) on general intellectual ability, declarative memory, procedural memory, executive function, academic achievement, fine motor dexterity, and socioemotional health. The SUMMIT trial was registered, number ISRCTN34151616.	Children of mothers given MMN had a mean score of 0·11 SD (95% CI 0·01-0·20, p=0·0319) higher in procedural memory than those given IFA, equivalent to the increase in scores with half a year of schooling. Children of anaemic mothers in the MMN group scored 0·18 SD (0·06-0·31, p=0·0047) higher in general intellectual ability, similar to the increase with 1 year of schooling. Overall, 18 of 21 tests showed a positive coefficient of MMN versus IFA (p=0·0431) with effect sizes from 0·00-0·18 SD. In multiple regression models, socioenvironmental determinants had coefficients of 0·00-0·43 SD and 22 of 35 tests were significant at the 95% CI level, whereas biomedical coefficients were 0·00-0·10 SD and eight of 56 tests were significant, indicating larger and more consistent impact of socioenvironmental factors (p<0·0001).	Maternal MMN had long-term benefits for child cognitive development at 9-12 years of age, thereby supporting its role in early childhood development, and policy change toward MMN. The stronger association of socioenvironmental determinants with improved cognition suggests present reproductive, maternal, neonatal, and child health programmes focused on biomedical determinants might not sufficiently enhance child cognition, and that programmes addressing socioenvironmental determinants are essential to achieve thriving populations.	Grand Challenges Canada Saving Brains Program.	
28103481	Accumulating evidence indicates that cerebellar long-term potentiation (LTP) is necessary for procedural learning. However, little is known about its underlying molecular mechanisms. Whereas AMPA receptor (AMPAR) subunit rules for synaptic plasticity have been extensively studied in relation to declarative learning, it is unclear whether these rules apply to cerebellum-dependent motor learning. Here we show that LTP at the parallel-fiber-to-Purkinje-cell synapse and adaptation of the vestibulo-ocular reflex depend not on GluA1- but on GluA3-containing AMPARs. In contrast to the classic form of LTP implicated in declarative memory formation, this form of LTP does not require GluA1-AMPAR trafficking but rather requires changes in open-channel probability of GluA3-AMPARs mediated by cAMP signaling and activation of the protein directly activated by cAMP (Epac). We conclude that vestibulo-cerebellar motor learning is the first form of memory acquisition shown to depend on GluA3-dependent synaptic potentiation by increasing single-channel conductance.
28100737	Reward motivation has been demonstrated to enhance declarative memory by facilitating systems-level consolidation. Although high-reward information is often intermixed with lower reward information during an experience, memory for high value information is prioritized. How is this selectivity achieved? One possibility is that postencoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influence of differential reward motivation on the selectivity of postencoding markers of systems-level memory consolidation. Human participants encoded intermixed, trial-unique memoranda that were associated with either high or low-value during fMRI acquisition. Encoding was interleaved with periods of rest, allowing us to investigate experience-dependent changes in connectivity as they related to later memory. Behaviorally, we found that reward motivation enhanced 24 h associative memory. Analysis of patterns of postencoding connectivity showed that, even though learning trials were intermixed, there was significantly greater connectivity with regions of high-level, category-selective visual cortex associated with high-reward trials. Specifically, increased connectivity of category-selective visual cortex with both the VTA and the anterior hippocampus predicted associative memory for high- but not low-reward memories. Critically, these results were independent of encoding-related connectivity and univariate activity measures. Thus, these findings support a model by which the selective stabilization of memories for salient events is supported by postencoding interactions with sensory cortex associated with reward.Reward motivation is thought to promote memory by supporting memory consolidation. Yet, little is known as to how brain selects relevant information for subsequent consolidation based on reward. We show that experience-dependent changes in connectivity of both the anterior hippocampus and the VTA with high-level visual cortex selectively predicts memory for high-reward memoranda at a 24 h delay. These findings provide evidence for a novel mechanism guiding the consolidation of memories for valuable events, namely, postencoding interactions between neural systems supporting mesolimbic dopamine activation, episodic memory, and perception.	
28066212	Following the presentation of a reminder, consolidated memories become reactivated followed by a process of re-stabilization, which is referred to as reconsolidation. The most common behavioral tool used to reveal this process is interference produced by new learning shortly after memory reactivation. Memory interference is defined as a decrease in memory retrieval, the effect is generated when new information impairs an acquired memory. In general, the target memory and the interference task used are the same. Here we investigated how different memory systems and/or their valence could produce memory reconsolidation interference. We showed that a reactivated neutral declarative memory could be interfered by new learning of a different neutral declarative memory. Then, we revealed that an aversive implicit memory could be interfered by the presentation of a reminder followed by a threatening social event. Finally, we showed that the reconsolidation of a neutral declarative memory is unaffected by the acquisition of an aversive implicit memory and conversely, this memory remains intact when the neutral declarative memory is used as interference. These results suggest that the interference of memory reconsolidation is effective when two task rely on the same memory system or both evoke negative valence.
28046095	We examined learning and retention in nonverbal and verbal declarative memory in Hungarian children with (n = 21) and without (n = 21) SLI. Recognition memory was tested both 10 minutes and one day after encoding. On nonverbal items, only the children with SLI improved overnight, with no resulting group differences in performance. In the verbal domain, the children with SLI consistently showed worse performance than the typically-developing children, but the two groups showed similar overnight changes. The findings suggest the possibility of spared or even enhanced declarative memory consolidation in SLI.
28039931	This paper presents a computational model that integrates a dynamically structured holographic memory system into the ACT-R cognitive architecture to explain how linguistic representations are encoded and accessed in memory. ACT-R currently serves as the most precise expression of the moment-by-moment working memory retrievals that support sentence comprehension. The ACT-R model of sentence comprehension is able to capture a range of linguistic phenomena, but there are cases where the model makes the wrong predictions, such as the over-prediction of retrieval interference effects during sentence comprehension. Here, we investigate one such case involving the processing of sentences with negative polarity items (NPIs) and consider how a dynamically structured holographic memory system might provide a cognitively plausible and principled explanation of some previously unexplained effects. Specifically, we show that by replacing ACT-R's declarative memory with a dynamically structured memory, we can explain a wider range of behavioral data involving reading times and judgments of grammaticality. We show that our integrated model provides a better fit to human error rates and response latencies than the original ACT-R model. These results provide proof-of-concept for the unification of two independent computational cognitive frameworks.
27991184	The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Class 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (±1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material.
27929345	Memory retrieval requires an effective recruitment of inhibitory control to successfully reject unnecessary memories. The use of cocaine is associated with poor cognitive control processes, but little is known about the impact of chronic and recreational use of cocaine on inhibitory control during intentional forgetting. We studied whether chronic and recreational users of cocaine show impairments on the mechanism responsible for intentional forgetting of memories. Two experiments were carried out on chronic cocaine users in rehabilitation (Experiment 1) and recreational cocaine polydrug users (Experiment 2) performing a directed forgetting (DF) task, an index of memory suppression. Participants were matched for sex, age, and intelligence (Raven's standard progressive matrices) with cocaine-free controls and compared on their performance on a DF procedure. Chronic cocaine users in rehabilitation and recreational cocaine polydrug users, as compared with controls, were not able to intentionally suppress the required information and they did not show a reliable DF effect. The consumption of cocaine appears to alter the control processes implicated in intentional suppression of nonrelevant memories in episodic memory. The use of cocaine, even for recreational purposes, seems to be associated with poor performance in effectively triggering this control mechanism. The inability to suppress interference in declarative memory may have repercussion for daily activities. (PsycINFO Database Record
27920146	Reward motivation has been demonstrated to enhance declarative memory by facilitating systems level consolidation. While high reward information is often intermixed with lower reward information during an experience, memory for those experiences prioritizes high value information. How is this selectivity achieved? One possibility is that post-encoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influence of differential reward motivation on the selectivity of post-encoding markers of systems-level memory consolidation. Human participants encoded intermixed, trial-unique memoranda that were associated with either high or low value during fMRI acquisition. Encoding was interleaved with periods of rest, allowing us to investigate experience-dependent changes in connectivity as they related to later memory. Behaviorally, we found that reward motivation enhanced 24-hour associative memory. Analysis of patterns of post-encoding connectivity showed that even though learning trials were intermixed, there was significantly greater connectivity with regions of high-level, category-selective visual cortex associated with high reward trials. Specifically, increased connectivity of category-selective visual cortex with both the ventral tegmental area and the anterior hippocampus predicted associative memory for high- but not low-reward memories. Critically, these results were independent of encoding-related connectivity and univariate activity measures. Thus, these findings support a model by which the selective stabilization of memories for salient events is supported by post-encoding interactions with sensory cortex associated with reward.Reward motivation is thought to promote memory by supporting memory consolidation. Yet, little is known as to how brain selects relevant information for subsequent consolidation based on reward. We show that experience-dependent changes in connectivity of both the anterior hippocampus and the ventral tegmental area with high-level visual cortex selectively predicts memory for high-reward memoranda at a 24-hour delay. These findings provide evidence for a novel mechanism guiding the consolidation of memories for valuable events, namely post-encoding interactions between neural systems supporting mesolimbic dopamine activation, episodic memory, and perception.	
27918181	The growth of social media and user-created content on online sites provides unique opportunities to study models of human declarative memory. By framing the task of choosing a hashtag for a tweet and tagging a post on Stack Overflow as a declarative memory retrieval problem, 2 cognitively plausible declarative memory models were applied to millions of posts and tweets and evaluated on how accurately they predict a user's chosen tags. An ACT-R based Bayesian model and a random permutation vector-based model were tested on the large data sets. The results show that past user behavior of tag use is a strong predictor of future behavior. Furthermore, past behavior was successfully incorporated into the random permutation model that previously used only context. Also, ACT-R's attentional weight term was linked to an entropy-weighting natural language processing method used to attenuate high-frequency words (e.g., articles and prepositions). Word order was not found to be a strong predictor of tag use, and the random permutation model performed comparably to the Bayesian model without including word order. This shows that the strength of the random permutation model is not in the ability to represent word order, but rather in the way in which context information is successfully compressed. The results of the large-scale exploration show how the architecture of the 2 memory models can be modified to significantly improve accuracy, and may suggest task-independent general modifications that can help improve model fit to human data in a much wider range of domains. (PsycINFO Database Record
27913294	There is robust evidence that sleep facilitates declarative memory consolidation. Integration of newly acquired memories into existing neocortical knowledge networks has been proposed to underlie this effect. Here, we test whether sleep affects memory retention for word-picture associations differently when it was learned explicitly or using a fast mapping strategy. Fast mapping is an incidental form of learning that references new information to existing knowledge and possibly allows neocortical integration already during encoding. If the integration of information into neocortical networks is a main function of sleep-dependent memory consolidation, material learned via fast mapping should therefore benefit less from sleep. Supporting this idea, we find that sleep has a protective effect on explicitly learned associations. In contrast, memory for associations learned by fast mapping does not benefit from sleep and remains stable regardless of whether sleep or wakefulness follows learning. Our results thus indicate that the need for sleep-mediated consolidation depends on the strategy used for learning and might thus be related to the level of integration of newly acquired memory achieved during encoding.
27900481	Considerable evidence suggests that human category learning recruits multiple memory systems. A popular assumption is that procedural memory is used to form stimulus-to-response mappings, whereas declarative memory is used to form and test explicit rules about category membership. The multiple systems framework has been successful in motivating and accounting for a broad array of empirical observations over the past 20 years. Even so, only a couple of studies have examined how the different categorization systems interact. Both previous studies suggest that switching between explicit and procedural responding is extremely difficult. But they leave unanswered the critical questions of whether trial-by-trial system switching is possible, and if so, whether it is qualitatively different than trial-by-trial switching between two explicit tasks. The experiment described in this article addressed these questions. The results (1) confirm that effective trial-by-trial system switching, although difficult, is possible; (2) suggest that switching between tasks mediated by different memory systems is more difficult than switching between two declarative memory tasks; and (3) point to a serious shortcoming of current category-learning theories.
27890324	Learning and the formation of memory are reflected in various memory systems in the human brain such as the hippocampus based declarative memory system and the striatum-cortex based system involved in motor sequence learning. It is a matter of debate how both memory systems interact in humans during learning and consolidation and how this interaction is influenced by sleep. We studied the effect of an acute dysfunction of hippocampal CA1 neurons on the acquisition (on-line condition) and off-line changes of a motor skill in patients with a transient global amnesia (TGA). Sixteen patients (68 ± 4.4 yrs) were studied in the acute phase and during follow-up using a declarative and procedural test, and were compared to controls. Acute TGA patients displayed profound deficits in all declarative memory functions. During the acute amnestic phase, patients were able to acquire the motor skill task reflected by increasing finger tapping speed across the on-line condition, albeit to a lesser degree than during follow-up or compared to controls. Retrieval two days later indicated a greater off-line gain in motor speed in patients than controls. Moreover, this gain in motor skill performance was negatively correlated to the declarative learning deficit. Our results suggest a differential interaction between procedural and declarative memory systems during acquisition and consolidation of motor sequences in older humans. During acquisition, hippocampal dysfunction attenuates fast learning and thus unmasks the slow and rigid learning curve of striatum-based procedural learning. The stronger gains in the post-consolidation condition in motor skill in CA1 lesioned patients indicate a facilitated consolidation process probably occurring during sleep, and suggest a competitive interaction between the memory systems. These findings might be a reflection of network reorganization and plasticity in older humans and in the presence of CA1 hippocampal pathology.
27882455	This study examined the differential effects of aging on consolidation processes that strengthen newly acquired memory traces in veridical form (memory stabilization) versus consolidation processes that are responsible for integrating these memory traces into an existing body of knowledge (item integration). Older adults learned 13 nonwords and were tested on their memory for the nonwords, and on whether these nonwords impacted upon processing of similar-sounding English words immediately and 24 hours later. Participants accurately recognized the nonwords immediately, but showed significant decreases in delayed recognition and recall. In comparison, the nonwords impacted upon processing of similar-sounding words only in the delayed test. Together, these findings suggest that memory consolidation processes may be more evident in item integration than memory stabilization processes for new declarative memories in older adults.
27860305	Patients with amnestic mild cognitive impairment (a-MCI) are deficient in storing memory traces relative to recollective forms of declarative memory. Controversial data have, instead, been reported concerning the storage of new memory traces relative to familiarity, with some studies reporting impairment and others sparing of the storage of this form of memory. No data have been reported concerning the consolidation of recollection and familiarity memory traces subsequent to their storage.To investigate consolidation deficits resulting in accelerated forgetting of the memory trace, we submitted 16 patients with a-MCI and 19 age-matched normal controls (NC) to a verbal version of the experimental paradigm devised by Huppert and Piercy (1977, Neuropsychologia, 15, 643; 1978, Nature, 275, 317), which we modified to obtain a subjective judgement of the memory process (i.e., recollection or familiarity) for each remembered word that had prompted the 'old' response. The y/n recognition tests with a remember/know paradigm were given 10 min, 1 hr, and 24 hr after the study phase.	Data demonstrated that patients with a-MCI forgot the memory traces relative to both the recollection and the familiarity components of recognition at the same rate as NC.	Evidence was particularly strong for the familiarity component (where a-MCI patients scored the same as NC at all three delay intervals), but was less robust for the recollection data (where an equivalent forgetting rate across the three delay intervals could be demonstrated only for subgroups of a-MCI patients and NC who obtained comparable scores on the 10-min test).	
27845773	Neurons in the medial temporal lobe (MTL), a critical area for declarative memory, have been shown to change their tuning in associative learning tasks. Yet, it is unclear how durable these neuronal representations are and if they outlast the execution of the task. To address this issue, we studied the responses of MTL neurons in neurosurgical patients to known concepts (people and places). Using association scores provided by the patients and a web-based metric, here we show that whenever MTL neurons respond to more than one concept, these concepts are typically related. Furthermore, the degree of association between concepts could be successfully predicted based on the neurons' response patterns. These results provide evidence for a long-term involvement of MTL neurons in the representation of durable associations, a hallmark of human declarative memory.
27845293	Present study investigated possible differences in the learning and memory of declarative memory task in rats selected according to the differences in immobilization response that is in high immobilization "depressive" and low immobilization "non-depressive" rats. Understanding the character of learning and memory disturbances in basal conditions of animal models of depression is still very topical for more intimate definition of the pathophysiology of major depressive disorder and appropriate searching the ways of its correction. Experiments were carried out on the adult white wild rats (with the weight 200-250 g, n=20). Selection of rats according to the level of immobilization was made by means of forced swim test. Learning and memory disturbances were studied using passive avoidance test that is fear motivated one trial declarative memory task. It was shown by us that 100% of low immobilization "non-depressive" rats remember painful stimulation and therefore they are not enter in the dark compartment during whole period of observation during testing session. Behavior of high immobilization "depressive" rats is not similar in passive avoidance camera; 50% of "depressive" rats, with long escape latency during training session (92±10 sec), remember painful stimulation during testing session and therefore they are not enter in the dark compartment during whole observation period. The remaining 50%, that are not differ significantly from the low immobility "non-depressive" rats by the latency of escape (5±1 sec) during training session, are not able to remember painful stimulation during testing session and therefore they enter in the dark compartment with shortest escape latency (6±1 sec). In conclusion, high immobility "depressive" rats perform passive avoidance declarative memory task at the chance level that is a direct indicator for the serious disturbances of declarative memory mechanisms in "depressive" rats selected in forced swim test according to the level of immobility.
27837699	Declarative memories of stressful events are less prone to forgetting than mundane events. Animal research has demonstrated that such stress effects on consolidation of hippocampal-dependent memories require the amygdala. In humans, it has been shown that during learning, increased amygdala-hippocampal interactions are related to more efficient memory encoding. Animal models predict that following learning, amygdala-hippocampal interactions are instrumental to strengthening the consolidation of such declarative memories. Whether this is the case in humans is unknown and remains to be empirically verified. To test this, we analyzed data from a sample of 120 healthy male participants who performed an incidental encoding task and subsequently underwent resting-state functional MRI in a stressful and a neutral context. Stress was assessed by measures of salivary cortisol, blood pressure, heart rate, and subjective ratings. Memory was tested afterwards outside of the scanner. Our data show that memory was stronger in the stress context compared to the neutral context and that stress-induced cortisol responses were associated with this memory enhancement. Interestingly, amygdala-hippocampal connectivity during post-encoding awake rest regardless of context (stress or neutral) was associated with the enhanced memory performance under stress. Thus, our findings are in line with a role for intrinsic functional connectivity during rest between the amygdala and the hippocampus in the state effects of stress on strengthening memory.
27815214	Arousal's selective effects on cognition go beyond the simple enhancement of emotional stimuli, sometimes enhancing and other times impairing processing of proximal neutral information. Past work shows that arousal impairs encoding of subsequent neutral stimuli regardless of their top-down priority via the engagement of β-adrenoreceptors. In contrast, retrograde amnesia induced by emotional arousal can flip to enhancement when preceding neutral items are prioritized in top-down attention. Whether β-adrenoreceptors also contribute to this retrograde memory enhancement of goal-relevant neutral stimuli is unclear. In this pharmacological study, we administered 40mg of propranolol or 40mg of placebo to healthy young adults to examine whether emotional arousal's bidirectional effects on declarative memory relies on β-adrenoreceptor activation. Following pill intake, participants completed an emotional oddball task in which they were asked to prioritize a neutral object appearing just before an emotional or neutral oddball image within a sequence of 7 neutral objects. Under placebo, emotional oddballs impaired memory for lower priority oddball+1 objects but had no effect on memory for high priority oddball-1 objects. Propranolol blocked this anterograde amnesic effect of arousal. Emotional oddballs also enhanced selective memory trade-offs significantly more in the placebo than drug condition, such that high priority oddball-1 objects were more likely to be remembered at the cost of their corresponding lower priority oddball+1 objects under arousal. Lastly, those who recalled more high priority oddball-1 objects preceding an emotional versus neutral oddball image showed greater increases in salivary alpha-amylase, a biomarker of noradrenergic system activation, across the task. Together these findings suggest that different noradrenergic mechanisms contribute to the anterograde and retrograde mnemonic effects of arousal on proximal neutral memoranda.
27810497	Spontaneous co-speech hand gestures provide a visuospatial representation of what is being communicated in spoken language. Although it is clear that gestures emerge from representations in memory for what is being communicated (De Ruiter, 1998; Wesp, Hesse, Keutmann, & Wheaton, 2001), the mechanism supporting the relationship between gesture and memory is unknown. Current theories of gesture production posit that action - supported by motor areas of the brain - is key in determining whether gestures are produced. We propose that when and how gestures are produced is determined in part by hippocampally-mediated declarative memory. We examined the speech and gesture of healthy older adults and of memory-impaired patients with hippocampal amnesia during four discourse tasks that required accessing episodes and information from the remote past. Consistent with previous reports of impoverished spoken language in patients with hippocampal amnesia, we predicted that these patients, who have difficulty generating multifaceted declarative memory representations, may in turn have impoverished gesture production. We found that patients gestured less overall relative to healthy comparison participants, and that this was particularly evident in tasks that may rely more heavily on declarative memory. Thus, gestures do not just emerge from the motor representation activated for speaking, but are also sensitive to the representation available in hippocampal declarative memory, suggesting a direct link between memory and gesture production.
27720868	Emotionally salient experiences induce the formation of explicit memory traces, besides eliciting automatic or implicit emotional memory in rodents. This study aims at investigating the implementation of a novel task for studying the formation of limbic memory engrams as a result of the acquisition- and retrieval- of fear-conditioning - biased declarative memory traces, measured by animal discrimination of an "emotional-object". Moreover, by using this new method we investigated the potential interactions between stimulation of cannabinoid transmission and integration of emotional information and cognitive functioning.The Emotional-Object Recognition task is composed of 3 following sessions: habituation; cued fear-conditioned learning; emotional recognition. Rats are exposed to Context "B chamber" for habituation and cued fear-conditioning, and tested in Context "A chamber" for emotional-object recognition.	Cued fear-conditioning induces a reduction in emotional-object exploration time during the Emotional-Object Recognition task in controls. The activation of cannabinoid signalling impairs limbic memory formation, with respect to vehicle.	The Emotional-Object Recognition test overcomes several limitations of commonly employed methods that explore declarative-, spatial memory and fear-conditioning in a non-integrated manner. It allows the assessment of unbiased cognitive indicators of emotional learning and memory.	The Emotional-Object Recognition task is a valuable tool for investigating whether, and at what extent, specific drugs or pathological conditions that interfere with the individual affective/emotional homeostasis, can modulate the formation of emotionally salient explicit memory traces, thus jeopardizing control and regulation of animal behavioural strategy.	
27720856	Sleep is known to support the consolidation of newly encoded and initially labile memories. Once consolidated, remote memories can return to a labile state upon reactivation and need to become reconsolidated in order to persist. Here we asked whether sleep also benefits the reconsolidation of remote memories after their reactivation and how reconsolidation during sleep compares to sleep-dependent consolidation processes. In three groups, participants were trained on a visuo-spatial learning task in the presence of a contextual odor. Participants in the 'reconsolidation' group learned the task on day 1. On day 2, they were subjected to a reactivation procedure by presenting the odor cue and a mock recall test in the learning context before a 40-min sleep or wake period. Participants in the 'remote consolidation' group followed the same procedure but did not receive reactivation on day 2. Participants in the 'recent consolidation' group skipped the procedure on day 1 and learned the task immediately before the sleep or wake period. After the sleep or wake interval, memory stability was tested in all subjects. The results show that this short 40-min sleep period significantly facilitated the reconsolidation of reactivated memories, whereas the consolidation of non-reactivated remote memories was less affected and recently encoded memories did not benefit at all. These findings tentatively suggest that sleep has a beneficial effect on the reconsolidation of remote memories, acting at a faster rate than sleep-associated consolidation.
27641508	Advances in our ability to visualize changes in single neuron morphology during or after training have largely contributed to renew the interest into the structural basis of memory. Nevertheless the idea that structural alterations in memory-specific neural circuits can be univocally considered as correlates of memory needs to be carefully considered in view of evidence showing that a variety of sensorial/motor/emotional stimuli also alter the morphology of neurons in those circuits. The aim of this review is to examine the respective impact of memory vs other forms of experiences in triggering structural plasticity in the rodent brain, the challenge being to disentangle alterations due to the formation of declarative/relational memories from those developing in the same regions in relation to non-memory functions.
27806157	Neurocognition is a central characteristic of schizophrenia and other psychotic disorders. Identifying the pattern and severity of neurocognitive functioning during the "near-psychotic," clinical high-risk (CHR) state of psychosis is necessary to develop accurate risk factors for psychosis and more effective and potentially preventive treatments.To identify core neurocognitive dysfunctions associated with the CHR phase, measure the ability of neurocognitive tests to predict transition to psychosis, and determine if neurocognitive deficits are robust or explained by potential confounders.	In this case-control study across 8 sites, baseline neurocognitive data were collected from January 2009 to April 2013 in the second phase of the North American Prodrome Longitudinal Study (NAPLS 2). The dates of analysis were August 2015 to August 2016. The setting was a consortium of 8 university-based, outpatient programs studying the psychosis prodrome in North America. Participants were 264 healthy controls (HCs) and 689 CHR individuals, aged 12 to 35 years.	Neurocognitive associations with transition to psychosis and effects of medication on neurocognition. Nineteen neuropsychological tests and 4 factors derived from factor analysis were used: executive and visuospatial abilities, verbal abilities, attention and working memory abilities, and declarative memory abilities.	This study included 264 HCs (137 male and 127 female) and 689 CHR participants (398 male and 291 female). In the HCs, 145 (54.9%) were white and 119 (45.1%) were not, whereas 397 CHR participants (57.6%) were white and 291 (42.3%) were not. In the HCs, 45 (17%) were of Hispanic origin, whereas 127 CHR participants (18.4%) were of Hispanic origin. The CHR individuals were significantly impaired compared with HCs on attention and working memory abilities and declarative memory abilities. The CHR converters had large deficits in attention and working memory abilities and declarative memory abilities (Cohen d, approximately 0.80) compared with controls and performed significantly worse on these dimensions than nonconverters (Cohen d, 0.28 and 0.48, respectively). These results were not accounted for by general cognitive ability or medications. In Cox proportional hazards regression, time to conversion in those who transitioned to psychosis was significantly predicted by high verbal (premorbid) abilities (β = 0.40; hazard ratio [HR], 1.48; 95% CI, 1.08-2.04; P = .02), impaired declarative memory abilities (β = -0.87; HR, 0.42; 95% CI, 0.31-0.56; P < .001), age (β = -0.10; HR, 0.90; 95% CI, 0.84-0.97; P = .003), site, and a combined score of unusual thought content or delusional ideas and suspiciousness or persecutory ideas items (β = 0.44; HR, 1.56; 95% CI, 1.36-1.78; P < .001).	Neurocognitive impairment, especially in attention and working memory abilities and declarative memory abilities, is a robust characteristic of CHR participants, especially those who later develop psychosis. Interventions targeting the enhancement of neurocognitive functioning are warranted in this population.	
27791089	Declarative memory consolidation is hypothesized to require a two-stage, reciprocal cortical-hippocampal dialogue. According to this model, higher frequency signals convey information from the cortex to hippocampus during wakefulness, but in the reverse direction during slow-wave sleep (SWS). Conversely, lower-frequency activity propagates from the information "receiver" to the "sender" to coordinate the timing of information transfer. Reversal of sender/receiver roles across wake and SWS implies that higher- and lower-frequency signaling should reverse direction between the cortex and hippocampus. However, direct evidence of such a reversal has been lacking in humans. Here, we use human resting-state fMRI and electrocorticography to demonstrate that δ-band activity and infraslow activity propagate in opposite directions between the hippocampus and cerebral cortex. Moreover, both δ activity and infraslow activity reverse propagation directions between the hippocampus and cerebral cortex across wake and SWS. These findings provide direct evidence for state-dependent reversals in human cortical-hippocampal communication.
27797165	During communication, we form assumptions about what our communication partners know and believe. Information that is mutually known between the discourse partners-their common ground-serves as a backdrop for successful communication. Here we present an introduction to the focus of this topic, which is the role of memory in common ground and language use. Two types of questions emerge as central to understanding the relationship between memory and common ground, specifically questions having to do with the representation of common ground in memory, and the use of common ground during language processing.
27693851	When parts of the brain suffer from damage, certain functional deficits or impairments are the expected and typical outcome. A myriad of examples show such negative consequences, which afford the daily tasks of neurologists, neuropsychologists, and also behavioral neuroscientists working with experimental brain lesions. Compared to lesion-induced deficits, examples for functional enhancements or facilitation after brain lesions are rather rare and usually not well studied. Here, the mammalian hippocampus seems to provide an exception, since substantial evidence shows that its damage can have facilitatory behavioral effects under certain conditions. This review will address these effects and their possible mechanisms. It will show that facilitatory effects of hippocampal lesions, although mostly studied in rats, can be found in many mammalian species, that is, they are apparently not species-specific. Furthermore, they can be found with various lesion techniques, from tissue ablation, to neurotoxic damage, and from damage of hippocampal structure itself to damage of fiber systems innervating it. The major emphasis of this review, however, lies on the behavioral effects and their interpretations. Thus, facilitatory effects can be found in several learning paradigms, especially active avoidance, and some forms of Pavlovian and instrumental conditioning. These will be discussed in light of pertinent theories of hippocampal function, such as inhibition, spatial cognition, and multiple memory systems theories, which state that facilitatory effects of hippocampal lesions may reflect the loss of interference between hippocampal spatial and striatal procedural cognition. Using the example of the rat sequential reaction time task, it will also be discussed how such lesions can have direct and indirect consequences on certain behavioral readouts. A final note will advocate considering possible functional facilitation also in neurologic patients, especially those with hippocampal damage, since such a strategy might provide new avenues for therapeutic treatments.
27710778	We investigated whether the benefit of slow wave sleep (SWS) for memory consolidation typically observed in healthy individuals is disrupted in people with accelerated long-term forgetting (ALF) due to epilepsy. SWS is thought to play an active role in declarative memory in healthy individuals and, furthermore, electrographic epileptiform activity is often more prevalent during SWS than during wakefulness or other sleep stages. We studied the relationship between SWS and the benefit of sleep for memory retention using a word-pair associates task. In both the ALF and the healthy control groups, sleep conferred a memory benefit. However, the relationship between the amount of SWS and sleep-related memory benefits differed significantly between the groups. In healthy participants, the amount of SWS correlated positively with sleep-related memory benefits. In stark contrast, the more SWS, the smaller the sleep-related memory benefit in the ALF group. Therefore, contrary to its role in healthy people, SWS-associated brain activity appears to be deleterious for memory in patients with ALF.
27720737	The presence of multiple memory systems supported by different neural substrata has been demonstrated in animal and human studies. In mammals, two variants of eyeblink classical conditioning, differing only in the temporal relationships between the conditioned stimulus (CS) and the unconditioned stimulus (US), have been widely used to study the neural substrata of these different memory systems. Delay conditioning, in which both stimuli coincide in time, depends on a non-relational memory system supported by the cerebellum and associated brainstem circuits. In contrast, trace conditioning, in which a stimulus-free time gap separates the CS and the US, requires a declarative or relational memory system, thus depending on forebrain structures in addition to the cerebellum. The distinction between the explicit or relational and the implicit or procedural memory systems that support trace and delay classical conditioning has been extensively studied in mammals, but studies in other vertebrate groups are relatively scarce. In the present experiment we analyzed the differential involvement of the cerebellum and the telencephalon in delay and trace eyeblink-like classical conditioning in goldfish. The results show that whereas the cerebellum lesion prevented the eyeblink-like conditioning in both procedures, the telencephalon ablation impaired exclusively the acquisition of the trace conditioning. These data showing that comparable neural systems support delay and trace eyeblink conditioning in teleost fish and mammals suggest that these separate memory systems and their neural bases could be a shared ancestral brain feature of the vertebrate lineage.
27765468	In recent years sleep-related memory consolidation has become a central topic in the sleep research field. Several studies have shown that in healthy individuals sleep promotes memory consolidation. Notwithstanding this, the consequences of sleep disorders on offline memory consolidation remain poorly investigated. Research studies indicate that patients with insomnia, obstructive sleep apnea, and narcolepsy often exhibit sleep-related impairment in the consolidation of declarative and procedural information. On the other hand, patients with parasomnias, such as sleep-walking, night terrors and rapid eye movement (REM) behavior disorder, do not present any memory impairment. These studies suggest that only sleep disorders characterized by increased post-learning arousal and disrupted sleep architecture seem to be associated with offline memory consolidation issues. Such impairments, arising already in childhood, may potentially affect the development and maintenance of an individual's cognitive abilities, reducing their quality of life and increasing the risk of accidents. However, promising findings suggest that successfully treating sleep symptoms can result in the restoration of memory functions and marked reduction of direct and indirect societal costs of sleep disorders.
27589526	Glycogen synthase kinase (GSK)-3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer's disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ), and neurodegeneration. We have previously shown that an antisense oligonucleotide directed at the Tyr 216 site on GSK-3β (GAO) when injected centrally can decrease GSK-3β levels, improve learning and memory, and decrease oxidative stress. In addition, we showed that GAO can cross the blood-brain barrier. Herein the impact of peripherally administered GAO in both the non-transgenic SAMP8 and transgenic Tg2576 (APPswe) models of AD were examined respective to learning and memory. Brain tissues were then evaluated for expression changes in the phosphorylated-Tyr 216 residue, which leads to GSK-3β activation, and the phosphorylated-Ser9 residue, which reduces GSK-3β activity. SAMP8 GAO-treated mice showed improved acquisition and retention using aversive T-maze, and improved declarative memory as measured by the novel object recognition (NOR) test. Expression of the phosphorylated-Tyr 216 was decreased and the phosphorylated-Ser9 was increased in GAO-treated SAMP8 mice. Tg2576 GAO-treated mice improved acquisition and retention in both the T-maze and NOR tests, with an increased phosphorylated-Ser9 GSK-3β expression. Results demonstrate that peripheral administration of GAO improves learning and memory, corresponding with alterations in GSK-3β phosphorylation state. This study supports peripherally administered GAO as a viable means to mediate GSK-3β activity within the brain and a possible treatment for AD.

27736656	It is largely recognized that the mesial temporal lobe and its substructure support declarative long-term memory (LTM). So far, different theories have been suggested, and the organization of declarative verbal LTM in the brain is still a matter of debate. In the current study, we retrospectively selected 151 right-handed patients with temporal lobe epilepsy with and without hippocampal sclerosis, with a homogeneous (seizure-free) clinical outcome. We analyzed verbal memory performance within a normalized scores context, by means of prose recall and word paired-associate learning tasks. Patients were tested at presurgical baseline, 6months, 2 and 5years after anteromesial temporal lobe surgery, using parallel versions of the neuropsychological tests. Our main finding revealed a key involvement of the left temporal lobe and, in particular, of the left hippocampus in prose recall rather than word paired-associate task. We also confirmed that shorter duration of epilepsy, younger age, and withdrawal of antiepileptic drugs would predict a better memory outcome. When individual memory performance was taken into account, data showed that females affected by left temporal lobe epilepsy for longer duration were more at risk of presenting a clinically pathologic LTM at 5years after surgery. Taken together, these findings shed new light on verbal declarative memory in the mesial temporal lobe and on the behavioral signature of the functional reorganization after the surgical treatment of temporal lobe epilepsy.
27729083	Disrupted-in-schizophrenia 1(DISC1) is a promising candidate susceptibility gene for a spectrum of psychiatric illnesses that share cognitive impairments in common, including schizophrenia, bipolar disorder and major depression. Here we report that DISC1 L100P homozygous mutant shows normal anxiety- and depression-like behavior, but impaired object recognition which is prevented by administration of atypical antipsychotic drug clozapine. Ca2+ image analysis reveals suppression of glutamate-evoked elevation of cytoplasmic [Ca2+] in L100P hippocampal slices. L100P mutant slices exhibit decreased excitatory synaptic transmission (sEPSCs and mEPSCs) in dentate gyrus (DG) and impaired long-term potentiation in the CA1 region of the hippocampus. L100P mutation does not alter proteins expression of the excitatory synaptic markers, PSD95 and synapsin-1; neither does it changes dendrites morphology of primary cultured hippocampal neurons. Our findings suggest that the existence of abnormal synaptic transmission and plasticity in hippocampal network may disrupt declarative information processing and contribute to recognition deficits in DISC1 L100P mutant mice.
27721578	The present review highlights results from recent studies that delivered brief electrical stimulation to the basolateral complex of the amygdala in rats to reveal its capacity to prioritize declarative memories on a moment-to-moment basis even after the moment has passed. The results indicate that this memory enhancement depends on the hippocampus and elicits intrahippocampal gamma synchrony that possibly corresponds with sharpened hippocampal spike-timing dependent plasticity. These recent findings are discussed in relation to past studies of emotional memory in rodents and humans.
27713407	Adaptive memory requires context-dependent control over how information is retrieved, evaluated and used to guide action, yet the signals that drive adjustments to memory decisions remain unknown. Here we show that prediction errors (PEs) coded by the striatum support control over memory decisions. Human participants completed a recognition memory test that incorporated biased feedback to influence participants' recognition criterion. Using model-based fMRI, we find that PEs-the deviation between the outcome and expected value of a memory decision-correlate with striatal activity and predict individuals' final criterion. Importantly, the striatal PEs are scaled relative to memory strength rather than the expected trial outcome. Follow-up experiments show that the learned recognition criterion transfers to free recall, and targeting biased feedback to experimentally manipulate the magnitude of PEs influences criterion consistent with PEs scaled relative to memory strength. This provides convergent evidence that declarative memory decisions can be regulated via striatally mediated reinforcement learning signals.
27711166	Evolutionary divergence of the mitochondrial genome has given rise to distinct haplogroups. These haplogroups have arisen in specific geographical locations and are responsible for subtle functional changes in the mitochondria that may provide an evolutionary advantage in a given environment. Based on these functional differences, haplogroups could define disease susceptibility in chronic settings. In this study, we undertook a detailed neuropsychological analysis of a cohort of long-term HIV-1-infected individuals in conjunction with sequencing of their mitochondrial genomes. Stepwise regression analysis showed that the best model for predicting both working memory and declarative memory were age and years since diagnosis. In contrast, years since diagnosis and sub-haplogroup were significantly predictive of psychomotor speed. Consistent with this, patients with haplogroup L3e obtained better scores on psychomotor speed and dexterity tasks when compared to the remainder of the cohort, suggesting that this haplogroup provides a protective advantage when faced with the combined stress of HIV-1 infection and long-term antiretroviral therapies. Differential performance on declarative memory tasks was noted for individuals with other sub-L haplogroups, but these differences were not as robust as the association between L3e and psychomotor speed and dexterity tasks. This work provides evidence that mitochondrial haplogroup is related to neuropsychological test performance among patients in chronic disease settings such as HIV-1 infection.
27695407	Encounters with new people result in the extraction and storage in memory of both their external features, allowing us to recognize them later, and their internal traits, allowing us to better control our current interactions with them and anticipate our future ones. Just as we extract, encode, store, retrieve and update the representations of others so, too, do we process representations of ourselves. These representations, which rely on declarative memory, may be altered or cease to be accessible in amnesia. Nonetheless, studies of amnesic patients have yielded the surprising observation that memory impairments alone do not prevent patients from making accurate trait self-judgments. In this review article, we discuss prevailing explanations for preserved self-evaluation in amnesia and propose an alternative one, based on the concept of introspective computation. We also consider molecular and anatomical aspects of brain functioning that potentially support introspective computation.
27690745	Practice effects on neuropsychological tests, which are improvements in test scores due to repeated exposure to testing materials, are robust in healthy elders, but muted in older adults with cognitive disorders. Conversely, few studies have investigated practice effects on motor tasks involving procedural memory, particularly across test-retest periods exceeding 24 hours. The current study examined one-week practice effects on a novel upper extremity motor task in 54 older adults with amnestic mild cognitive impairment. Results indicate that these individuals with primary memory deficits did improve on this motor task within a brief training session as well as across one week. These practice effects were unrelated to demographic characteristics or global cognition. One-week practice effects were, however, negatively related to delayed memory function, with larger practice effects being associated with poorer delayed memory and potentially better visuospatial ability. The presence of longer term practice effects on a procedural motor task not only has implications for how longitudinal assessments with similar measures involving implicit memory might be interpreted, but may also inform future rehabilitative strategies for patients with more severe declarative memory deficits.
27679589	Sleep supports memory consolidation. However, the conceptually important influence of the amount of items encoded in a memory test on this effect has not been investigated. In two experiments, participants (n = 101) learned lists of word-pairs varying in length (40, 160, 320 word-pairs) in the evening before a night of sleep (sleep group) or of sleep deprivation (wake group). After 36 h (including a night allowing recovery sleep) retrieval was tested. Compared with wakefulness, post-learning sleep enhanced retention for the 160 word-pair condition (p < 0.01), importantly, this effect completely vanished for the 320 word-pair condition. This result indicates a limited capacity for sleep-dependent memory consolidation, which is consistent with an active system consolidation view on sleep's role for memory, if it is complemented by processes of active forgetting and/or gist abstraction. Whereas the absolute benefit from sleep should have increased with increasing amounts of successfully encoded items, if sleep only passively protected memory from interference. Moreover, the finding that retention performance was significantly diminished for the 320 word-pair condition compared to the 160 word-pair condition in the sleep group, makes it tempting to speculate that with increasing loads of information encoded during wakefulness, sleep might favor processes of forgetting over consolidation. 
27677776	Data from experimental animals and human subjects has provided convergent evidence for the key role of the striatum in the formation of stimulus-response habits. Habits can be distinguished from associative memories that support goal-directed actions based on their insensitivity to reward devaluation and contingency degradation. Behavior on many instrumental learning tasks can be supported by both declarative knowledge and habits, and these contributions shift with the amount of training. This shift appears to be accompanied by the involvement of different cortico-striatal loops in controlling behavior. Factors that encourage the shift toward and maintenance of habits include learning under conditions of stress, distraction, and interval or probabilistic schedules of reinforcement.
27676446	Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited. Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning. Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning. This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors-Δ9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning. Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories. The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder. Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.
27660264	Several efforts have been made to understand the involvement of rapid eye movement (REM) sleep for cognitive processes. Consolidation or retention of recognition memories is severely disrupted by REM sleep deprivation (REMSD). In this regard, pedunculopontine tegmental nucleus (PPT) and other brainstem nuclei, such as pontine nucleus (Pn) and oculomotor nucleus (OCM), appear to be candidates to take part in this REM sleep circuitry with potential involvement in cognition. Therefore, the objective of this study was to investigate a possible association between the performance of Wistar rats in a declarative memory and PPT, Pn, and OCM activities after different periods of REMSD. We examined c-Fos and choline acetyltransferase (ChaT) expressions as indicators of neuronal activity as well as a familiarity-based memory test. The animals were distributed in groups: control, REMSD, and sleep rebound (REB). At the end of the different REMSD (24, 48, 72, and 96 h) and REB (24 h) time points, the rats were immediately tested in the object recognition test and then the brains were collected. Results indicated that OCM neurons presented an increased activity, due to ChaT-labeling associated with REMSD that negatively correlated (r = -0.32) with the cognitive performance. This suggests the existence of a cholinergic compensatory mechanism within the OCM during REMSD. We also showed that 24 h of REMSD impacted similarly in memory, compared to longer periods of REMSD. These data extend the notion that REM sleep is influenced by areas other than PPT, i.e., Pn and OCM, which could be key players in both sleep processes and cognition.
27660240	The main paradigm of cognitive neuroscience is the connectionist concept postulating that the higher nervous activity is performed through interactions of neurons forming complex networks, whereas the function of individual neurons is restricted to generating electrical potentials and transmitting signals to other cells. In this article, I describe the observations from three fields-neurolinguistics, physiology of memory, and sensory perception-that can hardly be explained within the constraints of a purely connectionist concept. Rather, these examples suggest that cognitive functions are determined by specific properties of individual neurons and, therefore, are likely to be accomplished primarily at the intracellular level. This view is supported by the recent discovery that the brain's ability to create abstract concepts of particular individuals, animals, or places is performed by neurons ("concept cells") sparsely distributed in the medial temporal lobe.
27658720	Electroconvulsive therapy (ECT) is a highly effective and well-tolerated therapy for severe and treatment-resistant depression. Cognitive side-effects are still feared by some patients and clinicians. Importantly, cognitive impairments are among the most disabling symptoms of depression itself.Patients suffering from a severe episode of depression were treated with either ECT or treatment as usual (TAU) in an in-patient setting. Matched healthy participants served as controls (HC). Verbal memory was tested with the California Verbal Learning Test (CVLT) before the specific treatment started (ECT = 15, TAU = 16, HC = 31) and 2 months after the last ECT session or 2 months after discharge respectively.	Before the specific treatment started, depressed patients performed substantially worse compared with HC in total, short- and long-delay recall in the CVLT, while the ECT group showed the worst performance. More severely depressed patients showed worse performances in these measures. Intriguingly, verbal memory showed a significant improvement in ECT-treated patients, but not in the other groups. No differences between the groups were found at follow-up.	Contrary to the widely feared assumption that ECT has long-term impact on memory functions, we found evidence that ECT is superior to TAU in improving verbal memory in depressed patients.	
27613509	To date, there are no reliable markers for predicting onset of schizophrenia in individuals at high risk (HR). Substantial promise is, however, shown by a variety of pattern classification approaches to neuroimaging data. Here, we examined the predictive accuracy of support vector machine (SVM) in later diagnosing schizophrenia, at a single-subject level, using a cohort of HR individuals drawn from multiply affected families and a combination of neuroanatomical, schizotypal and neurocognitive variables. Baseline structural magnetic resonance imaging (MRI), schizotypal and neurocognitive data from 17 HR subjects, who subsequently developed schizophrenia and a matched group of 17 HR subjects who did not make the transition, yet had psychotic symptoms, were included in the analysis. We employed recursive feature elimination (RFE), in a nested cross-validation scheme to identify the most significant predictors of disease transition and enhance diagnostic performance. Classification accuracy was 94% when a self-completed measure of schizotypy, a declarative memory test and structural MRI data were combined into a single learning algorithm; higher than when either quantitative measure was used alone. The discriminative neuroanatomical pattern involved gray matter volume differences in frontal, orbito-frontal and occipital lobe regions bilaterally as well as parts of the superior, medial temporal lobe and cerebellar regions. Our findings suggest that an early SVM-based prediction of schizophrenia is possible and can be improved by combining schizotypal and neurocognitive features with neuroanatomical variables. However, our predictive model needs to be tested by classifying a new, independent HR cohort in order to estimate its validity.
27587287	The acquisition of conceptual knowledge in scientific domains is among the central aims of school instruction because this semantic declarative knowledge helps individuals make interferences and explain complex phenomena. Recent research shows that naïve concepts acquired during childhood persist in long-term memory long after learning the scientifically correct concepts in school. In this study, we investigated the effects of stress on the retrieval of these conceptual representations. To this end, 40 healthy men were randomly assigned to either psychosocial stress or a control condition and evaluated, as quickly and accurately as possible, statements that were compatible with scientific concepts or incompatible with those concepts. Some of these statements were true and some were false. Incompatible statements in this case are statements which are in line with adults' scientific concepts, but not with children's naïve theories. In contrast, compatible statements are in line with both. Stress induction was successful as evidenced by increases in blood pressure and cortisol concentrations in the stress group compared to the control group. Responses were delayed and less accurate for incompatible compared to compatible statements. Psychosocial stress had no main effect on retrieval, but abolished reaction time differences on false- vs. true-incompatible statements. This effect was mirrored in correlations between individuals' cortisol increases and reaction times. These results suggest that stress, as embodied by increases in cortisol concentrations, interferes with the retrieval of conceptual knowledge. They help to better understand conceptual knowledge retrieval in real-life situations such as examinations or problem solving in the workplace. 
27584668	Cognitive performance is characterized by at least two distinct life course trajectories. Many cognitive abilities (e.g., "effortful processing" abilities, including fluid reasoning and processing speed) improve throughout early adolescence and start declining in early adulthood, whereas other abilities (e.g., "crystallized" abilities like vocabulary breadth) improve throughout adult life, remaining robust even at late ages. Although schooling may impact performance and cognitive "reserve," it has been argued that these age patterns of cognitive performance are human universals. Here we examine age patterns of cognitive performance among Tsimane forager-horticulturalists of Bolivia and test whether schooling is related to differences in cognitive performance over the life course to assess models of active versus passive cognitive reserve. We used a battery of eight tasks to assess a range of latent cognitive traits reflecting attention, processing speed, verbal declarative memory, and semantic fluency (n = 919 individuals, 49.9% female). Tsimane cognitive abilities show similar age-related differences as observed in industrialized populations: higher throughout adolescence and only slightly lower in later adulthood for semantic fluency but substantially lower performance beginning in early adulthood for all other abilities. Schooling is associated with greater cognitive abilities at all ages controlling for sex but has no attenuating effect on cognitive performance in late adulthood, consistent with models of passive cognitive reserve. We interpret the minimal attenuation of semantic fluency late in life in light of evolutionary theories of postreproductive life span, which emphasize indirect fitness contributions of older adults through the transfer of information, labor, and food to descendant kin. (PsycINFO Database Record
27575853	Affixal inflectional morphology has been intensively examined as a model of productive aspects of language. Nevertheless, little is known about the neurocognition of the learning and generalization of affixal inflection, or the influence of certain factors that may affect these processes. In an event-related fMRI study, we examined the neurocognition of the learning and generalization of plural inflections in an artificial language, as well as the influence of both affix type frequency (the proportion of words receiving a given affix) and affix predictability (based on phonological cues in the stem). Adult participants were trained in three sessions, and were scanned after the first and last sessions while inflecting trained and untrained words. Untrained words yielded more activation than trained words in medial frontal (including pre-SMA) and left inferior frontal cortices, which have previously shown activation in compositional grammatical processing. A reliance on phonological cues for untrained word inflection correlated positively with pre-SMA activation, but negatively with activation in the pars triangularis. Thus, pre-SMA may be involved in phonological cue-based composition, while the pars triangularis underlies alternative processes. Inflecting trained items yielded activation in the caudate head bilaterally, only in the first session, consistent with a role for procedural memory in learning grammatical regularities. The medial frontal and left inferior regions activated by untrained items were also activated by trained items, but more weakly than untrained items, with weakest activation for trained-items taking the high-frequency affix. This suggests less involvement of compositional processes for inflecting trained than untrained items, and least of all for trained inflected forms with high-frequency affixes, consistent with the storage of such forms (e.g., in declarative memory). Overall, the findings further elucidate the neural bases of the learning and generalization of affixal morphology, and the roles of affix type frequency and affix phonological predictability in these processes. Moreover, the results support and further specify the declarative/procedural model, in particular in adult language learning.
27549389	This study evaluates the effectiveness of a training program designed to improve cross-functional coordination in airline operations.Teamwork across professional specializations is essential for safe and efficient airline operations, but aviation education primarily emphasizes positional knowledge and skill. Although crew resource management training is commonly used to provide some degree of teamwork training, it is generally focused on specific specializations, and little training is provided in coordination across specializations.	The current study describes and evaluates a multifaceted training program designed to enhance teamwork and team performance of cross-functional teams within a simulated airline flight operations center. The training included a variety of components: orientation training, position-specific declarative knowledge training, position-specific procedural knowledge training, a series of high-fidelity team simulations, and a series of after-action reviews.	Following training, participants demonstrated more effective teamwork, development of transactive memory, and more effective team performance.	Multifaceted team training that incorporates positional training and team interaction in complex realistic situations and followed by after-action reviews can facilitate teamwork and team performance.	Team training programs, such as the one described here, have potential to improve the training of aviation professionals. These techniques can be applied to other contexts where multidisciplinary teams and multiteam systems work to perform highly interdependent activities.	
27517876	Working memory (WM) holds and manipulates representations for ongoing cognition. Oberauer (Psychology of Learning and Motivation, 51, 45-100, 2009) distinguishes between two analogous WM sub-systems: a declarative WM which handles the objects of thought, and a procedural WM which handles the representations of (cognitive) actions. Here, we assessed whether analogous effects are observed when participants switch between memory sets (declarative representations) and when they switch between task sets (procedural representations). One mechanism assumed to facilitate switching in procedural WM is the inhibition of previously used, but currently irrelevant task sets, as indexed by n-2 task-repetition costs (Mayr & Keele, Journal of Experimental Psychology: General, 129(1), 4-26, 2000). In this study we tested for an analogous effect in declarative WM. We assessed the evidence for n-2 list-repetition costs across eight experiments in which participants switched between memory lists to perform speeded classifications, mental arithmetic, or a local recognition test. N-2 list-repetition costs were obtained consistently in conditions assumed to increase interference between memory lists, and when lists formed chunks in long-term memory. Further analyses across experiments revealed a substantial contribution of episodic memory to n-2 list-repetition costs, thereby questioning the interpretation of n-2 repetition costs as reflecting inhibition. We reanalyzed the data of eight task-switching experiments, and observed that episodic memory also contributes to n-2 task-repetition costs. Taken together, these results show analogous processing principles in declarative and procedural WM, and question the relevance of inhibitory processes for efficient switching between mental sets.
27516751	Poor sleep quality negatively affects memory performance, and working memory in particular. We investigated sleep habits related to sleep quality including sleep duration, daytime nap duration, nap frequency, and dream content recall frequency (DCRF). Declarative working memory can be subdivided into verbal working memory (VWM) and visuospatial working memory (VSWM). We hypothesized that sleep habits would have different effects on VWM and VSWM. To our knowledge, our study is the first to investigate differences between VWM and VSWM related to daytime nap duration, nap frequency, and DCRF. Furthermore, we tested the hypothesis that the effects of duration and frequency of daytime naps and DCRF on VWM and VSWM differed according to sex. We assessed 779 healthy right-handed individuals (434 males and 345 females; mean age: 20.7 ± 1.8 years) using a digit span forward and backward VWM task, a forward and backward VSWM task, and sleep habits scales. A correlation analysis was used to test the relationships between VWM capacity (VWMC) and VSWM capacity (VSWMC) scores and sleep duration, nap duration, nap frequency, and DCRF. Furthermore, multiple regression analyses were conducted to identify factors associated with VWMC and VSWMC scores and to identify sex-related differences. We found significant positive correlations between VSWMC and nap duration and DCRF, and between VWMC and sleep duration in all subjects. Furthermore, we found that working memory capacity (WMC) was positively correlated with nap duration in males and with sleep duration in females, and DCRF was positively correlated with VSWMC in females. Our finding of sex-related differences in the effects of sleep habits on WMC has not been reported previously. The associations between WMC and sleep habits differed according to sex because of differences in the underlying neural correlates of VWM and VSWM, and effectiveness of the sleep habits in males and females. 
27511011	It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). In subjects carrying at least one copy of the BDNF Met allele, a more consolidated sleep was not associated with better memory performance in most memory tests (β-values from -0.309 to -0.392, p values from 0.06 to 0.15). Strikingly, increased sleep consolidation was associated with poorer performance in learning a short story presented verbally in Met allele carriers (β = -0.585, p = 0.005). This study provides new evidence regarding the interacting roles of consolidated sleep and BDNF polymorphism in the ability to learn and stresses the importance of considering BDNF polymorphism when studying how sleep affects cognition.Individuals with the BDNF Val/Val (valine allele) polymorphism showed better memory performance after a night of consolidated sleep. However, we observed that middle-aged and older individuals who are carriers of the BDNF Met allele displayed no positive association between sleep quality and their ability to learn the next morning. This interaction between sleep and BDNF polymorphism was more salient for hippocampus-dependent tasks than for other cognitive tasks. Our results support the hypothesis that reduced activity-dependent secretion of BDNF impairs the benefits of sleep on synaptic plasticity and next-day memory. Our work advances the field by revealing new evidence of a clear genetic heterogeneity in how sleep consolidation contributes to the ability to learn.	
27506309	Cognitive performance is impaired by hypoxia despite global cerebral oxygen delivery and metabolism being maintained. Using arterial spin labelled (ASL) magnetic resonance imaging, this is the first study to show regional reductions in cerebral blood flow (CBF) in response to decreased oxygen supply (hypoxia) at 2 h that increased in area and became more pronounced at 10 h. Reductions in CBF were seen in brain regions typically associated with the 'default mode' or 'task negative' network. Regional reductions in CBF, and associated vasoconstriction, within the default mode network in hypoxia is supported by increased vasodilatation in these regions to a subsequent hypercapnic (5% CO2 ) challenge. These results suggest an anatomical mechanism through which hypoxia may cause previously reported deficits in cognitive performance.Hypoxia causes an increase in global cerebral blood flow, which maintains global cerebral oxygen delivery and metabolism. However, neurological deficits are abundant under hypoxic conditions. We investigated regional cerebral microvascular responses to acute (2 h) and prolonged (10 h) poikilocapnic normobaric hypoxia. We found that 2 h of hypoxia caused an expected increase in frontal cortical grey matter perfusion but unexpected perfusion decreases in regions of the brain normally associated with the 'default mode' or 'task negative' network. After 10 h in hypoxia, decreased blood flow to the major nodes of the default mode network became more pronounced and widespread. The use of a hypercapnic challenge (5% CO2 ) confirmed that these reductions in cerebral blood flow from hypoxia were related to vasoconstriction. Our findings demonstrate steady-state deactivation of the default network under acute hypoxia, which become more pronounced over time. Moreover, these data provide a unique insight into the nuanced localized cerebrovascular response to hypoxia that is not attainable through traditional methods. The observation of reduced perfusion in the posterior cingulate and cuneal cortex, which are regions assumed to play a role in declarative and procedural memory, provides an anatomical mechanism through which hypoxia may cause deficits in working memory.	
27492601	This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40IU) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance. 
27466184	Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.
27461084	Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory and underlying mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning, or fear memory. Viral delivery of designer receptors exclusively activated by designer drugs was used to selectively silence the activity of 5-HT neurons in the raphe. Inhibition of 5-HT neurons in the median raphe, but not the dorsal raphe, was sufficient to impair object recognition in adult mice. In vivo electrophysiology in behaving mice showed that long-term potentiation in the hippocampus of 5-HT-deficient mice was altered, and administration of the 5-HT1A agonist 8-OHDPAT rescued the memory deficits. Our data suggest that hyposerotonergia selectively affects declarative hippocampal-dependent memory. Serotonergic projections from the median raphe are necessary to regulate object memory and hippocampal synaptic plasticity processes, through an inhibitory control mediated by 5-HT1A receptors.
27445958	It remains unclear whether probabilistic category learning in the feedback-based weather prediction task (FB-WPT) can be mediated by a non-declarative or procedural learning system. To address this issue, we compared the effects of training time and verbal working memory, which influence the declarative learning system but not the non-declarative learning system, in the FB and paired-associate (PA) WPTs, as the PA task recruits a declarative learning system. The results of Experiment 1 showed that the optimal accuracy in the PA condition was significantly decreased when the training time was reduced from 7 to 3 s, but this did not occur in the FB condition, although shortened training time impaired the acquisition of explicit knowledge in both conditions. The results of Experiment 2 showed that the concurrent working memory task impaired the optimal accuracy and the acquisition of explicit knowledge in the PA condition but did not influence the optimal accuracy or the acquisition of self-insight knowledge in the FB condition. The apparent dissociation results between the FB and PA conditions suggested that a non-declarative or procedural learning system is involved in the FB-WPT and provided new evidence for the multiple-systems theory of human category learning. 
27436232	Pro-inflammatory cytokines can promote sleep and neuronal processes underlying memory formation. However, this has mainly been revealed in animal studies. In this double-blind, placebo-controlled within-subject designed study, we examined how changes in the balance between pro- and anti-inflammatory signalling affect sleep and sleep-associated memory consolidation in humans. After learning declarative memory tasks (word pairs, texts) and a procedural memory task (finger tapping) in the evening, 21 healthy young men orally received either 200 mg of the anti-inflammatory antibiotic minocycline or placebo shortly before nocturnal sleep. Sleep was allowed between 23:00 and 07:00 h and recorded polysomnographically. Retrieval of memories was tested two days later. Because of outliers or missing data, final sample size was reduced to n = 14-19. Our data suggest that rather than weakening sleep as expected based on animal studies, the anti-inflammatory agent promoted sleep and memory consolidation. Specifically, minocycline increased slow-wave activity (0.68-4.0 Hz) during non-rapid eye movement sleep stage 2 and selectively enhanced episodic aspects in memory (i.e. memory for the temporal order of events in the texts). In combination with previous results, our findings indicate that, in humans, reducing pro-inflammatory signalling can act towards deepening non-rapid eye movement sleep and enhancing its memory forming efficacy.
27422437	The application of auditory clicks during non-rapid eye movement (NREM) sleep phase-locked to the up state of the slow oscillation (closed-loop stimulation) has previously been shown to enhance the consolidation of declarative memories. We designed and applied sequences of three clicks during deep NREM sleep to achieve a quasi-phase-dependent open-loop stimulation. This stimulation was successful in eliciting slow oscillation power in the stimulation period. Although fast and slow spindle power were markedly decreased during the stimulation period, memory consolidation did not differ from control. During putative up states fast spindle power remained, however, at control levels. We conclude that concurrence of slow oscillations and fast spindles suffices to maintain memory consolidation at control levels despite an overall decreased spindle activity. 
27422017	Translational assays of cognition that are similarly implemented in both lower and higher-order species, such as rodents and primates, provide a means to reconcile preclinical modeling of psychiatric neuropathology and clinical research. To this end, Pavlovian conditioning has provided a useful tool for investigating cognitive processes in both lab animal models and humans. This review focuses on trace conditioning, a form of Pavlovian conditioning typified by the insertion of a temporal gap (i.e., trace interval) between presentations of a conditioned stimulus (CS) and an unconditioned stimulus (US). This review aims to discuss pre-clinical and clinical work investigating the mnemonic processes recruited for trace conditioning. Much work suggests that trace conditioning involves unique neurocognitive mechanisms to facilitate formation of trace memories in contrast to standard Pavlovian conditioning. For example, the hippocampus and prefrontal cortex (PFC) appear to play critical roles in trace conditioning. Moreover, cognitive mechanistic accounts in human studies suggest that working memory and declarative memory processes are engaged to facilitate formation of trace memories. The aim of this review is to integrate cognitive and neurobiological accounts of trace conditioning from preclinical and clinical studies to examine involvement of working and declarative memory. 
27421709	Episodic-like memory tests often aid in determining an animal's ability to recall the what, where, and which (context) of an event. To date, this type of memory has been demonstrated in humans, wild chacma baboons, corvids (Scrub jays), humming birds, mice, rats, Yucatan minipigs, and cuttlefish. The potential for this type of memory in zebrafish remains unexplored even though they are quickly becoming an essential model organism for the study of a variety of human cognitive and mental disorders. Here we explore the episodic-like capabilities of zebrafish (Danio rerio) in a previously established mammalian memory paradigm. We demonstrate that when zebrafish were presented with a familiar object in a familiar context but a novel location within that context, they spend more time in the novel quadrant. Thus, zebrafish display episodic-like memory as they remember what object they saw, where they saw it (quadrant location), and on which occasion (yellow or blue walls) it was presented.
27418578	Declarative memories are our so-called daily language memories, which we are able to describe or explicitly experience through the act of remembering. This conscious recollection makes it possible for us to think about the future based on our previous experience (episodic memory) and knowledge (semantic memory). This cognitive function is substantiated by the medial temporal lobe (MTL), a hierarchically organized complex in which the perirhinal cortex and parahippocampal cortex provide item and context information to the hippocampus via the entorhinal cortex, and the hippocampus plays the main role in association and recollection. This conventional view provides an easily understood structure to the declarative memory system. However, neurophysiological studies reporting the activities of single neurons bring a more complicated view. In this article, I review single-unit studies, particularly those focused on the perirhinal cortex and hippocampus, and suggest that association processes for declarative memory are more distributed over the MTL areas. The perirhinal cortex represents both between-domain associations (e.g., item-reward, item-place and item-time) and within-domain associations (e.g., item-item) and contributes to both subcategories of declarative memory (i.e., episodic and semantic memory) in a way that is complementary with the hippocampus.
27417054	We sought to examine whether patients with focal epilepsy exhibit sleep dependent memory consolidation, whether memory retention rates correlated with particular aspects of sleep physiology, and how the process was affected by seizures.We prospectively recruited patients with focal epilepsy and assessed declarative memory using a task consisting of 15 pairs of colored pictures on a 5×6 grid. Patients were tested 12h after training, once after 12h of wakefulness and once after 12h that included sleep. EMG chin electrodes were placed to enable sleep scoring. The number and density of sleep spindles were assessed using a wavelet-based algorithm.	Eleven patients were analyzed age 21-56years. The percentage memory retention over 12h of wakefulness was 62.7% and over 12h which included sleep 83.6% (p=0.04). Performance on overnight testing correlated with the duration of slow wave sleep (SWS) (r=+0.63, p<0.05). Three patients had seizures during the day, and 3 had nocturnal seizures. Day-time seizures did not affect retention rates, while those patients who had night time seizures had a drop in retention from an average of 92% to 60.5%.	There is evidence of sleep dependent memory consolidation in patients with epilepsy which mostly correlates with the amount of SWS. Our preliminary findings suggest that nocturnal seizures likely disrupt sleep dependent memory consolidation.	Findings highlight the importance of SWS in sleep dependent memory consolidation and the adverse impact of nocturnal seizures on this process.	
27399159	The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. © 2016 Wiley Periodicals, Inc. 
27397863	Cue reactivity to natural and social rewards is essential for motivational behavior. However, cue reactivity to drug rewards can also elicit craving in addicted subjects. The degree to which drug and natural rewards share neural substrates is not known. The objective of this study is to conduct a comprehensive meta-analysis of neuroimaging studies on drug, gambling and natural stimuli (food and sex) to identify the common and distinct neural substrates of cue reactivity to drug and natural rewards. Neural cue reactivity studies were selected for the meta-analysis by means of activation likelihood estimations, followed by sensitivity and clustering analyses of averaged neuronal response patterns. Data from 176 studies (5573 individuals) suggests largely overlapping neural response patterns towards all tested reward modalities. Common cue reactivity to natural and drug rewards was expressed by bilateral neural responses within anterior cingulate gyrus, insula, caudate head, inferior frontal gyrus, middle frontal gyrus and cerebellum. However, drug cues also generated distinct activation patterns in medial frontal gyrus, middle temporal gyrus, posterior cingulate gyrus, caudate body and putamen. Natural (sexual) reward cues induced unique activation of the pulvinar in thalamus. Neural substrates of cue reactivity to alcohol, drugs of abuse, food, sex and gambling are largely overlapping and comprise a network that processes reward, emotional responses and habit formation. This suggests that cue-mediated craving involves mechanisms that are not exclusive for addictive disorders but rather resemble the intersection of information pathways for processing reward, emotional responses, non-declarative memory and obsessive-compulsive behavior. 
27395443	Apolipoprotein (APOE) ɛ4 genotype has been identified as a risk factor for late-onset Alzheimer disease (AD). The memory system is mostly involved in AD, and memory deficits represent its key feature. A growing body of studies has focused on the earlier identification of cognitive dysfunctions in younger and older APOE ɛ4 carriers, but investigation on middle-aged individuals remains rare. Here we sought to investigate if the APOE ɛ4 genotype modulates declarative memory and its influences on perception in the middle of the life span. We tested 60 middle-aged individuals recruited according to their APOE allele variants (ɛ3/ɛ3, ɛ3/ɛ4, ɛ4/ɛ4) on a long-term memory-based orienting of attention task. Results showed that the APOE ɛ4 genotype impaired neither explicit memory nor memory-based orienting of spatial attention. Interestingly, however, we found that the possession of the ɛ4 allele broke the relationship between declarative long-term memory and memory-guided orienting of visuo-spatial attention, suggesting an earlier modulation exerted by pure genetic characteristics on cognition. These findings are discussed in light of possible accelerated brain ageing in middle-aged ɛ4-carriers, and earlier structural changes in the brain occurring at this stage of the lifespan. 
27391085	Although there is variability in nonnative grammar learning outcomes, the contributions of training paradigm design and memory subsystems are not well understood. To examine this, we presented learners with an artificial grammar that formed words via simple and complex morphophonological rules. Across three experiments, we manipulated training paradigm design and measured subjects' declarative, procedural, and working memory subsystems. Experiment 1 demonstrated that passive, exposure-based training boosted learning of both simple and complex grammatical rules, relative to no training. Additionally, procedural memory correlated with simple rule learning, whereas declarative memory correlated with complex rule learning. Experiment 2 showed that presenting corrective feedback during the test phase did not improve learning. Experiment 3 revealed that structuring the order of training so that subjects are first exposed to the simple rule and then the complex improved learning. The cumulative findings shed light on the contributions of grammatical complexity, training paradigm design, and domain-general memory subsystems in determining grammar learning success. 
27389345	Memory is a dynamic process. While memory becomes increasingly resistant to interference after consolidation, a brief reactivation renders it unstable again. Previous studies have shown that interference, when applied upon reactivation, impairs the consolidated memory, presumably by disrupting the reconsolidation of the memory. However, attempts have failed in disrupting human declarative memory, raising a question about whether declarative memory becomes unstable upon reactivation. Here, we used a double-cue/one-target paradigm, which associated the same target with two different cues in initial memory formation. Only one cue/target association was later reactivated and treated with behavioral interference. Our results showed, for the first time, that reactivation-coupled interference caused cue-independent memory impairment that generalized to other cues associated with the memory. Critically, such memory impairment appeared immediately after interference, before the reconsolidation process was completed, suggesting that common manipulations of reactivation-coupled interference procedures might disrupt other processes in addition to the reconsolidation process in human declarative memory. 
27383152	There is now converging evidence that the declarative memory system (hippocampus dependent) contributes to sequential motor learning in concert with the procedural memory system (striatum dependent). Because of the competition for shared neuronal resources, introducing a declarative memory task can impair learning of a new motor sequence and interference may occur during the procedural consolidation process. Here, we investigated the extent to which interference effects between memory systems are seen at the retrieval phase of skill learning. Healthy participants were assigned to a control (n = 15) or a declarative condition (n = 15) and trained on a sequence of finger movements (FOS task). Both groups showed similar improvement at the end of the practice session on the first day. Twenty-four hours later, controls were tested solely on the FOS task, while subjects in the declarative condition first engaged in a visuospatial task. Additional offline gains in performance were observed only in the control condition. The introduction of a visuospatial memory task just before retrieval of the motor skill was sufficient to eliminate these gains. This suggests that interference between procedural and declarative memory systems may also occur during subsequent motor recall. It is proposed that the interference effects are linked, in part, to the spatial nature of the motor and declarative tasks, which specifically depends upon hippocampal involvement. 
27381076	Sleep-related consolidation of declarative memories, as well as associated neurophysiological events such as slow oscillatory and spindle activity, deteriorate in the course of aging. This process is accelerated in neurodegenerative disease. Transcranial slow oscillatory stimulation (so-tDCS) during sleep has been shown to enhance slow oscillatory brain activity and thereby improve memory consolidation in young subjects. Here, we investigated whether so-tDCS applied to older adults during an afternoon nap exerts similar effects. Eighteen older human subjects were assessed using visuo-spatial (picture memory, primary, and location memory) and verbal memory tasks before and after a 90-min nap either comprising weak so-tDCS at 0.75Hz over fronto-central location or sham (no) stimulation in a within-subject design. Electroencephalographic activity was recorded throughout the naps and immediate effects of stimulation on brain activity were evaluated. Here, spectral power within three frequency bands of interest were computed, i.e., slow oscillatory activity, slow spindle and fast spindle activity; in 1-min stimulation-free intervals following 5 stimulation blocks. So-tDCS significantly increased frontal slow oscillatory activity as well as fast spindle activity, and significantly improved picture memory retention after sleep. Retention in the location memory subtask and in the verbal memory task was not affected. These findings may indicate a novel strategy to counteract cognitive decline in aging in a convenient manner during brief daytime naps.
27375453	The present study is part of a series of experiments, where we analyze why and how damage of the rat's dorsal hippocampus (dHC) can enhance performance in a sequential reaction time task (SRTT). In this task, sequences of distinct visual stimulus presentations are food-rewarded in a fixed-ratio-13-schedule. Our previous study (Busse and Schwarting, 2016) had shown that rats with lesions of the dHC show substantially shorter session times and post-reinforcement pauses (PRPs) than controls, which allows for more practice when daily training is kept constant. Since sequential behavior is based on instrumental performance, a sequential benefit might be secondary to that. In order to test this hypothesis in the present study, we performed two experiments, where pseudorandom rather than sequential stimulus presentation was used in rats with excitotoxic dorsal hippocampal lesions. Again, we found enhanced performance in the lesion-group in terms of shorter session times and PRPs. During the sessions we found that the lesion-group spent less time with non-instrumental behavior (i.e., grooming, sniffing, and rearing) after prolonged instrumental training. Also, such rats showed moderate evidence for an extinction impairment under devalued food reward conditions and significant deficits in a response-outcome (R-O)-discrimination task in comparison to a control-group. These findings suggest that facilitatory effects on instrumental performance after dorsal hippocampal lesions may be primarily a result of complex behavioral changes, i.e., reductions of behavioral flexibility and/or alterations in motivation, which then result in enhanced instrumental learning. 
27355834	Physical and psychosocial rehabilitation following spinal cord injury (SCI) leans heavily on learning and practicing new skills. However, despite research relating motor sequence learning to spinal cord activity and clinical observations of impeded skill-learning after SCI, implicit procedural learning following spinal cord damage has not been examined.To test the hypothesis that spinal cord injury (SCI) in the absence of concomitant brain injury is associated with a specific implicit motor sequence learning deficit that cannot be explained by depression or impairments in other cognitive measures.	Ten participants with SCI in T1-T11, unharmed upper limb motor and sensory functioning, and no concomitant brain injury were compared to ten matched control participants on measures derived from the serial reaction time (SRT) task, which was used to assess implicit motor sequence learning. Explicit generation of the SRT sequence, depression, and additional measures of learning, memory, and intelligence were included to explore the source and specificity of potential learning deficits.	There was no between-group difference in baseline reaction time, indicating that potential differences between the learning curves of the two groups could not be attributed to an overall reduction in response speed in the SCI group. Unlike controls, the SCI group showed no decline in reaction time over the first six blocks of the SRT task and no advantage for the initially presented sequence over the novel interference sequence. Meanwhile, no group differences were found in explicit learning, depression, or any additional cognitive measures.	The dissociation between impaired implicit learning and intact declarative memory represents novel empirical evidence of a specific implicit procedural learning deficit following SCI, with broad implications for rehabilitation and adjustment.	
27354098	Long-term declarative memory depends on pattern separation and pattern completion to maintain memory specificity. Previous studies aimed at evaluating the underlying neuronal substrates of these computational processes have used a mnemonic discrimination paradigm and functional magnetic resonance imaging (fMRI). An alternative method is electroencephalography and event-related potentials (ERPs), which have a superior time resolution to fMRI. Here, we use ERP analysis to examine neuronal activity during performance of a mnemonic discrimination task. We examined both the late positive component and FN400 components, which have previously been shown to demonstrate an old-new effect. We hypothesized that pattern separation processes would be reflected in correct rejection of similar lures while pattern completion processes would be reflected in falsely categorizing lures as repeated. We did not observe differences between the ERPs associated with these two processes.
27343998	Apart from its function in speech motor control, the supplementary motor area (SMA) has largely been neglected in models of speech and language processing in the brain. The aim of this review paper is to summarize more recent work, suggesting that the SMA has various superordinate control functions during speech communication and language reception, which is particularly relevant in case of increased task demands. The SMA is subdivided into a posterior region serving predominantly motor-related functions (SMA proper) whereas the anterior part (pre-SMA) is involved in higher-order cognitive control mechanisms. In analogy to motor triggering functions of the SMA proper, the pre-SMA seems to manage procedural aspects of cognitive processing. These latter functions, among others, comprise attentional switching, ambiguity resolution, context integration, and coordination between procedural and declarative memory structures. Regarding language processing, this refers, for example, to the use of inner speech mechanisms during language encoding, but also to lexical disambiguation, syntax and prosody integration, and context-tracking. 
27341028	Choline is a dietary component and precursor of acetylcholine, a crucial neurotransmitter for memory-related brain functions. In two double-blind, placebo-controlled cross-over experiments, we investigated whether the food supplement choline bitartrate improved declarative memory and working memory in healthy, young students one to two hours after supplementation. In experiment 1, 28 participants performed a visuospatial working memory task. In experiment 2, 26 participants performed a declarative picture memorization task. In experiment 3, 40 participants performed a verbal working memory task in addition to the visuospatial working memory and declarative picture task. All tasks were conducted approximately 60 minutes after the ingestion of 2.0-2.5g of either choline bitartrate or placebo. We found that choline did not significantly enhance memory performance during any of the tasks. The null hypothesis that choline does not improve memory performance as compared to placebo was strongly supported by Bayesian statistics. These results are in contrast with animal studies suggesting that choline supplementation boosts memory performance and learning. We conclude that choline likely has no acute effects on cholinergic memory functions in healthy human participants. 
27339012	Numerical cognition relies on interactions within and between multiple functional brain systems, including those subserving quantity processing, working memory, declarative memory, and cognitive control. This chapter describes recent advances in our understanding of memory and control circuits in mathematical cognition and learning. The working memory system involves multiple parietal-frontal circuits which create short-term representations that allow manipulation of discrete quantities over several seconds. In contrast, hippocampal-frontal circuits underlying the declarative memory system play an important role in formation of associative memories and binding of new and old information, leading to the formation of long-term memories that allow generalization beyond individual problem attributes. The flow of information across these systems is regulated by flexible cognitive control systems which facilitate the integration and manipulation of quantity and mnemonic information. The implications of recent research for formulating a more comprehensive systems neuroscience view of the neural basis of mathematical learning and knowledge acquisition in both children and adults are discussed. 
27321589	Sleep may play a role in consolidating emotional memories. However, studies on the effects of REM sleep on negative vs. neutral memories have produced inconsistent evidence. Here, we assess the role of NREM and REM sleep before and after learning in promoting the consolidation of neutral and arousing pleasant and unpleasant memories. Forty-six (32 F) healthy university students were exposed to a set of pictures at 1:00PM (Session 1) and to an equivalent set at 4:45PM (Session 2). All the pictures in Session 1 and Session 2 were presented again, intermixed with new similar pictures at 5:15PM in a memory recognition task. Following Session 1, participants took a 90/120-min nap (NAP group), while 16 participants remained awake (WAKE group). Via polysomnographic recording, the NAP group was segregated into REM (N=14) and NoREM groups (N=16). Indices of memory consolidation for both stimuli presented before (discriminability of Session 1 pictures in Session 3) and after sleep (discriminability of Session 2 pictures in Session 3) were calculated. Memory consolidation for pictures presented both before and after the sleep period was higher in the NAP group as compared to the WAKE group, but no differential role of REM sleep emerged. A memory consolidation advantage was evident for neutral over pleasant (but not unpleasant) pictures. Taken together, these results indicate that a daytime nap (with or without REM sleep) facilitates consolidation of declarative memories presented before and after sleep irrespective of their valence. 
27318231	Acoustic stimulation synchronized to slow waves (SWs) can enhance these sleep features and facilitate memory consolidation during nocturnal sleep. Here, we investigated whether a similar benefit could be accrued following stimulation during an afternoon nap. We also evaluated the event-related dynamics of associated EEG spectral changes and their correlation with memory performance.Sixteen healthy young adults (mean age: 22 ± 1.4 years; nine males) were studied under two conditions: stimulation (STIM) and no stimulation (SHAM), in counter-balanced order. In the STIM condition, acoustic stimulation was delivered using blocks of five tones, each phase-locked to the SW up-state during a 90-min nap opportunity. In the SHAM condition, these time points were marked, but tones were not presented. Prior to the nap, participants learned 40 semantically related word pairs and immediate recall was tested. A delayed recall test was administered 45 min after awakening.	Compared to the SHAM condition, acoustic stimulation increased SW amplitude, theta, and fast spindle activity and attenuated the forgetting of word pairs (p values < 0.05).	Phase-locked acoustic stimulation can promote sleep-dependent declarative memory during a daytime nap. This can be achieved by stimulation in Stage 2 and SWS without a requirement for high-amplitude slow wave detection.	
27315433	Theoretical and empirical studies of memory have long been framed by a distinction between declarative and non-declarative memory. We question the sharpness of the distinction by reporting evidence from amnesic L.S.J., who despite retrograde memory losses in declarative knowledge domains, shows sparing of declarative knowledge related to premorbid skill (e.g., playing an instrument). We previously showed that L.S.J. had severe losses of retrograde declarative knowledge across areas of premorbid expertise (e.g., artists of famous works) and everyday knowledge (e.g., company names for logos). Here we present evidence that L.S.J. has sparing of what we call skill-related declarative knowledge, in four domains in which she had premorbid skill (art, music, aviation, driving). L.S.J.'s pattern of loss and sparing raises questions about the strict separation between classically-defined memory types and aligns with a recent proposal by Stanley and Krakauer [2013. Motor skill depends on knowledge of facts. Frontiers in Human Neuroscience, 7,1-11].
27311899	To determine whether an elevated fetal umbilical artery Doppler (UAD) pulsatility index (PI) at 28 weeks' gestation, in the absence of fetal growth restriction (FGR) and prematurity, is associated with adverse neurocognitive outcome in children aged 12 years.Prospective cohort study, comparing children with a normal fetal UAD PI (<90th centile) (n=110) and those with an elevated PI (≥90th centile) (n=40). UAD was performed at 28, 32 and 34 weeks gestation. At 12 years of age, all children were assessed under standardised conditions at Queen's University, Belfast, UK to determine cognitive and behavioural outcomes using the British Ability Score-II and Achenbach Child Behavioural Checklist Parent Rated Version under standardised conditions. Regression analysis was performed, controlling for confounders such as gender, socioeconomic status and age at assessment.	The mean age of follow-up was 12.4 years (±0.5 SD) with 44% of children male (n=63). When UAD was assessed at 28 weeks, the elevated fetal UAD group had lower scores in cognitive assessments of information processing and memory. Parameters included (1) recall of objects immediate verbal (p=0.002), (2) delayed verbal (p=0.008) and (3) recall of objects immediate spatial (p=0.0016). There were no significant differences between the Doppler groups at 32 or 34 weeks' gestation.	An elevated UAD PI at 28 weeks' gestation in the absence of FGR or prematurity is associated with lower scores of declarative memory in children aged 12 years. A potential explanation for this is an element of placental insufficiency in the presence of the appropriately grown fetus, which affects the development of the fetal hippocampus and information processing and memory long-term. These findings, however, had no impact on overall academic ability, mental processing and reasoning or overall behavioural function.	
27306680	Weight predictions used to scale lifting forces adapt quickly when repeatedly lifting unusually weighted objects and are readily updated by explicit information provided about weight. In contrast, weight predictions used when making perceptual judgments about weight are more resistant to change and are largely unaffected by explicit information about weight. These observations suggest that distinct memory systems underlie weight prediction when lifting objects and judging their weights. Here we examined whether these weight predictions differ in their reliance on declarative and nondeclarative memory resources by comparing the adaptability of these predictions in older adults, who exhibit relatively impaired declarative memory processes, to those in younger adults. In the size condition, we measured lift forces as participants repeatedly lifted a pair of size-weight inverted objects in alternation. To assess weight judgments, we measured the size-weight illusion every 10 lifts. The material condition was similar, except that we used material-weight inverted objects and measured the material-weight illusion. The strengths of these illusions prior to lifting, and the attenuation of the illusions that arise when lifting inverted objects, were similar for both groups. The magnitude of the change in the illusions was positively correlated with implicit memory performance in both groups, suggesting that predictions used when judging weight rely on nondeclarative memory resources. Updating of lifting forces also did not differ between groups. However, within the older group the success with which lifting forces were updated was positively correlated with working memory performance, suggesting that weight predictions used when lifting rely on declarative memory resources. 
27303346	A fundamental question in psycholinguistic theory is whether equivalent success in sentence comprehension may come about by different underlying operations. Of special interest is whether adult aging, especially when accompanied by reduced hearing acuity, may shift the balance of reliance on formal syntax vs. plausibility in determining sentence meaning. In two experiments participants were asked to identify the thematic roles in grammatical sentences that contained either plausible or implausible semantic relations. Comprehension of sentence meanings was indexed by the ability to correctly name the agent or the recipient of an action represented in the sentence. In Experiment 1 young and older adults' comprehension was tested for plausible and implausible sentences with the meaning expressed with either an active-declarative or a passive syntactic form. In Experiment 2 comprehension performance was examined for young adults with age-normal hearing, older adults with good hearing acuity, and age-matched older adults with mild-to-moderate hearing loss for plausible or implausible sentences with meaning expressed with either a subject-relative (SR) or an object-relative (OR) syntactic structure. Experiment 1 showed that the likelihood of interpreting a sentence according to its literal meaning was reduced when that meaning expressed an implausible relationship. Experiment 2 showed that this likelihood was further decreased for OR as compared to SR sentences, and especially so for older adults whose hearing impairment added to the perceptual challenge. Experiment 2 also showed that working memory capacity as measured with a letter-number sequencing task contributed to the likelihood that listeners would base their comprehension responses on the literal syntax even when this processing scheme yielded an implausible meaning. Taken together, the results of both experiments support the postulate that listeners may use more than a single uniform processing strategy for successful sentence comprehension, with the existence of these alternative solutions only revealed when literal syntax and plausibility do not coincide. 

27291639	As chronic sleep restriction is a widespread problem among adolescents, the present study investigated the effects of a 1-week sleep restriction (SR) versus control period on the consolidation of long-term memory for prose passages. We also determined whether the benefit of prioritization on memory is modulated by adequate sleep occurring during consolidation. Fifty-six healthy adolescents (25 male, aged 15-19 years) were instructed to remember a prose passage in which half of the content was highlighted (prioritized), and were told that they would receive an additional bonus for remembering highlighted content. Following an initial free recall test, participants underwent a 7-night period in which they received either a 5-h (SR) or 9-h (control) nightly sleep opportunity, monitored by polysomnography on selected nights. Free recall of the passage was tested at the end of the sleep manipulation period (1 week after encoding), and again 6 weeks after encoding. Recall of highlighted content was superior to that of non-highlighted content at all three time-points (initial, 1 week, 6 weeks). This beneficial effect of prioritization on memory was stronger 1 week relative to a few minutes after encoding for the control, but not the SR group. N3 duration was similar in the control and SR groups. Overall, the present study shows that the benefits of prioritization on memory are enhanced over time, requiring time and sleep to unfold fully. Partial sleep deprivation (i.e. 5-h nocturnal sleep opportunity) may attenuate such benefits, but this may be offset by preservation of N3 sleep duration.
27266967	There are large individual differences in age-related cognitive decline. Hypothalamic-pituitary-adrenal axis (HPA-axis) functioning has been suggested as one of the mechanisms underlying these differences. This study aimed to investigate the relationships between the diurnal cortisol cycle, measured as the cortisol awakening response (CAR), and the diurnal cortisol slope (DCS) and the memory performance of healthy older people. To do so, we assessed the verbal, visual, and working memory performance of 64 participants (32 men) from 57 to 76 years old who also provided 14 saliva samples on two consecutive weekdays to determine their diurnal cortisol cycle. The CAR was linearly and negatively associated with verbal (significantly) and visual (marginally) memory domains, but not with working memory. Sex did not moderate these relationships. Furthermore, no associations were found between the DCS and any of the three memory domains assessed. Our results indicate that the two components of the diurnal cortisol cycle have different relationships with memory performance, with the CAR being more relevant than DCS in understanding the link from HPA-axis activity and regulation to different types of memory. These results suggest that the CAR is related to memory domains dependent on hippocampal functioning (i.e., declarative memory), but not to those that are more dependent on prefrontal cortex functioning (i.e., working memory). 
27253768	The ability to recall facts is improved when learning takes place at spaced intervals, or when sleep follows shortly after learning. However, many students cram for exams and trade sleep for other activities. The aim of this study was to examine the interaction of study spacing and time in bed (TIB) for sleep on vocabulary learning in adolescents.In the Need for Sleep Study, which used a parallel-group design, 56 adolescents aged 15-19 years were randomly assigned to a week of either 5 h or 9 h of TIB for sleep each night as part of a 14-day protocol conducted at a boarding school. During the sleep manipulation period, participants studied 40 Graduate Record Examination (GRE)-type English words using digital flashcards. Word pairs were presented over 4 consecutive days (spaced items), or all at once during single study sessions (massed items), with total study time kept constant across conditions. Recall performance was examined 0 h, 24 h, and 120 h after all items were studied.	For all retention intervals examined, recall of massed items was impaired by a greater amount in adolescents exposed to sleep restriction. In contrast, cued recall performance on spaced items was similar between sleep groups.	Spaced learning conferred strong protection against the effects of sleep restriction on recall performance, whereas students who had insufficient sleep were more likely to forget items studied over short time intervals. These findings in adolescents demonstrate the importance of combining good study habits and good sleep habits to optimize learning outcomes.	
27247261	Previous studies have demonstrated an enhancement of hippocampal-dependent declarative memory consolidation, associated slow wave sleep (SWS) and slow wave activity (SWA) after weak slow oscillatory stimulation (so-tDCS) during early non-rapid eye movement sleep (NREM) in young adults. Recent studies in older individuals could not confirm these findings. However, it remained unclear if this difference was due to variations in study protocol or to the age group under study.Here, we asked if so-tDCS promotes neurophysiological events and associated sleep-dependent memory in the visuo-spatial domain in older adults, using a stimulation protocol that closely resembled the one employed in young adults.	In a randomized, placebo-controlled single-blind (participant) crossover study so-tDCS (0.75 Hz; max. current density 0.522 mA/cm(2)) vs. sham stimulation was applied over the frontal cortex of 21 healthy older subjects. Impact of stimulation on frequency band activity (linear mixed models), two declarative and one procedural memory tasks (repeated measures ANOVA) and percentage of sleep stages (comparison of means) was assessed.	so-tDCS, as compared to sham, increased SWA and spindle activity immediately following stimulation, accompanied by significantly impaired visuo-spatial memory consolidation. Furthermore, verbal and procedural memory remained unchanged, while percentage of NREM sleep stage 4 was decreased over the entire night (uncorrected).	so-tDCS increased SWA and spindle activity in older adults, events previously associated with stimulation-induced improved consolidation of declarative memories in young subjects. However, consolidation of visuo-spatial (primary outcome) and verbal memories was not beneficially modulated, possibly due to decline in SWS over the entire night that may have prevented and even reversed immediate beneficial effects of so-tDCS on SWA.	
27242414	The purpose of this study was to determine whether exposure to specific auditory sequences leads to the induction of new motor memories and to investigate the role of the dorsal premotor cortex (dPMC) in this crossmodal learning process. Fifty-two young healthy non-musicians were familiarized with the sound to key-press mapping on a computer keyboard and tested on their baseline motor performance. Each participant received subsequently either continuous theta burst stimulation (cTBS) or sham stimulation over the dPMC and was then asked to remember a 12-note melody without moving. For half of the participants, the contour of the melody memorized was congruent to a subsequently performed, but never practiced, finger movement sequence (Congruent group). For the other half, the melody memorized was incongruent to the subsequent finger movement sequence (Incongruent group). Hearing a congruent melody led to significantly faster performance of a motor sequence immediately thereafter compared to hearing an incongruent melody. In addition, cTBS speeded up motor performance in both groups, possibly by relieving motor consolidation from interference by the declarative melody memorization task. Our findings substantiate recent evidence that exposure to a movement-related tone sequence can induce specific, crossmodal encoding of a movement sequence representation. They further suggest that cTBS over the dPMC may enhance early offline procedural motor skill consolidation in cognitive states where motor consolidation would normally be disturbed by concurrent declarative memory processes. These findings may contribute to a better understanding of auditory-motor system interactions and have implications for the development of new motor rehabilitation approaches using sound and non-invasive brain stimulation as neuromodulatory tools. 
27217115	A large body of evidence in animals and humans implicates the amygdala in promoting memory for arousing experiences. Although the amygdala can trigger threat-related noradrenergic-sympathetic arousal, in humans amygdala activation and noradrenergic-sympathetic arousal do not always concur. This raises the question how these two processes play a role in enhancing emotional declarative memory. This study was designed to disentangle these processes in a combined subsequent-memory/fear-conditioning paradigm with neutral items belonging to two conceptual categories as conditioned stimuli. Functional MRI, skin conductance (index of sympathetic activity), and pupil dilation (indirect index of central noradrenergic activity) were acquired throughout procedures. Recognition memory for individual items was tested 24 h later. We found that pupil dilation and skin conductance responses were higher on CS+ (associated with a shock) compared with CS- trials, irrespective of later memory for those items. By contrast, amygdala activity was only higher for CS+ items that were later confidently remembered compared with CS+ items that were later forgotten. Thus, amygdala activity and not noradrenergic-sympathetic arousal, predicted enhanced declarative item memory. This dissociation is in line with animal models stating that the amygdala integrates arousal-related neuromodulatory changes to alter mnemonic processes elsewhere in the brain. 
27191180	Obstructive sleep apnea is associated with memory impairments, and higher rates of depressive symptoms and major depressive disorder compared with community estimates. Autobiographical memory overgenerality, a behaviour characterized by difficulty recalling specific memories from one's own life, is recognized as a marker of depression. Previous studies have demonstrated the predictive quality of specific autobiographical memory recall on the course of depression in patients with obstructive sleep apnea. However, it remains unclear whether impaired autobiographical memory is simply a feature of depression, or whether it is also impaired in patients with obstructive sleep apnea without depression. This study aimed to investigate whether autobiographical memory impairments can be observed in patients with obstructive sleep apnea, independent of the severity of depressive symptoms. Twenty-one patients with obstructive sleep apnea symptomatic for depressive symptoms (mean age = 43.43 years, SD = 9.97), 17 patients with obstructive sleep apnea asymptomatic for depressive symptoms (mean age = 40.65 years, SD = 9.39), and 20 healthy controls without sleep-disordered breathing (mean age = 32.80 years, SD = 6.69) completed an Autobiographical Memory Test. Patients with obstructive sleep apnea symptomatic for depressive symptoms recalled significantly fewer specific memories when compared with healthy controls (P = 0.010). No difference in the recall of specific autobiographical memory was observed between symptomatic and asymptomatic patients with obstructive sleep apnea. With regard to valence, symptomatic patients with obstructive sleep apnea recalled significantly fewer negative specific memories when compared with controls (P = 0.010). Impairment in specific autobiographical memory recall can be observed in patients with obstructive sleep apnea, regardless of the severity of depressive symptoms; however, this effect may not be as prominent in younger patients with obstructive sleep apnea.
27114514	Reconsolidation theory proposes that retrieval can destabilize an existing memory trace, opening a time-dependent window during which that trace is amenable to modification. Support for the theory is largely drawn from nonhuman animal studies that use invasive pharmacological or electroconvulsive interventions to disrupt a putative postretrieval restabilization ("reconsolidation") process. In human reconsolidation studies, however, it is often claimed that postretrieval new learning can be used as a means of "updating" or "rewriting" existing memory traces. This proposal warrants close scrutiny because the ability to modify information stored in the memory system has profound theoretical, clinical, and ethical implications. The present study aimed to replicate and extend a prominent 3-day motor-sequence learning study [Walker MP, Brakefield T, Hobson JA, Stickgold R (2003) Nature 425(6958):616-620] that is widely cited as a convincing demonstration of human reconsolidation. However, in four direct replication attempts (n = 64), we did not observe the critical impairment effect that has previously been taken to indicate disruption of an existing motor memory trace. In three additional conceptual replications (n = 48), we explored the broader validity of reconsolidation-updating theory by using a declarative recall task and sequences similar to phone numbers or computer passwords. Rather than inducing vulnerability to interference, memory retrieval appeared to aid the preservation of existing sequence knowledge relative to a no-retrieval control group. These findings suggest that memory retrieval followed by new learning does not reliably induce human memory updating via reconsolidation.
27109918	Sleep promotes memory, particularly for declarative learning. However, its role in non-declarative, emotional memories is less well understood. Some studies suggest that sleep may influence fear-related memories, and thus may be an important factor determining the outcome of treatments for emotional disorders such as post-traumatic stress disorder. Here, we investigated the effect of sleep deprivation and time of day on fear extinction memory consolidation. Mice were subjected to a cued Pavlovian fear and extinction paradigm at the beginning of their resting or active phase. Immediate post-extinction learning sleep deprivation for 5h compromised extinction memory when tested 24h after learning. Context-dependent extinction memory recall was completely prevented by sleep-manipulation during the resting phase, while impairment was milder during the active phase and extinction memory retained its context-specificity. Importantly, control experiments excluded confounding factors such as differences in baseline locomotion, fear generalization and stress hormone levels. Together, our findings indicate that post-learning sleep supports cued fear extinction memory consolidation in both circadian phases. The lack of correlation between memory efficacy and sleep time suggests that extinction memory may be influenced by specific sleep events in the early consolidation period. 
27094721	Despite advances in individual and combined treatments for major depression, issues with non-response and partial-response remain relatively common, motivating the search for new treatment strategies. This study aims to develop one such novel treatment. In this proof-of-concept study, we are investigating whether the treatment enhancing effects of d-cycloserine (DCS) administration can be extended outside the extinction-learning paradigms where they have been primarily examined. Using uniform delivery of cognitive behavioral therapy (CBT) content via computer-administered interventions for depression, we are assessing the value of pre-session administrations of DCS for retention of therapeutic learning. Recall of this information is evaluated in conjunction with performance on standardized tests of memory recall with both emotional and non-emotional stimuli. Specifically, in a randomized, double-blind trial we will compare the benefits of two pre-session administrations of DCS augmentation to those achieved by similar administrations of modafinil or placebo. Because modafinil is associated with a number of discriminable effects in addition to cognitive enhancement (e.g., feelings of vigor, alertness, positive mood); whereas these effects would not be expected with DCS, we will assess drug context effects in relation to memory augmentation effects. 
27072418	Caring for children diagnosed with a chronic psychological disorder such as an eating disorder (ED) can be used as a model of chronic stress. This kind of stress has been reported to have deleterious effects on caregivers' cognition, particularly in verbal declarative memory of women caregivers. Moreover, high depressive mood and variations in testosterone (T) levels moderate this cognitive decline. The purpose of this study was to characterize whether caregivers of individuals with EDs (n = 27) show declarative memory impairments compared to non-caregivers caregivers (n = 27), using for this purpose a standardized memory test (Rey's Auditory Verbal Learning Test). Its purpose was also to examine the role of depressive mood and T in memory decline. Results showed that ED caregivers presented high depressive mood, which was associated to worse verbal memory performance, especially in the case of women. In addition, all caregivers showed high T levels. Nonetheless, only in the case of women caregivers did T show a curvilinear relationship with verbal memory performance, meaning that the increases of T were associated to the improvement in verbal memory performance, but only up to a certain point, as after such point T continued to increase and memory performance decreased. Thus, chronic stress due to caregiving was associated to disturbances in mood and T levels, which in turn was associated to verbal memory decline. These findings should be taken into account in the implementation of intervention programs for helping ED caregivers cope with caregiving situations and to prevent the risk of a pronounced verbal memory decline. 
27066987	Electrical stimulation of the brain is a unique tool to perturb endogenous neural signals, allowing us to evaluate the necessity of given neural processes to cognitive processing. An important issue, gaining increasing interest in the literature, is whether and how stimulation can be employed to selectively improve or disrupt declarative memory processes. Here, we provide a comprehensive review of both invasive and non-invasive stimulation studies aimed at modulating memory performance. The majority of past studies suggest that invasive stimulation of the hippocampus impairs memory performance; similarly, most non-invasive studies show that disrupting frontal or parietal regions also impairs memory performance, suggesting that these regions also play necessary roles in declarative memory. On the other hand, a handful of both invasive and non-invasive studies have also suggested modest improvements in memory performance following stimulation. These studies typically target brain regions connected to the hippocampus or other memory "hubs," which may affect endogenous activity in connected areas like the hippocampus, suggesting that to augment declarative memory, altering the broader endogenous memory network activity is critical. Together, studies reporting memory improvements/impairments are consistent with the idea that a network of distinct brain "hubs" may be crucial for successful memory encoding and retrieval rather than a single primary hub such as the hippocampus. Thus, it is important to consider neurostimulation from the network perspective, rather than from a purely localizationalist viewpoint. We conclude by proposing a novel approach to neurostimulation for declarative memory modulation that aims to facilitate interactions between multiple brain "nodes" underlying memory rather than considering individual brain regions in isolation. 
27046022	We examined the role of sleep-related memory consolidation processes in learning new form-meaning mappings. Specifically, we examined a Complementary Learning Systems account, which implies that sleep-related consolidation should be more beneficial for new hippocampally dependent arbitrary mappings (e.g. new vocabulary items) relative to new systematic mappings (e.g. grammatical regularities), which can be better encoded neocortically. The hypothesis was tested using a novel language with an artificial grammatical gender system. Stem-referent mappings implemented arbitrary aspects of the new language, and determiner/suffix+natural gender mappings implemented systematic aspects (e.g. tib scoiffesh + ballerina, tib mofeem + bride; ked jorool + cowboy, ked heefaff + priest). Importantly, the determiner-gender and the suffix-gender mappings varied in complexity and salience, thus providing a range of opportunities to detect beneficial effects of sleep for this type of mapping. Participants were trained on the new language using a word-picture matching task, and were tested after a 2-hour delay which included sleep or wakefulness. Participants in the sleep group outperformed participants in the wake group on tests assessing memory for the arbitrary aspects of the new mappings (individual vocabulary items), whereas we saw no evidence of a sleep benefit in any of the tests assessing memory for the systematic aspects of the new mappings: Participants in both groups extracted the salient determiner-natural gender mapping, but not the more complex suffix-natural gender mapping. The data support the predictions of the complementary systems account and highlight the importance of the arbitrariness/systematicity dimension in the consolidation process for declarative memories. 
27039143	Behavioral evidence shows that sleep is crucial for the consolidation of declarative memories in children as in adults. However, the underlying cerebral mechanisms remain virtually unexplored. Using magnetoencephalography, we investigated in children (8.0-12.5years) the impact of sleep (90-minute nap) on the neurophysiological processes underlying the creation and consolidation of novel associations between unknown objects and their functions. Learning-dependent changes in brain activity were observed within hippocampal and parahippocampal regions, followed by sleep-dependent changes in the prefrontal cortex, whereas no equivalent change was observed after a similar period of wakeful rest. Hence, our results show that in school-age children a 90-minute daytime nap after learning is sufficient to trigger the reorganization of memory-related brain activity toward prefrontal areas, where it incorporates into pre-existing semantic knowledge. This functional reorganization process in children is similar to that observed in adults but occurs at a much faster rate, which may contribute to the development of the impressive learning skills that characterize childhood. 
27038677	Because estrogens have mostly been studied in gonadectomized females, effects of chronic exposure to environmental estrogens in the general population are underestimated. Estrogens can enhance hippocampus-dependent memory through the modulation of information storage. However, declarative memory, the hippocampus-dependent memory of facts and events, demands more than abilities to retain information. Specifically, memory of repetitive events of everyday life such as "where I parked" requires abilities to organize/update memories to prevent proactive interference from similar memories of previous "parking events". Whether such organizational processes are estrogen-sensitive is unknown. We here studied, in intact young and aged adult mice, drinking-water (1μM) estradiol effects on both retention and organizational components of hippocampus-dependent memory, using a radial-maze task of everyday-like memory. Demand on retention vs organization was manipulated by varying the time-interval separating repetitions of similar events. Estradiol increased performance in young and aged mice under minimized organizational demand, but failed to improve the age-associated memory impairment and diminished performance in young mice under high organizational demand. In fact, estradiol prolonged mnemonic retention of successive events without improving organization abilities, hence resulted in more proactive interference from irrelevant memories. c-Fos imaging of testing-induced brain activations showed that the deterioration of young memory was associated with dentate gyrus dysconnectivity, reminiscent of that seen in aged mice. Our findings support the view that estradiol is promnesic but also reveal that such property can paradoxically impair memory. These findings have important outcomes regarding health issues relative to the impact of environmental estrogens in the general population. 
27021017	Sleep has previously been claimed to be essential for the continued learning processes of declarative information as well as procedural learning. This study was conducted to examine the importance of sleep, especially the effects of midday naps, on motor sequence and visuomotor adaptation learning. Thirty-five (27 females) healthy, young adults aged between 18 and 30years of age participated in the current study. Addressing potential differences in explicit sequence and motor adaptation learning participants were asked to learn both, a nine-element explicit sequence and a motor adaptation task, in a crossover fashion on two consecutive days. Both tasks were performed with their non-dominant left hand. Prior to learning, each participant was randomized to one of three interventions; (1) power nap: 10-20min sleep, (2) long nap: 50-80min sleep or (3) a 45-min wake-condition. Performance of the motor learning task took place prior to and after a midday rest period, as well as after a night of sleep. Both sleep conditions were dominated by Stage N2 sleep with embedded sleep spindles, which have been described to be associated with enhancement of motor performance. Significant performance changes were observed in both tasks across all interventions (sleep and wake) confirming that learning took place. In the present setup, the magnitude of motor learning was not sleep-dependent in young adults - no differences between the intervention groups (short nap, long nap, no nap) could be found. The effect of the following night of sleep was not influenced by the previous midday rest or sleep period. This finding may be related to the selectiveness of the human brain enhancing especially memory being thought of as important in the future. Previous findings on motor learning enhancing effects of sleep, especially of daytime sleep, are challenged. 
27013683	Age-related memory impairments have been associated with structural changes in the dopaminergic system, but the underlying mechanisms remain unclear. Recent work indicates that iron accumulation might be of particular relevance. As iron accumulates, a degeneration of myelin sheaths has been observed in the elderly, but the relationship between both and their impact on memory performance in healthy elderly humans remain important open questions. To address this issue, we combined an established behavioral paradigm to test memory performance [verbal learning memory test (VLMT)] with state of the art quantitative magnetic resonance imaging techniques allowing us to quantify the degree of myelination and iron accumulation via markers of tissue microstructure in a group of young (18-32 years) and healthy elderly humans (55-79 years). As expected, we observed a decrease in gray matter volume and myelin, and an increase of iron in the elderly relative to the young subjects within widespread brain regions, including the basal ganglia. Furthermore, higher levels of iron within the ventral striatum were accompanied by a negative correlation between myelin and iron specific for the elderly participants. Importantly, both markers of iron and myelin (and their ratio) predicted the performance of the elderly in the VLMT. This suggests that ventral striatum iron accumulation is linked to demyelination and impairments in declarative memory. Together, our data provide novel insights into underlying microstructural mechanisms of memory decline in the elderly.Memory decline in healthy elderly is a common phenomenon, but the underlying neural mechanisms remain unclear. We used a novel approach that allowed us to combine behavior and whole-brain measures of iron, myelin, and gray matter in the participant's individual subspace to analyze structure-structure and structure-behavior interactions. We were able to show, that age-related high levels of iron are accompanied by a negative correlation of iron and myelin in the ventral striatum, which predicted individual memory performance. As such, our findings provide unprecedented insights into the basic mechanisms of memory decline in the elderly.	
27010751	Creativity relies on a diverse set of cognitive processes associated with distinct neural correlates, and one important aspect of creativity, divergent thinking, has been associated with the hippocampus. However, hippocampal contributions to another important aspect of creativity, convergent problem solving, have not been investigated. We tested the necessity of hippocampus for convergent problem solving using a neuropsychological method. Participants with amnesia due to hippocampal damage (N = 5) and healthy normal comparison participants (N = 5) were tested using a task that promoted solutions based on existing knowledge (Bowden and Jung-Beeman, 2003). During each trial, participants were given a list of three words (e.g., fly, man, place) and asked to respond with a word that could be combined with each of the three words (e.g., fire). The amnesic group produced significantly fewer correct responses than the healthy comparison group. These findings indicate that the hippocampus is necessary for normal convergent problem solving and that changes in the status of the hippocampus should affect convergent problem solving in the context of creative problem-solving across short intervals. This proposed contribution of the hippocampus to convergent problem solving is consistent with an expanded perspective on hippocampal function that acknowledges its role in cognitive processes beyond declarative memory. © 2016 Wiley Periodicals, Inc. 
27003830	Past research has demonstrated links between cortical activity, measured via EEG power, and cognitive processes during infancy. In a separate line of research, family socioeconomic status (SES) has been strongly associated with children's early cognitive development, with socioeconomic disparities emerging during the second year of life for both language and declarative memory skills. The present study examined associations among resting EEG power at birth, SES, and language and memory skills at 15-months in a sample of full-term infants. Results indicate no associations between SES and EEG power at birth. However, EEG power at birth was related to both language and memory outcomes at 15-months. Specifically, frontal power (24-48Hz) was positively correlated with later Visual Paired Comparison (VPC) memory scores. Power (24-35Hz) in the parietal region was positively correlated with later PLS-Auditory Comprehension language scores. These findings suggest that SES disparities in brain activity may not be apparent at birth, but measures of resting neonatal EEG power are correlated with later memory and language skills independently of SES. 
26991776	Consolidated memories return to a labile state after the presentation of cues (reminders) associated with acquisition, followed by a period of stabilization (reconsolidation). However not all cues are equally effective in initiating the process, unpredictable cues triggered it, predictable cues do not. We hypothesize that the different effects observed by the different reminder types on memory labilization-reconsolidation depend on a differential neural involvement during reminder presentation. To test it, we developed a declarative task and compared the efficacy of three reminder types in triggering the process in humans (Experiment 1). Finally, we compared the brain activation patterns between the different conditions using functional magnetic resonance imaging (fMRI) (Experiment 2). We confirmed that the unpredictable reminder is the most effective in initiating the labilization-reconsolidation process. Furthermore, only under this condition there was differential left hippocampal activation during its presentation. We suggest that the left hippocampus is detecting the incongruence between actual and past events and allows the memory to be updated. 
26981787	The memory profile of individuals with Down syndrome (DS) has mainly been examined through traditional laboratory tasks, often revealing substantial deficits in episodic and declarative memory. Little is known about the relation between memory abilities as measured in the laboratory versus naturalistic settings in this population, and no questionnaire assessments of everyday memory have been formally validated for this group. The current study's aims were twofold: 1) to describe the psychometric characteristics of a parent-reported everyday memory measure (the Observer Memory Questionnaire - Parent Form, OMQ-PF) in this population with known hippocampal and memory impairment (i.e., DS, ages 7-35 years), and 2) to determine if the measure has the sensitivity to detect impairments, thus providing some of the first data to document parent reports of everyday memory in individuals with DS. The results indicate that this scale is a reliable instrument for detecting and tracking memory deficits over time in this population. We found a correlation between parent reports of everyday memory difficulties and well-replicated deficits in a laboratory-based memory task (i.e., place-object paired associates learning). Our results suggest that the OMQ-PF has the potential to be used as a tool to help to track the status of memory function in this group both for use in descriptive studies and in studies of behavior and pharmacological intervention.
26973574	Although sex differences have been observed in various cognitive domains, there has been little work examining sex differences in the cognition of music. We tested the prediction that women would be better than men at recognizing familiar melodies, since memories of specific melodies are likely to be learned (at least in part) by declarative memory, which shows female advantages. Participants were 24 men and 24 women, with half musicians and half non-musicians in each group. The two groups were matched on age, education, and various measures of musical training. Participants were presented with well-known and novel melodies, and were asked to indicate their recognition of familiar melodies as rapidly as possible. The women were significantly faster than the men in responding, with a large effect size. The female advantage held across musicians and non-musicians, and across melodies with and without commonly associated lyrics, as evidenced by an absence of interactions between sex and these factors. Additionally, the results did not seem to be explained by sex differences in response biases, or in basic motor processes as tested in a control task. Though caution is warranted given that this is the first study to examine sex differences in familiar melody recognition, the results are consistent with the hypothesis motivating our prediction, namely that declarative memory underlies knowledge about music (particularly about familiar melodies), and that the female advantage at declarative memory may thus lead to female advantages in music cognition (particularly at familiar melody recognition). Additionally, the findings argue against the view that female advantages at tasks involving verbal (or verbalizable) material are due solely to a sex difference specific to the verbal domain. Further, the results may help explain previously reported cognitive commonalities between music and language: since declarative memory also underlies language, such commonalities may be partly due to a common dependence on this memory system. More generally, because declarative memory is well studied at many levels, evidence that music cognition depends on this system may lead to a powerful research program generating a wide range of novel predictions for the neurocognition of music, potentially advancing the field. 
26973502	It is well acknowledged that motor sequences can be learned quickly through online learning. Subsequently, the initial acquisition of a motor sequence is boosted or consolidated by offline learning. However, little is known whether offline learning can drive the fast learning of motor sequences (i.e., initial sequence learning in the first training session). To examine offline learning in the fast learning stage, we asked four groups of young adults to perform the serial reaction time (SRT) task with either a fixed or probabilistic sequence and with or without preliminary knowledge (PK) of the presence of a sequence. The sequence and PK were manipulated to emphasize either procedural (probabilistic sequence; no preliminary knowledge (NPK)) or declarative (fixed sequence; with PK) memory that were found to either facilitate or inhibit offline learning. In the SRT task, there were six learning blocks with a 2 min break between each consecutive block. Throughout the session, stimuli followed the same fixed or probabilistic pattern except in Block 5, in which stimuli appeared in a random order. We found that PK facilitated the learning of a fixed sequence, but not a probabilistic sequence. In addition to overall learning measured by the mean reaction time (RT), we examined the progressive changes in RT within and between blocks (i.e., online and offline learning, respectively). It was found that the two groups who performed the fixed sequence, regardless of PK, showed greater online learning than the other two groups who performed the probabilistic sequence. The groups who performed the probabilistic sequence, regardless of PK, did not display online learning, as indicated by a decline in performance within the learning blocks. However, they did demonstrate remarkably greater offline improvement in RT, which suggests that they are learning the probabilistic sequence offline. These results suggest that in the SRT task, the fast acquisition of a motor sequence is driven by concurrent online and offline learning. In addition, as the acquisition of a probabilistic sequence requires greater procedural memory compared to the acquisition of a fixed sequence, our results suggest that offline learning is more likely to take place in a procedural sequence learning task. 
26952269	The reconsolidation process is the mechanism by which the strength and/or content of consolidated memories are updated. This process is triggered by the presentation of a reminder (training cues). It is not always possible to trigger the reconsolidation process. For example, memory age and strength are boundary conditions for the reconsolidation process. Here, we investigated the dynamic changes in these conditions. We propose that the boundary conditions of the reconsolidation process are not fixed and vary as a consequence of the interaction between memory features and reminder characteristics. To modify memory properties, participants received a threatening social protocol that improves memory acquisition or a control condition (fake, without social interaction) prior to learning pairs of meaningless syllables. To determine whether a strong young or old declarative memory undergoes the reconsolidation process, we used an interference task (a second list of pairs of meaningless syllables) to disrupt memory re-stabilization. To assess whether the older memory could be strengthened, we repeated the triggering of reconsolidation. Strong young or old memories modulated by a threatening experience could be interfered during reconsolidation and updated (strengthened) by reconsolidation. Rather than being fixed, boundary conditions vary according to the memory features (strong memory), which indicates the dynamic nature of the reconsolidation process. Our findings demonstrate that it is possible to modify these limits by recruiting the reconsolidation process and making it functionally operative again. This novel scenario opens the possibility to new therapeutically approaches that take into account the reconsolidation process. 
26951117	Tool-related knowledge and skills are supported by a complex set of memory processes that are not well understood. Some aspects of tools are mediated by either declarative or procedural memory, while other aspects may rely on an interaction of both systems. Although motor skill learning is believed to be primarily supported by procedural memory, there is debate in the current literature regarding the role of declarative memory. Growing evidence suggests that declarative memory may be involved during early stages of motor skill learning, although findings have been mixed. In the current experiment, healthy, younger adults were trained to use a set of novel complex tools and were tested on their memory for various aspects of the tools. Declarative memory encoding was interrupted by dividing attention during training. Findings showed that dividing attention during training was detrimental for subsequent memory for tool attributes as well as accurate demonstration of tool use and tool grasping. However, dividing attention did not interfere with motor skill learning, suggesting that declarative memory is not essential for skill learning associated with tools. 
26944609	The stress hormone cortisol is assumed to influence cognitive functions. While cortisol-induced alterations of declarative memory in particular are well-investigated, considerably less is known about its influence on executive functions. Moreover, most research has been focused on slow effects, and rapid non-genomic effects have not been studied. The present study sought to investigate the impact of acute cortisol administration as well as basal cortisol levels on cognitive flexibility, a core executive function, within the non-genomic time frame. Thirty-eight healthy male participants were randomly assigned to intravenously receive either cortisol or a placebo before performing a task switching paradigm with happy and angry faces as stimuli. Cortisol levels were measured at six points during the experiment. Additionally, before the experiment, basal cortisol measures for the cortisol awakening response were collected on three consecutive weekdays immediately following awakening and 30, 45, and 60min after. First and foremost, results showed a pronounced impact of acute and basal cortisol on reaction time switch costs, particularly for angry faces. In the placebo group, low basal cortisol was associated with minimal switch costs, whereas high basal cortisol was related to maximal switch costs. In contrast, after cortisol injection, basal cortisol levels showed no impact. These results show that cognitive flexibility-enhancing effects of acute cortisol administration are only seen in men with high basal cortisol levels. This result supports the context dependency of cortisol administration and shows the relevance of taking basal cortisol levels into account. 
26944423	For nearly a century, neurobiologists have searched for the engram-the neural representation of a memory. Early studies showed that the engram is widely distributed both within and across brain areas and is supported by interactions among large networks of neurons. Subsequent research has identified engrams that support memory within dedicated functional systems for habit learning and emotional memory, but the engram for declarative memories has been elusive. Nevertheless, recent years have brought progress from molecular biological approaches that identify neurons and networks that are necessary and sufficient to support memory, and from recording approaches and population analyses that characterize the information coded by large neural networks. These new directions offer the promise of revealing the engrams for episodic and semantic memories. 
26928024	Obesity is a common medical illness that is increasingly recognised as conferring risk of decline in cognitive performance, independent of other comorbid medical conditions. Individuals with mood disorders (bipolar disorder (BD) or major depressive disorder (MDD)) display an increased prevalence of both obesity and risk factors for cardiovascular diseases. Moreover, BD and MDD are associated with impairment in cognitive functioning across multiple domains. The independent contribution of obesity to cognitive decline in this population has not been explored. This study examines the impact of obesity on cognition by comparing neuropsychological performance in obese individuals, with or without a mood disorder before and after undergoing bariatric surgery.This study compares measures of declarative memory, executive functioning and attention in obese individuals (body mass index >35 kg/m(2)) with BD or MDD, and 2 control populations (obese individuals without a psychiatric illness and healthy non-obese controls) prior to and following bariatric surgery. Participants (ages 18-60) receive a psychiatric diagnosis via the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; SCID). Mood ratings, physical measurements, nutritional and health questionnaires are also administered. A standardised battery of neuropsychological tests aimed at establishing performance in areas of declarative memory, executive functioning and attention are administered. Warrington's Recognition Memory Task (RMT) and an N-Back Task are performed in a 3 T functional MRI to investigate patterns of neural activation during cognitive performance. Additionally, anatomical MRI data are obtained to investigate potential changes in neural structures. Baseline data will be analysed for between-group differences and later compared with postsurgical data to investigate cognitive change.	This study has been approved by the Hamilton Integrated Research Ethics Board (09-3254). Results will be available in peer-reviewed scientific publications and scientific meetings presentations, and released in lay form to media.	
26925719	Deferred imitation (DI) may be regarded as an early declarative-like memory ability shaping the infant's ability to learn about novelties and regularities of the surrounding world. In the current longitudinal study, infants were assessed at 9 and 16months. DI was assessed using five novel objects. Each infant's communicative development was measured by parental questionnaires. The results indicate stability in DI performance and early communicative development between 9 and 16months. The early achievers at 9months were still advanced at 16months. Results also identified a predictive relationship between the infant's gestural development at 9months and the infant's productive and receptive language at 16months. Moreover, the results show that declarative memory, measured with DI, and gestural communication at 9months independently predict productive language at 16months. These findings suggest a connection between the ability to form non-linguistic and linguistic mental representations. These results indicate that the child's DI ability when predominantly preverbal might be regarded as an early domain-general declarative memory ability underlying early productive language development. 
26923851	Acute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair the retrieval of non-hippocampal memories. In particular, stress shortly before retention testing was shown to impair the retrieval of striatal stimulus-response associations in humans. However, the mechanism underlying this stress-induced retrieval impairment of non-hippocampal stimulus-response memory remains elusive. In the present study, we investigated whether an acute elevation in glucocorticoid levels mediates the impairing effects of stress on retrieval of stimulus-response memory. Male Sprague-Dawley rats were trained on a stimulus-response task in an eight-arm radial maze until they learned to associate a stimulus, i.e., cue, with a food reward in one of the arms. Twenty-four hours after successful acquisition, they received a systemic injection of vehicle, corticosterone (1mg/kg), the corticosterone-synthesis inhibitor metyrapone (35mg/kg) or were left untreated 1h before retention testing. We found that the corticosterone injection impaired the retrieval of stimulus-response memory. We further found that the systemic injection procedure per se was stressful as the vehicle administration also increased plasma corticosterone levels and impaired the retrieval of stimulus-response memory. However, memory retrieval was not impaired when rats were tested 2min after the systemic vehicle injection, before any stress-induced elevation in corticosterone levels had occurred. Moreover, metyrapone treatment blocked the effect of injection stress on both plasma corticosterone levels and memory retrieval impairment, indicating that the endogenous corticosterone response mediates the stress-induced memory retrieval impairment. None of the treatments affected rats' locomotor activity or motivation to search for the food reward within the maze. These findings show that stress may affect memory processes beyond the hippocampus and that these stress effects are due to the action of glucocorticoids. 
26918588	Consolidation of declarative memories has been associated with slow wave sleep in young adults. Previous work suggests that, in spite of changes in sleep, sleep-dependent consolidation of declarative memories may be preserved with aging, although reduced relative to young adults. Previous work on young adults shows that, with consolidation, retrieval of declarative memories gradually becomes independent of the hippocampus. To investigate whether memories are similarly reorganized over sleep at the neural level, we compared functional brain activation associated with word pair recall following a nap and equivalent wake in young and older adults. SWS during the nap predicted better subsequent memory recall and was negatively associated with retrieval-related hippocampal activation in young adults. In contrast, in older adults there was no relationship between sleep and memory performance or with retrieval-related hippocampal activation. Furthermore, compared with young adults, postnap memory retrieval in older adults required strong functional connectivity of the hippocampus with the PFC, whereas there were no differences between young and older adults in the functional connectivity of the hippocampus following wakefulness. These results suggest that, although neural reorganization takes place over sleep in older adults, the shift is unique from that seen in young adults, perhaps reflecting memories at an earlier stage of stabilization. 
26913926	The importance of preventing and controlling hypertension (HTN) and diabetes mellitus (DM) to mitigate risks to physical health has long been understood by health care professionals. More recently, a growing body of evidence implicates HTN and DM in age-related cognitive decline and risk for dementia, though consensus has yet to be reached on whether older adults living with comorbid HTN and DM are at heightened risk for cognitive impairment. The present study sought to contribute to this topic through a coordinated analysis of 3 longitudinal studies of aging from England, Sweden, and the United States (total N = 12,513). Identical multilevel linear growth models were fit to each to estimate the impact of baseline disease status on initial level and change in verbal declarative memory performance. Overall, few associations between HTN, DM, and cognition were observed. Rate of decline was steeper for Swedish participants with independent HTN but attenuated for their American counterparts. Americans with comorbid HTN and DM showed attenuated decline. Treatment with medication was substantially less prevalent in the earlier-born and lower-educated Swedish sample, which may help to explain our pattern of results. In addition, those living with multiple conditions may be more likely to receive treatment, mitigating cognitive decline. Our results present a nuanced view of the interactions between HTN, DM, and cognition, and lead us to recommend consideration of treatment status or proxies such as birth cohort and education, in combination with age at assessment and specific measure used to interpret research in this area. (PsycINFO Database Record
26860478	Most research in cognitive aging is based on literate participants from high-income and Western populations. The extent to which findings generalize to low-income and illiterate populations is unknown. The main aim was to examine the structure of between-person differences in cognitive functions among elderly from rural Bangladesh. We used data from the Poverty and Health in Aging (PHA) project in Bangladesh. The participants (n = 452) were in the age range 60-92 years. Structural equation modeling was used to estimate the fit of a five-factor model (episodic recall, episodic recognition, verbal fluency, semantic knowledge, processing speed) and to examine whether the model generalized across age, sex, and literacy. This study demonstrates that an established model of cognition is valid also among older persons from rural Bangladesh. The model demonstrated strong (or scalar) invariance for age, and partial strong invariance for sex and literacy. Semantic knowledge and processing speed showed weak (or metric) sex invariance, and semantic knowledge demonstrated also sensitivity to illiteracy. In general, women performed poorer on all abilities. The structure of individual cognitive differences established in Western populations also fits a population in rural Bangladesh well. This is an important prerequisite for comparisons of cognitive functioning (e.g., declarative memory) across cultures. It is also worth noting that absolute sex differences in cognitive performance among rural elderly in Bangladesh differ from those usually found in Western samples. 
26859518	Working memory can be a major source of interference in dual tasking. However, there is no consensus on whether this interference is the result of a single working memory bottleneck, or of interactions between different working memory components that together form a complete working-memory system. We report a behavioral and an fMRI dataset in which working memory requirements are manipulated during multitasking. We show that a computational cognitive model that assumes a distributed version of working memory accounts for both behavioral and neuroimaging data better than a model that takes a more centralized approach. The model's working memory consists of an attentional focus, declarative memory, and a subvocalized rehearsal mechanism. Thus, the data and model favor an account where working memory interference in dual tasking is the result of interactions between different resources that together form a working-memory system. 
26858622	Sleep after learning strengthens memory consolidation. According to the active system consolidation hypothesis, sleep supports the integration of newly acquired memories into cortical knowledge networks, presumably accompanied by a process of decontextualization of the memory trace (i.e., a gradual loss of memory for the learning context). However, the availability of contextual information generally facilitates memory recall and studies on the interaction of sleep and context on memory retrieval have revealed inconsistent results. Here, we do not find any evidence for a role of sleep in the decontextualization of newly learned declarative memories. In two separate studies, 104 healthy young adults incidentally learned words associated with a context. After a 12 h retention interval filled with either sleep or wakefulness, recall (Experiment 1) or recognition (Experiment 2) was tested with the same or different context. Overall, memory retrieval was significantly improved when the learning context was reinstated, as compared to a different context. However, this context effect of memory was not modulated by sleep vs. wakefulness. These findings argue against a decontextualization of memories, at least across a single night of sleep. 
26844575	Recent reports have suggested that the attended features of an item may be rapidly forgotten once they are no longer relevant for an ongoing task (attribute amnesia). This finding relies on a surprise memory procedure that places high demands on declarative memory. We used intertrial priming to examine whether the representation of an item's identity is lost completely once it becomes task irrelevant. If so, then the identity of a target on one trial should not influence performance on the next trial. In 3 experiments, we replicated the finding that a target's identity is poorly recognized in a surprise memory test. However, we also observed location and identity repetition priming across consecutive trials. These data suggest that, although explicit recognition on a surprise memory test may be impaired, some information about a particular target's identity can be retained after it is no longer needed for a task. (PsycINFO Database Record 
26828569	This meta-analysis summarizes research examining whether transcranial electrical stimulation (transcranial direct current stimulation with oscillating and constant currents; transcranial alternating current stimulation), administered during sleep, can modulate declarative and procedural memory consolidation. Included in the meta-analysis were 13 experiments that represented data from 179 participants. Study findings were summarized using standardized mean difference (SMD) which is an effect size that summarizes differences in standard deviation units. Results showed electrical stimulation during sleep could enhance (SMD=0.447; p=.003) or disrupt (SMD=-0.476, p=.030) declarative memory consolidation. However, transcranial electric stimulation does not appear to be able to enhance (SMD=0.154, p=.279) or disrupt (SMD=0.076, p=.675) procedural memory consolidation. This meta-analysis provides strong evidence that TES is able to modulate some consolidation processes. Additional research is required to determine the mechanisms by which transcranial electrical stimulation is able to influence declarative memory consolidation. Finally, it is yet to be determined whether transcranial electrical stimulation can modulate procedural memory consolidation. 
26826846	The novel adamantane derivative APICA (N-(adamantan-1-yl)-1-pentyl-1H-indole-3-carboxamide) was recently identified as a cannabinomimetic indole of abuse. Despite its novel structure, APICA recalls cannabinomimetic indoles, such as representative member JWH-018. In present study, the effects of APICA (1-3mg/kg, i.p.) were tested in C57BL/6J mice, in the Tetrad task which includes the assessment of: body temperature; locomotor activity and behavioural reactivity; nociception; motor coordination; declarative memory. Furthermore, pre-treatment with the CB1 antagonist AM251 (3mg/kg, i.p.) or the CB2 antagonist AM630 (3mg/kg, i.p.) was carried out to characterize APICA activity. Our results show that APICA was able to dose-dependently decrease locomotor activity and behavioural reactivity in the open field, whereas only the highest dose was able to induce hypothermia, analgesia, motor incoordination and recognition memory impairment, with respect to vehicle (p<0.01; p<0.001). The pretreatment with the CB1 antagonist AM251 elicited an increase in body temperature, total distance travelled in the open field, latency to fall down in the Rotarod, and a decrease in tail flick latency (p<0.05; p<0.01). On the other hand, pretreatment with AM630 did not induced significant differences on APICA effects. This study supports preliminary reports on APICA cannabinomimetic properties, extending its detrimental effects on cognitive function. Moreover, these properties can be attributed to the CB1 receptor activity, indicating APICA as a selective CB1 receptor agonist. 
26806606	The hippocampus supports a cognitive map of space and is critical for encoding declarative memory (who, what, when and where). Recent studies have implicated hippocampal subfield CA2 in social and contextual memory but how it does so remains unknown. Here we find that in adult male rats, presentation of a social stimulus (novel or familiar rat) or a novel object induces global remapping of place fields in CA2 with no effect on neuronal firing rate or immediate early gene expression. This remapping did not occur in CA1, suggesting this effect is specific for CA2. Thus, modification of existing spatial representations might be a potential mechanism by which CA2 encodes social and novel contextual information. 
26799984	People can form opinions of other individuals based on information about their good or bad behavior. The present study investigated whether this affective learning might depend on memory links formed between initially neutral people and valenced information. First, participants viewed neutral faces paired with sentences describing prosocial or antisocial behaviors. Second, memory suppression manipulations with the potential to aid in the forgetting of valenced information were administered. Using the Think/No think paradigm, the effectiveness of four different suppression instructions was compared: Unguided Suppression, Guided Suppression, Distraction, and Thought Substitution. Overall, all the tasks appreciably reduced affective learning based on prosocial information, but only the Guided Suppression and Thought Substitution tasks reduced affective learning based on antisocial information. These results suggest that weakening the putative memory link between initially neutral people and valenced information can decrease the effect of learned associations on the evaluation of other people. We interpreted this as indicative that social affective learning may rely on declarative memories. 
26799371	Episodic retrieval allows people to access memories from the past to guide current thoughts and decisions. In many real-world situations, retrieval occurs under conditions of acute stress, either elicited by the retrieval task or driven by other, unrelated concerns. Memory under such conditions may be hindered, as acute stress initiates a cascade of neuromodulatory changes that can impair episodic retrieval. Here, we review emerging evidence showing that dissociable stress systems interact over time, influencing neural function. In addition to the adverse effects of stress on hippocampal-dependent retrieval, we consider how stress biases attention and prefrontal cortical function, which could further affect controlled retrieval processes. Finally, we consider recent data indicating that stress at retrieval increases activity in a network of brain regions that enable reflexive, rapid responding to upcoming threats, while transiently taking offline regions supporting flexible, goal-directed thinking. Given the ubiquity of episodic memory retrieval in everyday life, it is critical to understand the theoretical and applied implications of acute stress. The present review highlights the progress that has been made, along with important open questions. 
26793090	Healthy sleep is essential in children's cognitive, behavioral, and emotional development. However, remarkably little is known about the influence of sleep disorders on different memory processes in childhood. Such data could give us a deeper insight into the effect of sleep on the developing brain and memory functions and how the relationship between sleep and memory changes from childhood to adulthood. In the present study we examined the effect of sleep disorder on declarative and non-declarative memory consolidation by testing children with sleep-disordered breathing (SDB) which is characterized by disrupted sleep structure. We used a story recall task to measure declarative memory and Alternating Serial Reaction time (ASRT) task to assess non-declarative memory. This task enables us to measure two aspects of non-declarative memory, namely general motor skill learning and sequence-specific learning. There were two sessions: a learning phase and a testing phase, separated by a 12 h offline period with sleep. Our data showed that children with SDB exhibited a generally lower declarative memory performance both in the learning and testing phase; however, both the SDB and control groups exhibited retention of the previously recalled items after the offline period. Here we showed intact non-declarative consolidation in SDB group in both sequence-specific and general motor skill. These findings suggest that sleep disorders in childhood have a differential effect on different memory processes (online vs. offline) and give us insight into how sleep disturbances affects developing brain. 
26780572	Deep brain stimulation (DBS) is a circuit-based treatment shown to relieve symptoms from multiple neurologic and neuropsychiatric disorders. In order to treat the memory deficit associated with Alzheimer's disease (AD), several clinical trials have tested the efficacy of DBS near the fornix. Early results from these studies indicated that patients who received fornix DBS experienced an improvement in memory and quality of life, yet the mechanisms behind this effect remain controversial. It is known that transmission between the medial limbic and corticolimbic circuits plays an integral role in declarative memory, and dysfunction at the circuit level results in various forms of dementia, including AD. Here, we aimed to determine the potential underlying mechanism of fornix DBS by examining the functional circuitry and brain structures engaged by fornix DBS.A multimodal approach was employed to examine global and local temporal changes that occur in an anesthetized swine model of fornix DBS. Changes in global functional activity were measured by functional MRI (fMRI), and local neurochemical changes were monitored by fast scan cyclic voltammetry (FSCV) during electrical stimulation of the fornix. Additionally, intracranial microinfusions into the nucleus accumbens (NAc) were performed to investigate the global activity changes that occur with dopamine and glutamate receptor-specific antagonism.	Hemodynamic responses in both medial limbic and corticolimbic circuits measured by fMRI were induced by fornix DBS. Additionally, fornix DBS resulted in increases in dopamine oxidation current (corresponding to dopamine efflux) monitored by FSCV in the NAc. Finally, fornix DBS-evoked hemodynamic responses in the amygdala and hippocampus decreased following dopamine and glutamate receptor antagonism in the NAc.	The present findings suggest that fornix DBS modulates dopamine release on presynaptic dopaminergic terminals in the NAc, involving excitatory glutamatergic input, and that the medial limbic and corticolimbic circuits interact in a functional loop.	
26774855	As a characteristic feature of Alzheimer's disease (AD) hippocampal atrophy (HA) can be demonstrated in the majority of patients by using neuroimaging techniques in particular magnetic resonance imaging (MRI). Hippocampal atrophy is associated with declarative memory deficits and can also be associated with changes of adjacent medial temporal substructures such as the parahippocampal gyrus or the the entorhinal cortex. Similar findings are present in patients with mild cognitive impairment (MCI) albeit to a lesser extent. While these finding facilitate the diagnostic process in patients with clinical suspicious AD, the metric properties of hippocampal atrophy for delineating healthy aging from MCI and mild AD still appear to be rather limited; as such it is not sufficient to establish the diagnosis of AD (and even more so of MCI). This limitation partly refers to methodological issues and partly to the fact that hippocampal tissue integrity is subject to various pathogenetic influences other than AD. Moreover,the effects of hippocampal atrophy on the behavioral level (e.g. cognitive deficits) are modulated by the individual's cognitive reserve. From a clinical standpoint these observations are in line with the hypothesis that the onset and course of AD is influenced by a number of peristatic factors which are partly conceptualized in the concepts of brain and/or cognitive reserve. These complex interactions have to be considered when using the presence of hippocampal atrophy in the routine diagnostic procedure of AD.
26751865	The hippocampus is a brain structure involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and stress response. It plays an important role in the formation of declarative, spatial and contextual memory, as well as in the processing of emotional information. As a part of the limbic system, it is a very susceptible structure towards the effects of various stressors. The molecular mechanisms of structural and functional alternations that occur in the hippocampus under chronic stress imply an increased level of circulating glucocorticoids (GCs), which is an HPA axis response to stress. Certain data show that changes induced by chronic stress may be independent from the GCs levels, opening the possibility of existence of other poorly explored mechanisms and pathways through which stressors act. The hippocampal GABAergic parvalbumin-positive (PV+) interneurons represent an especially vulnerable population of neurons in chronic stress, which may be of key importance in the development of mood disorders. However, cellular and molecular hippocampal changes that arise as a consequence of chronic stress still represent a large and unexplored area. This review discusses the current knowledge about the PV+ interneurons of the hippocampus and the influence of chronic stress on this intriguing population of neurons. 
26748838	One of the goals of computerized tutoring systems is to optimize the learning of facts. Over a hundred years of declarative memory research have identified two robust effects that can improve such systems: the spacing and the testing effect. By making optimal use of both and adjusting the system to the individual learner using cognitive models based on declarative memory theories, such systems consistently outperform traditional methods (Van Rijn, Van Maanen, & Van Woudenberg, 2009). This adjustment process is driven by a continuously updated estimate of the rate of forgetting for each item and learner on the basis of the learner's accuracy and response time. In this study, we investigated to what extent these estimates of individual rates of forgetting are stable over time and across different materials. We demonstrate that they are stable over time but not across materials. Even though most theories of human declarative memory assume a single underlying rate of forgetting, we show that, in practice, it makes sense to assume different materials are forgotten at different rates. If a computerized, adaptive fact-learning system allowed different rates of forgetting for different materials, it could adapt to individual learners more readily. 
26739712	A subset of hippocampal GABAergic neurons, which are cholecystokinin-positive, highly express cannabinoid type 1 (CB1) receptors. Activation of these receptors inhibits GABA release and thereby limits inhibitory control. While genetic deletion of CB1 receptors from GABAergic neurons led to behavioural alterations and neuroinflammatory reactions, it remained unclear whether these changes in the knockout animals were a direct consequence of the enhanced transmitter release or reflected developmental deficits. The hippocampus is vital for the generation of spatial, declarative and working memory. Here, we addressed the question how CB1 receptors in GABAergic neurons influence hippocampal function. Patch clamp and field potential recordings in mice devoid of CB1 receptors in GABAergic neurons revealed an enhanced frequency and faster kinetics of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons while tonic inhibition, paired-pulse facilitation and long-term potentiation in the hippocampus were not affected. Evaluation of cognitive functions demonstrated impaired acquisition of spatial memory and deficits in novel object recognition and partner recognition in the knockout mice, while working memory and spatial memory remained intact. The density of GABAergic neurons was also similar in knockout mice and their littermates, which argues against global deficits in hippocampal development. Together, these results suggest that CB1 receptors in GABAergic neurons influence specific aspects of neuronal excitability and hippocampal learning.
26737938	The hippocampus is a critical deep brain structure in several aspects. It is directly related to the formation of new long-term declarative memory. The malfunction of the hippocampus closely relates to various disease and pathological conditions. It is also a model structure for the study of cortical function and synaptic plasticity in general because of its special neuro-anatomical structure and intrinsic connections within the hippocampus formation. Both the understanding of roles that the hippocampus plays in recognition memory and the study of neural plasticity require simultaneously recording of neural activities from multiple sub-regions of the hippocampus from behavioral animals. However the distribution of cells in the hippocampus make the recording from multiple sub-regions a big challenge with the traditional uni-length micro-wire arrays. Well-designed electrode arrays are required to reach multiple regions simultaneously because of the distinctive double C shape of the hippocampus cell body layers. In this work, we designed a multi-shanks electrode which uses Parylene C, a highly biocompatible and flexible polymer, as a base and has multiple recording sites specially positioned along the longitudinal axis to fit the curvy shape of the rat hippocampus. 
28355818	Taste research in rodents supports the relevance of memory in order to determine the content of consciousness by modifying both taste perception and later action. Associated with this issue is the fact that taste and visual modalities share anatomical circuits traditionally related to conscious memory. This challenges the view of taste memory as a type of non-declarative unconscious memory.
26712067	Music can be a powerful mnemonic device, as shown by a body of literature demonstrating that listening to text sung to a familiar melody results in better memory for the words compared to conditions where they are spoken. Furthermore, patients with a range of memory impairments appear to be able to form new declarative memories when they are encoded in the form of lyrics in a song, while unable to remember similar materials after hearing them in the spoken modality. Whether music facilitates the acquisition of completely new information, such as new vocabulary, remains unknown. Here we report three experiments in which adult participants learned novel words in the spoken or sung modality. While we found no benefit of musical presentation on free recall or recognition memory of novel words, novel words learned in the sung modality were more strongly integrated in the mental lexicon compared to words learned in the spoken modality. This advantage for the sung words was only present when the training melody was familiar. The impact of musical presentation on learning therefore appears to extend beyond episodic memory and can be reflected in the emergence and properties of new lexical representations.
26690566	Sleep plays an active role in memory consolidation. Because children with Down syndrome (DS) and Williams syndrome (WS) experience significant problems with sleep and also with learning, we predicted that sleep-dependent memory consolidation would be impaired in these children when compared to typically developing (TD) children. This is the first study to provide a cross-syndrome comparison of sleep-dependent learning in school-aged children. Children with DS (n = 20) and WS (n = 22) and TD children (n = 33) were trained on the novel Animal Names task where they were taught pseudo-words as the personal names of ten farm and domestic animals, e.g. Basco the cat, with the aid of animal picture flashcards. They were retested following counterbalanced retention intervals of wake and sleep. Overall, TD children remembered significantly more words than both the DS and WS groups. In addition, their performance improved following night-time sleep, whereas performance over the wake retention interval remained stable, indicating an active role of sleep for memory consolidation. Task performance of children with DS did not significantly change following wake or sleep periods. However, children with DS who were initially trained in the morning continued to improve on the task at the following retests, so that performance on the final test was greater for children who had initially trained in the morning than those who trained in the evening. Children with WS improved on the task between training and the first retest, regardless of whether sleep or wake occurred during the retention interval. This suggests time-dependent rather than sleep-dependent learning in children with WS, or tiredness at the end of the first session and better performance once refreshed at the start of the second session, irrespective of the time of day. Contrary to expectations, sleep-dependent learning was not related to baseline level of performance. The findings have significant implications for educational strategies, and suggest that children with DS should be taught more important or difficult information in the morning when they are better able to learn, whilst children with WS should be allowed a time delay between learning phases to allow for time-dependent memory consolidation, and frequent breaks from learning so that they are refreshed and able to perform at their best.
26687895	The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits. 
26657967	Motivational relevance can prioritize information for memory encoding and consolidation based on reward value. In this review, we pinpoint the possible psychological and neural mechanisms by which reward promotes learning, from guiding attention to enhancing memory consolidation. We then discuss how reward value can spill-over from one conditioned stimulus to a non-conditioned stimulus. Such generalization can occur across perceptually similar items or through more complex relations, such as associative or logical inferences. Existing evidence suggests that the neurotransmitter dopamine boosts the formation of declarative memory for rewarded information and may also control the generalization of reward values. In particular, temporally-correlated activity in the hippocampus and in regions of the dopaminergic circuit may mediate value-based decisions and facilitate cross-item integration. Given the importance of generalization in learning, our review points to the need to study not only how reward affects later memory but how learned reward values may generalize to related representations and ultimately alter memory structure. 
26645305	Sleep benefits memory consolidation across a variety of domains in young adults. However, while declarative memories benefit from sleep in young children, such improvements are not consistently seen for procedural skill learning. Here we examined whether performance improvements on a procedural task, although not immediately observed, are evident after a longer delay when augmented by overnight sleep (24 h after learning). We trained 47 children, aged 33-71 months, on a serial reaction time task and, using a within-subject design, evaluated performance at three time points: immediately after learning, after a daytime nap (nap condition) or equivalent wake opportunity (wake condition), and 24 h after learning. Consistent with previous studies, performance improvements following the nap did not differ from performance improvements following an equivalent interval spent awake. However, significant benefits of the nap were found when performance was assessed 24 h after learning. This research demonstrates that motor skill learning is benefited by sleep, but that this benefit is only evident after an extended period of time. 
26635577	Mounting evidence for the role of sleep spindles in neuroplasticity has led to an increased interest in these non-rapid eye movement (NREM) sleep oscillations. It has been hypothesized that fast and slow spindles might play a different role in memory processing. Here, we present a new sleep spindle detection algorithm utilizing a continuous wavelet transform (CWT) and individual adjustment of slow and fast spindle frequency ranges. Eighteen nap recordings of ten subjects were used for algorithm validation. Our method was compared with both a human scorer and a commercially available SIESTA spindle detector. For the validation set, mean agreement between our detector and human scorer measured during sleep stage 2 using kappa coefficient was 0.45, whereas mean agreement between our detector and SIESTA algorithm was 0.62. Our algorithm was also applied to sleep-related memory consolidation data previously analyzed with a SIESTA detector and confirmed previous findings of significant correlation between spindle density and declarative memory consolidation. We then applied our method to a study in monozygotic (MZ) and dizygotic (DZ) twins, examining the genetic component of slow and fast sleep spindle parameters. Our analysis revealed strong genetic influence on variance of all slow spindle parameters, weaker genetic effect on fast spindles, and no effects on fast spindle density and number during stage 2 sleep. 
26632337	GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg.i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications.
26613992	Assessing the mental status of patients with a neurobehavioral disorder is a critical element in the diagnosis and treatment of these patients. This assessment should always be performed after the patient's history it taken and a general physical as well as a neurologic examination is completed. The mental status examination commences with observing the patient's appearance and level of consciousness. The examiner should also pay attention to patient's social behavior, emotional state and mood. There are 3 major means of assessing a patient's mental status. One type attempts to determine if the patient is demented and the severity of the dementia as it pertains to their ability to perform activities of daily living as well as instrumental activities. A second type of assessment utilizes what may be termed as "screening tests" or "omnibus tests". These brief tests are performed independent of the patient's history and examination. The two most frequently used screening tests are the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The third means of assessing a patient's mental status is by using specific neuropsychological tests that focus on specific domains of cognition, such as frontal executive functions, attention, episodic verbal and visuospatial memory, declarative knowledge such as language (speech, reading and writing) and arithmetical, as well as visuospatial and perceptual abilities. These neurobehavioral, neuropsychiatric and neuropsychological assessments of patients with a cognitive decline and behavioral abnormalities should often be accompanied by laboratory tests, and neuroimaging that can help determine the underlying pathologic process so that effective therapeutic and management approaches can be provided. 
26606553	The amygdala and the hippocampus are associated with emotional processing and declarative memory, respectively. Studies have shown that patients with bilateral hippocampal damage caused by anoxia/ischemia, and patients with probable Alzheimer's disease (AD), can experience emotions for prolonged periods of time, even when they cannot remember what caused the emotion in the first place (Feinstein et al. (2010) Proc Natl Acad Sci USA 107:7674-7679; Guzmán-Vélez et al. (2014) Cogn Behav Neurol 27:117-129). This study aimed to investigate, for the first time, the roles of the amygdala and hippocampus in the dissociation between feelings of emotion and declarative memory for emotion-inducing events in patients with AD. Individuals with probable AD (N = 12) and age-matched healthy comparisons participants (HCP; N = 12) completed a high-resolution (0.44 × 0.44 × 0.80 mm) T2-weighted structural MR scan of the medial temporal lobe. Each of these individuals also completed two separate emotion induction procedures (sadness and happiness) using film clips. We collected real-time emotion ratings at baseline and multiple times postinduction, and administered a test of declarative memory shortly after each induction. Consistent with previous research, hippocampal volume was significantly smaller in patients with AD compared with HCP, and was positively correlated with memory for the film clips. Sustained feelings of emotion and amygdala volume did not significantly differ between patients with AD and HCP. Follow-up analyses showed a significant negative correlation between amygdala volume and sustained sadness, and a significant positive correlation between amygdala volume and sustained happiness. Our findings suggest that the amygdala is important for regulating and sustaining an emotion independent of hippocampal function and declarative memory for the emotion-inducing event. © 2015 Wiley Periodicals, Inc. 
26602839	Neuroimaging studies suggest that acute sleep deprivation can lead to adaptations, such as compensatory recruitment of cerebral structures, to maintain cognitive performance despite sleep loss. However, the understanding of the neurochemical alterations related to these adaptations remains incomplete.Investigate BDNF levels, cognitive performance and their relations in healthy subjects after acute sleep deprivation.	Nineteen sleep deprived (22.11±3.21years) and twenty control (25.10±4.42years) subjects completed depression, anxiety and sleep quality questionnaires. Sleep deprived group spent a full night awake performing different playful activities to keep themselves from sleeping. Attention, response inhibition capacity and working memory (prefrontal cortex-dependent) were assessed with Stroop and Digit Span tests. Declarative memory (hippocampus-dependent) was assessed with Logical Memory test. Serum BDNF was measured by sandwich ELISA. Data were analyzed with independent samples T-test, ANOVA, ANCOVA and curve estimation regressions. p<0.05 was deemed statistically significant.	The sleep deprived group showed higher BDNF levels and normal performance on attention, response inhibition capacity and working memory. However, declarative memory was impaired. A sigmoidal relation between BDNF and Stroop Test scores was found.	Increased BDNF could be related, at least in part, to the maintenance of normal prefrontal cognitive functions after sleep deprivation. This potential relation should be further investigated.	
26593110	The gene coding for the dopamine transporter (DAT), SLC6A3, contains a 40-base pair variable number of tandem repeats (VNTR) polymorphism (rs28363170) in its 3' untranslated region. This VNTR has been associated with attention deficit hyperactivity disorder (ADHD) and has been investigated in relation to cognition and brain function. Here, we report the results of a comprehensive meta-analysis with meta-regression examining the association of the VNTR with different domains of cognition in healthy adults. We extracted data from 28 independent studies and carried out meta-analyses for associations with working memory (k=10 samples, N=1193 subjects), inhibition (k=8 samples, N=829 subjects), executive functions including inhibition (k=10 samples, N=984 subjects), attention (k=6 samples, N=742 subjects) and declarative long-term memory (k=5 samples, N=251 subjects). None of the investigated dimensions showed significant associations with the VNTR (all p>0.26). Meta-regression including year of publication, gender, age, ethnicity and percentage of 10R-homozygotes similarly did not attain significance. We conclude that there is no evidence that rs28363170 may be a significant predictor of cognitive function in healthy adults. 
26569538	Exposure to endogenous cortisol is associated with hippocampal degeneration and may contribute to problems with declarative memory, but effects of persistent versus phasic cortisol elevations have not been established. The present longitudinal investigation examined persistent individual differences and phasic changes in cortisol as they related to verbal memory, executive functions, and subjective cognitive function.Older adults (n = 132, aged 60-93 years) were followed up for up to 5 years. They were assessed annually for verbal memory and every 6 months for executive functions, subjective cognitive function, and cortisol area under the curve (averaged over 3 days).	In multilevel models, persistently but not phasically higher cortisol was associated with worse verbal memory in both learning (t(181) = 2.99, p = .003) and recall (t(280) = 3.10, p = .002). This effect withstood adjustment for stress, depression, metabolic health, and age. There was evidence for attenuated primacy in learning with higher persistent cortisol. Phasic increases in cortisol were not associated with changes in memory, and cortisol was not related to executive functions or subjective cognitive function.	Higher secretion of cortisol may, over time, contribute to memory dysfunction in older adults.	
26563162	Sleep is beneficial for performance across a range of memory tasks in young adults, but whether memories are similarly consolidated in older adults is less clear. Performance benefits have been observed following sleep in older adults for declarative learning tasks, but this benefit may be reduced for non-declarative, motor skill learning tasks. To date, studies of sleep-dependent consolidation of motor learning in older adults are limited to motor sequence tasks. To examine whether reduced sleep-dependent consolidation in older adults is generalizable to other forms of motor skill learning, we examined performance changes over intervals of sleep and wake in young (n = 62) and older adults (n = 61) using a mirror-tracing task, which assesses visuo-motor adaptation learning. Participants learned the task either in the morning or in evening, and performance was assessed following a 12-h interval containing overnight sleep or daytime wake. Contrary to our prediction, both young adults and older adults exhibited sleep-dependent gains in visuo-motor adaptation. There was a correlation between performance improvement over sleep and percent of the night in non-REM stage 2 sleep. These results indicate that motor skill consolidation remains intact with increasing age although this relationship may be limited to specific forms of motor skill learning.
26560675	Declarative memory and procedural memory are known to be two fundamentally different kinds of memory that are dissociable in their psychological characteristics and measurement (explicit vs. implicit) and in the neural systems that subserve each kind of memory. Declarative memory abilities are known to improve from childhood through young adulthood, but the developmental maturation of procedural memory is largely unknown. We compared 10-year-old children and young adults on measures of declarative memory and working memory capacity and on four measures of procedural memory that have been strongly dissociated from declarative memory (mirror tracing, rotary pursuit, probabilistic classification, and artificial grammar). Children had lesser declarative memory ability and lesser working memory capacity than adults, but children exhibited learning equivalent to adults on all four measures of procedural memory. Therefore, declarative memory and procedural memory are developmentally dissociable, with procedural memory being adult-like by age 10years and declarative memory continuing to mature into young adulthood. 
26555632	Memories can be altered by negative or arousing experiences due to the activation of the stress-responsive sympatho-adrenal-medullary axis (SYM). Here, we used a neutral declarative memory that was acquired during multi-trial training to determine the effect of a threatening event on memory without emotional valence. To this end, participants received a new threatening social protocol before learning pairs of meaningless syllables and were tested either 15 min, 2 days or 8 days after acquisition. We first demonstrated that this threatening social situation activates not only the SYM axis (Experiment 1) and the hypothalamus-pituitary-adrenal axis (HPA; Experiment 2), but also, it improves the acquisition or early consolidation of the syllable pairs (Experiment 3). This improvement is not a transient effect; it can be observed after the memory is consolidated. Furthermore, this modulation increases the persistence of memory (Experiment 4). Thus, it is possible to affect memories with specific events that contain unrelated content and a different valence.
26549626	Sleep has been demonstrated to improve consolidation of many types of new memories. However, few prior studies have examined how sleep impacts learning of face-name associations. The recognition of a new face along with the associated name is an important human cognitive skill. Here we investigated whether post-presentation sleep impacts recognition memory of new face-name associations in healthy adults. Fourteen participants were tested twice. Each time, they were presented 20 photos of faces with a corresponding name. Twelve hours later, they were shown each face twice, once with the correct and once with an incorrect name, and asked if each face-name combination was correct and to rate their confidence. In one condition the 12-h interval between presentation and recall included an 8-h nighttime sleep opportunity ("Sleep"), while in the other condition they remained awake ("Wake"). There were more correct and highly confident correct responses when the interval between presentation and recall included a sleep opportunity, although improvement between the "Wake" and "Sleep" conditions was not related to duration of sleep or any sleep stage. These data suggest that a nighttime sleep opportunity improves the ability to correctly recognize face-name associations. Further studies investigating the mechanism of this improvement are important, as this finding has implications for individuals with sleep disturbances and/or memory impairments. 
26525152	Synaptic plasticity serves as a cellular substrate for information storage in the central nervous system. The entorhinal cortex (EC) and hippocampus are interconnected brain areas supporting basic cognitive functions important for the formation and retrieval of declarative memories. Here, we discuss how information flow in the EC-hippocampal loop is organized through circuit design. We highlight recently identified corticohippocampal and intrahippocampal connections and how these long-range and local microcircuits contribute to learning. This review also describes various forms of activity-dependent mechanisms that change the strength of corticohippocampal synaptic transmission. A key point to emerge from these studies is that patterned activity and interaction of coincident inputs gives rise to associational plasticity and long-term regulation of information flow. Finally, we offer insights about how learning-related synaptic plasticity within the corticohippocampal circuit during sensory experiences may enable adaptive behaviors for encoding spatial, episodic, social, and contextual memories. 
26523034	A common approach in memory research is to isolate the function(s) of individual brain regions, such as the hippocampus, without addressing how those regions interact with the larger network. To investigate the properties of the hippocampus embedded within large-scale networks, we used functional magnetic resonance imaging and graph theory to characterize complex hippocampal interactions during the active retrieval of vivid versus dim visual memories. The study yielded 4 main findings. First, the right hippocampus displayed greater communication efficiency with the network (shorter path length) and became a more convergent structure for information integration (higher centrality measures) for vivid than dim memories. Second, vivid minus dim differences in our graph theory measures of interest were greater in magnitude for the right hippocampus than for any other region in the 90-region network. Moreover, the right hippocampus significantly reorganized its set of direct connections from dim to vivid memory retrieval. Finally, beyond the hippocampus, communication throughout the whole-brain network was more efficient (shorter global path length) for vivid than dim memories. In sum, our findings illustrate how multivariate network analyses can be used to investigate the roles of specific regions within the large-scale network, while also accounting for global network changes.
26522618	Autobiographical memory (AM) is a ubiquitous human experience that belongs to long-term declarative memory. It plays interpersonal and intrapsychic functions. The main aim of this study is to present results of contemporary research on AM in recurrent depressive disorders. The available research literature suggests that AM dysfunctions are a precursor and risk factor for recurrent depressive disorders and that they also appear to be a consequence of depressive symptoms in a bidirectional and interacting manner. These data suggest that AM might be a viable therapeutic target for cognitive remediation strategies, given the impact of cognition on diverse clinical outcomes. 
26512433	Individuals with schizophrenia and affective disorders show relatively intact implicit memory as compared to declarative memory. Implicit memory is usually assessed with skill learning and priming tasks. Whereas priming is thought to involve storage changes in the posterior neocortex, skill learning is thought to rely more on the corticostriatal pathway. Since frontostriatal and frontotemporal dysfunctions are, respectively, found in schizophrenia and affective disorders, we hypothesised that individuals with schizophrenia and first-episode psychosis would exhibit disturbances in skill learning, but not priming.Thirty-five patients (11 first-episode psychosis; 11 schizophrenia; 13 affective disorders) and 10 controls completed a procedural learning and priming task. Participants had to identify fragmented images throughout five training sessions. The improvement of the threshold at which the images could be identified between the first and last session was used as an index of procedural learning. In a final session, the identification thresholds for old and new images were compared to assess the priming effect.	Whereas individuals with schizophrenia and first-episode psychosis showed impaired skill learning, the priming effect was similar in all groups.	Even though some aspects of learning and memory are affected in schizophrenia, our results suggest that the posterior cortical pathway remains efficient at modulating the priming effect. This intact ability could be used to guide the elaboration of new rehabilitation programmes.	
26506413	Long-term exercise is associated with improved performance on a variety of cognitive tasks including attention, executive function, and long-term memory. Remarkably, recent studies have shown that even a single bout of aerobic exercise can lead to immediate improvements in declarative learning and memory, but less is known about the effect of exercise on motor learning. Here we sought to determine the effect of a single bout of moderate intensity aerobic exercise on motor skill learning. In experiment 1, we investigated the effect of moderate aerobic exercise on motor acquisition. 24 young, healthy adults performed a motor learning task either immediately after 30 minutes of moderate intensity running, after running followed by a long rest period, or after slow walking. Motor skill was assessed via a speed-accuracy tradeoff function to determine how exercise might differentially affect two distinct components of motor learning performance: movement speed and accuracy. In experiment 2, we investigated both acquisition and retention of motor skill across multiple days of training. 20 additional participants performed either a bout of running or slow walking immediately before motor learning on three consecutive days, and only motor learning (no exercise) on a fourth day. We found that moderate intensity running led to an immediate improvement in motor acquisition for both a single session and on multiple sessions across subsequent days, but had no effect on between-day retention. This effect was driven by improved movement accuracy, as opposed to speed. However, the benefit of exercise was dependent upon motor learning occurring immediately after exercise-resting for a period of one hour after exercise diminished the effect. These results demonstrate that moderate intensity exercise can prime the nervous system for the acquisition of new motor skills, and suggest that similar exercise protocols may be effective in improving the outcomes of movement rehabilitation programs. 
26498155	This study demonstrates long-term declarative memory of imitative actions in a non-human animal species. We tested 12 pet dogs for their ability to imitate human actions after retention intervals ranging from 1 to 24 h. For comparison, another 12 dogs were tested for the same actions without delay between demonstration and recall. Our test consisted of a modified version of the Do as I Do paradigm, combined with the two-action procedure to control for non-imitative processes. Imitative performance of dogs remained consistently high independent of increasing retention intervals, supporting the idea that dogs are able to retain mental representations of human actions for an extended period of time. The ability to imitate after such delays supports the use of long-term declarative memory.
26468191	More than 50 years of research have led to the general agreement that the hippocampus contributes to memory, but there has been a major schism among theories of hippocampal function over this time. Some researchers argue that the hippocampus plays a broad role in episodic and declarative memory, whereas others argue for a specific role in the creation of spatial cognitive maps and navigation. Although both views have merit, neither provides a complete account of hippocampal function. Guided by recent reviews that attempt to bridge between these views, here we suggest that reconciliation can be accomplished by exploring hippocampal function from the perspective of Tolman's (1948) original conception of a cognitive map as organizing experience and guiding behavior across all domains of cognition. We emphasize recent studies in animals and humans showing that hippocampal networks support a broad range of domains of cognitive maps, that these networks organize specific experiences within the contextually relevant map, and that network activity patterns reflect behavior guided through cognitive maps. These results are consistent with a framework that bridges theories of hippocampal function by conceptualizing the hippocampus as organizing incoming information within the context of a multidimensional cognitive map of spatial, temporal, and associational context.Research of hippocampal function is dominated by two major views. The spatial view argues that the hippocampus tracks routes through space, whereas the memory view suggests a broad role in declarative memory. Both views rely on considerable evidence, but neither provides a complete account of hippocampal function. Here we review evidence that, in addition to spatial context, the hippocampus encodes a wide variety of information about temporal and situational context, about the systematic organization of events in abstract space, and about routes through maps of cognition and space. We argue that these findings cross the boundaries of the memory and spatial views and offer new insights into hippocampal function as a system supporting a broad range of cognitive maps.	
26460482	The neural cell adhesion molecule (NCAM) is a glycoprotein implicated in cell-cell adhesion, neurite outgrowth and synaptic plasticity. Polysialic acid (polySia) is mainly attached to NCAM (polySia-NCAM) and has an essential role in regulating NCAM-dependent developmental processes that require plasticity, that is, cell migration, axon guidance and synapse formation. Post-mortem and genetic evidence suggests that dysregulation of polySia-NCAM is involved in schizophrenia (SZ). We enrolled 45 patients diagnosed with SZ and 45 healthy individuals who were submitted to polySia-NCAM peripheral quantification, cognitive and psychopathological assessment and structural neuroimaging (brain volumes and diffusion tensor imaging). PolySia-NCAM serum levels were increased in SZ patients, independently of antipsychotic treatment, and were associated with negative symptoms, blunted affect and declarative memory impairment. The increased polySia-NCAM levels were associated with decreased volume in the left prefrontal cortex, namely Brodmann area 46, in patients and increased volume in the same brain area of healthy individuals. As this brain region is involved in the pathophysiology of SZ and its associated phenomenology, the data indicate that polySia-NCAM deserves further scrutiny because of its possible role in early neurodevelopmental mechanisms of the disorder.
26455892	Maternal transfer of fatty acids is important to fetal brain development. The prenatal environment may differentially affect the substrates supporting declarative memory abilities, as the level of fatty acids transferred across the placenta may be affected by the maternal fatty acid desaturase 2 (FADS2) rs174575 single nucleotide polymorphism. In this study, we hypothesized that toddler and maternal rs174575 genotype and FADS2 promoter methylation would be related to the toddlers' declarative memory performance. Seventy-one 16-month-old toddlers participated in an imitation paradigm designed to test immediate and long-term declarative memory abilities. FADS2 rs174575 genotype was determined and FADS2 promoter methylation was quantified from blood by bisulfite pyrosequencing for the toddlers and their natural mothers. Toddlers of GG mothers at the FADS2 rs174575 single nucleotide polymorphism did not perform as well on memory assessments as toddlers of CC or CG mothers when controlling for plasma α-linolenic acid and child genotype. Toddler methylation status was related to immediate memory performance, whereas maternal methylation status was related to delayed memory performance. Thus, prenatal experience and maternal FADS2 status have a pervasive, long-lasting influence on the brain development of the offspring, but as the postnatal environment becomes more primary, the offsprings' own biology begins to have an effect. 
26448203	The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18-30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information. 
26446222	Interference between similar or overlapping memories formed at different times poses an important challenge on the hippocampal declarative memory system. Difficulties in managing interference are at the core of disabling cognitive deficits in neuropsychiatric disorders. Computational models have suggested that, in the normal brain, the sparse activation of the dentate gyrus granule cells maintained by tonic inhibitory control enables pattern separation, an orthogonalization process that allows distinct representations of memories despite interference. To test this mechanistic hypothesis, we generated mice with significantly reduced expression of the α5-containing GABAA (α5-GABAARs) receptors selectively in the granule cells of the dentate gyrus (α5DGKO mice). α5DGKO mice had reduced tonic inhibition of the granule cells without any change in fast phasic inhibition and showed increased activation in the dentate gyrus when presented with novel stimuli. α5DGKO mice showed impairments in cognitive tasks characterized by high interference, without any deficiencies in low-interference tasks, suggesting specific impairment of pattern separation. Reduction of fast phasic inhibition in the dentate gyrus through granule cell-selective knock-out of α2-GABAARs or the knock-out of the α5-GABAARs in the downstream CA3 area did not detract from pattern separation abilities, which confirms the anatomical and molecular specificity of the findings. In addition to lending empirical support to computational hypotheses, our findings have implications for the treatment of interference-related cognitive symptoms in neuropsychiatric disorders, particularly considering the availability of pharmacological agents selectively targeting α5-GABAARs.Interference between similar memories poses a significant limitation on the hippocampal declarative memory system, and impaired interference management is a cognitive symptom in many disorders. Thus, understanding mechanisms of successful interference management or processes that can lead to interference-related memory problems has high theoretical and translational importance. This study provides empirical evidence that tonic inhibition in the dentate gyrus (DG), which maintains sparseness of neuronal activation in the DG, is essential for management of interference. The specificity of findings to tonic, but not faster, more transient types of neuronal inhibition and to the DG, but not the neighboring brain areas, is presented through control experiments. Thus, the findings link interference management to a specific mechanism, proposed previously by computational models.	
26442693	Sleep benefits the consolidation of psychological memory, and there are hints that sleep likewise supports immunological memory formation. Comparing psychological and immunological domains, we make the case for active system consolidation that is similarly established in both domains and partly conveyed by the same sleep-associated processes. In the psychological domain, neuronal reactivation of declarative memory during slow-wave sleep (SWS) promotes the redistribution of representations initially stored in hippocampal circuitry to extra-hippocampal circuitry for long-term storage. In the immunological domain, SWS seems to favor the redistribution of antigenic memories initially held by antigen-presenting cells, to persisting T cells serving as a long-term store. Because storage capacities are limited in both systems, system consolidation presumably reduces information by abstracting 'gist' for long-term storage. 
26441544	High frequency oscillations in the hippocampal structures recorded during sleep have been proved to be essential for long-term episodic memory consolidation in both animals and in humans. The aim of this study was to test if transcranial Alternating Current Stimulation (tACS) of the dorsolateral prefrontal cortex (DLPFC) in the hippocampal ripple range, applied bi-frontally during encoding, could modulate declarative memory performance, measured immediately after encoding, and after a night's sleep. An associative word-pair learning test was used. During an evening encoding phase, participants received 1 mA 140 Hz tACS or sham stimulation over both DLPFCs for 10 min while being presented twice with a list of word-pairs. Cued recall performance was investigated 10 min after training and the morning following the training session. Forgetting from evening to morning was observed in the sham condition, but not in the 140 Hz stimulation condition. 140 Hz tACS during encoding may have an effect on the consolidation of declarative material. 
26440609	Does advantageous decision-making require one to explicitly remember the outcome of a series of past decisions or to imagine future personal consequences of one's choices? Findings that amnesic people with hippocampal damage cannot form a clear preference for advantageous decks over many learning trials on the Iowa Gambling Task (IGT) have been taken to suggest that complex decision-making on the IGT depends on declarative (episodic) memory and hippocampal integrity. Alternatively, impaired IGT performance in amnesic individuals could be secondary to risk-taking and/or impulsive behaviour resulting from impaired episodic future thinking (i.e. prospection) known to accompany amnesia. We tested this possibility in the amnesic individual K.C. using the IGT and the Toronto Gambling Task (TGT), a novel task that dissociates impulsivity from risk-taking without placing demands on declarative memory. K.C. did not develop a preference for advantageous over disadvantageous decks on the IGT and, instead, showed a slight preference for short-term gains and an inability to acquire a more adaptive appreciation of longer-term losses. He also did not display impulsive or risk-taking behaviour on the TGT, despite a profound inability to imagine personal future experiences. These findings suggest that impaired decision-making on the IGT in amnesia is unlikely to reflect a predilection to act in the moment or failure to take future consequences into account. Instead, some forms of future-regarding decision-making may be dissociable, with performance on tasks relying on declarative learning or on episodic-constructive processes more likely to be impaired. 
26420440	In the pathogenesis of limbic encephalitis other promoting factors besides the pure existence of autoantibodies are increasingly discussed to play a significant role. This is to our knowledge the first described patient in whom the presence of autoantibodies precedes the manifestation of limbic encephalitis for many years.At the age of 38 years, in the serum of a patient with polyendocrine autoimmunity high titers of cytoplasmic islet cell antibodies and of anti-glutamate decarboxylase (GAD) 65 antibodies were observed as an incidential finding, GAD67 antibodies were negative at that time. After a latency of 18 years, she manifested with refractory temporal lobe epilepsy most likely due to autoimmune limbic encephalitis. After epilepsy onset, the patient underwent magnetic resonance imaging (MRI), electroencephalography, cerebrospinal fluid (CSF), serum and neuropsychological investigations during a follow-up period of 8 years. A pharmacoresistent epilepsy with seizure onset from the right temporal lobe and declarative memory deficits were observed affecting primarily the recall of verbal informations. MRI showed a slightly increased signal in the right amygdala without progression. GAD antibodies could be detected in serum (titre 1: 1000) and CSF (titre 1:1) by immunofluorescence. Both, GAD65 and GAD67 antibodies were observed in cell-based assays.	It can be assumed that in addition to a pre-existing systemic T-cell response associated with the longstanding polyendocrine autoimmunity, a delayed intrathecal autoimmunity developed leading to limbic encephalitis. This change might be reflected by the development of GAD67 antibodies in our patient. Besides the contribution of this case report to a better understandig of the pathomechanisms for the development of central nervous system (CNS) autoimmunity, it also has a clinical impact as early treatment of GAD antibody-associated CNS disorders has a better prognosis. Therefore, vigilance for symptoms indicating GAD antibody-associated CNS autoimmunity is mandatory in patients with GAD antibody-associated endocrine dysfunction.	
26414735	We used magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to evaluate the effects of boxing on brain structure and cognition in 10 boxers (8 retired, 2 active; mean age = 45.7 years; standard deviation [SD] = 9.71) and 9 participants (mean age = 43.44; SD = 9.11) in noncombative sports. Evans Index (maximum width of the anterior horns of the lateral ventricles/maximal width of the internal diameter of the skull) was significantly larger in the boxers (F = 4.52; p = 0.050; Cohen's f = 0.531). Word list recall was impaired in the boxers (F(1,14) = 10.70; p = 0.006; f = 0.84), whereas implicit memory measured by faster reaction time (RT) to a repeating sequence of numbers than to a random sequence was preserved (t = 2.52; p < 0.04). Fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) measured by tractography did not significantly differ between groups. However, DTI metrics were significantly correlated with declarative memory (e.g., left ventral striatum ADC with delayed recall, r = -0.74; p = 0.02) and with RT to the repeating number sequence (r = 0.70; p = 0.04) in the boxers. Years of boxing had the most consistent, negative correlations with FA, ranging from -0.65 for the right ventral striatum to -0.92 for the right cerebral peduncle. Years of boxing was negatively related to the number of words consistently recalled over trials (r = -0.74; p = 0.02), delayed recall (r = -0.83; p = 0.003), and serial RT (r = 0.66; p = 0.05). We conclude that microstructural integrity of white matter tracts is related to declarative memory and response speed in boxers and to the extent of boxing exposure. Implications for chronic traumatic encephalopathy are discussed.
26406604	Sleep supports the consolidation of declarative memory in children and adults. However, it is unclear whether sleep improves odor memory in children as well as adults. Thirty healthy children (mean age of 10.6, ranging from 8-12 yrs.) and 30 healthy adults (mean age of 25.4, ranging from 20-30 yrs.) participated in an incidental odor recognition paradigm. While learning of 10 target odorants took place in the evening and retrieval (10 target and 10 distractor odorants) the next morning in the sleep groups (adults: n = 15, children: n = 15), the time schedule was vice versa in the wake groups (n = 15 each). During encoding, adults rated odors as being more familiar. After the retention interval, adult participants of the sleep group recognized odors better than adults in the wake group. While children in the wake group showed memory performance comparable to the adult wake group, the children sleep group performed worse than adult and children wake groups. Correlations between memory performance and familiarity ratings during encoding indicate that pre-experiences might be critical in determining whether sleep improves or worsens memory consolidation. 
26398254	This study aims to investigate working, declarative, and procedural memory in children with (central) auditory processing disorder who showed poor phonological awareness. Thirty 9- and 10-year-old children participated in the study and were distributed into two groups: a control group consisting of 15 children with typical development, and an experimental group consisting of 15 children with (central) auditory processing disorder who were classified according to three behavioral tests and who showed poor phonological awareness in the CONFIAS test battery. The memory systems were assessed through the adapted tests in the program E-PRIME 2.0. The working memory was assessed by the Working Memory Test Battery for Children (WMTB-C), whereas the declarative memory was assessed by a picture-naming test and the procedural memory was assessed by means of a morphosyntactic processing test. The results showed that, when compared to the control group, children with poor phonological awareness scored lower in the working, declarative, and procedural memory tasks. The results of this study suggest that in children with (central) auditory processing disorder, phonological awareness is associated with the analyzed memory systems. 
26395552	The association between APOE genotype and cognitive function suggests a positive role for the e2 allele and a negative role for the e4 allele. Both alleles have relatively low frequencies in the general population; hence, meta-analyses have been based on many small, heterogeneous studies. Here, we report the APOE-cognition associations in the largest single analysis to date. APOE status and cognitive ability were measured in 18 337 participants from the Generation Scotland study between 2006 and 2011. The age range was 18-94 years with a mean of 47 (SD 15). Four cognitive domains were assessed: verbal declarative memory (paragraph recall), processing speed (digit symbol substitution), verbal fluency (phonemic verbal fluency), and vocabulary (Mill Hill synonyms). Linear regression was used to assess the associations between APOE genetic status and cognition. Possession of the e4 allele was associated with lower scores on the measures of memory and processing speed in subjects aged >60. Across all age ranges, the e4 allele was linked to better verbal fluency scores. In younger subjects (≤60 years) the e4 allele was linked to higher vocabulary scores. There were no associations between the e2 allele and cognitive ability. As seen in previous meta-analyses, the APOE e4 allele is linked to poorer cognitive performance in the domains of memory and processing speed. By contrast, positive associations were seen between the e4 allele and measures of verbal fluency and vocabulary. All associations were relatively small and, in many cases, nominally significant despite the very large sample size. 
26372625	Hippocampus and striatum play distinctive roles in memory processes since declarative and non-declarative memory systems may act independently. However, hippocampus and striatum can also be engaged to function in parallel as part of a dynamic system to integrate previous experience and adjust behavioral responses. In these structures the formation, storage, and retrieval of memory require a synaptic mechanism that is able to integrate multiple signals and to translate them into persistent molecular traces at both the corticostriatal and hippocampal/limbic synapses. The best cellular candidate for this complex synthesis is represented by long-term potentiation (LTP). A common feature of LTP expressed in these two memory systems is the critical requirement of convergence and coincidence of glutamatergic and dopaminergic inputs to the dendritic spines of the neurons expressing this form of synaptic plasticity. In experimental models of Parkinson's disease abnormal accumulation of α-synuclein affects these two memory systems by altering two major synaptic mechanisms underlying cognitive functions in cholinergic striatal neurons, likely implicated in basal ganglia dependent operative memory, and in the CA1 hippocampal region, playing a central function in episodic/declarative memory processes. 
26372003	One interpretation of re-experiencing symptoms in post-traumatic stress disorder (PTSD) is that memories related to emotional information are stored strongly, but with insufficient specificity, so that stimuli which are minimally related to the traumatic event are sufficient to trigger recall. If so, re-experiencing symptoms may reflect a general bias against encoding background information during a learning experience, and this tendency might not be limited to learning about traumatic or even autobiographical events. To test this possibility, we administered a discrimination-and-transfer task to 60 Veterans (11.2% female, mean age 54.0 years) self-assessed for PTSD symptoms in order to examine whether re-experiencing symptoms were associated with increased generalization following associative learning. The discrimination task involved learning to choose the rewarded object from each of six object pairs; each pair differed in color or shape but not both. In the transfer phase, the irrelevant feature in each pair was altered. Regression analysis revealed no relationships between re-experiencing symptoms and initial discrimination learning. However, re-experiencing symptom scores contributed to the prediction of transfer performance. Other PTSD symptom clusters (avoidance/numbing, hyperarousal) did not account for significant additional variance. The results are consistent with an emerging interpretation of re-experiencing symptoms as reflecting a learning bias that favors generalization at the expense of specificity. Future studies will be needed to determine whether this learning bias may pre-date and confer risk for, re-experiencing symptoms in individuals subsequently exposed to trauma, or emerges only in the wake of trauma exposure and PTSD symptom development. 
26351997	Klein's target article argues that autonoetic consciousness is a necessary condition for memory; this unusually narrow view of the scope of memory implies that only episodic memory is, strictly speaking, memory. The narrow view is opposed to the standard broad view, on which causal connection with past experience is sufficient for memory; on the broad view, both declarative (i.e., episodic and semantic) and procedural memory count as genuine forms of memory. Klein mounts a convincing attack on the broad view, arguing that it opens the 'doors of memory' too far, but this commentary contends that the narrow view does not open them far enough. It may be preferable to adopt an intermediate view of the scope of memory, on which causal connection is sufficient for memory only when it involves encoding, storage, and retrieval of content. More demanding than the simple causal condition but less demanding than the autonoesis condition, the encoding-storage-retrieval condition implies that both episodic and semantic memory count as genuine forms of memory but that procedural memory does not.
26343804	Recent research has linked psychological (personality) factors and specific genetic risk polymorphisms to performance on neurocognitive phenotypes. We examined whether episodic or semantic memory performance is associated with (a) three personality traits (i.e. neuroticism, extraversion, and openness to experience), (b) two neurodegenerative-related polymorphisms (i.e. Apolipoprotein E (APOE; rs7412; rs429358), Clusterin (CLU; rs11136000)), and (c) cross-domain risk interactions (magnification effects).Linear growth models were examined to test independent associations between personality traits and declarative memory performance, and potential interaction effects with APOE and CLU genetic risk. Normal older adults (n = 282) with personality and genetic data from the Victoria Longitudinal Study were included at baseline and for up to 14 years of follow-up.	First, we observed that higher openness to experience levels were associated with better episodic and semantic memory. Second, three significant gene × personality interactions were associated with poorer memory performance at baseline. These synergistic effects are: (a) APOE allelic risk (ε4+) carriers with lower openness to experience levels, (b) CLU (no risk: T/T) homozygotes with higher extraversion levels, and (c) CLU (no risk: T/T) homozygotes with lower neuroticism levels.	Specific neurodegenerative-related genetic polymorphisms (i.e. APOE and CLU) moderate and magnify the risk contributed by selected personality trait levels (i.e. openness to experience, extraversion) on declarative memory performance in non-demented aging. Future research could target interactions of other personality traits and genetic polymorphisms in different clinical populations to predict other neurocognitive deficits or transitions to cognitive impairment and dementia.	
26310406	There is growing interest in the long-term outcomes of patients surviving out-of-hospital cardiac arrest (OHCA). This paper aims to summarise the available literature on the long-term cognitive, health-related quality of life (QoL) and mental health outcomes of survivors of OHCA. Between 30% and 50% of survivors of OHCA experience cognitive deficits for up to several years post-discharge. Deficits of attention, declarative memory, executive function, visuospatial abilities and verbal fluency are commonly reported. Survivors of OHCA appear to report high rates of mental illness, with up to 61% experiencing anxiety, 45% experiencing depression and 27% experiencing post-traumatic stress. Fatigue appears to be a commonly reported long-term outcome for survivors of OHCA. Investigations of long-term QoL for these patients have produced mixed findings. Carers of survivors of OHCA report high rates of depression, anxiety and post-traumatic stress, with insufficient social and financial support. The heterogeneous range of instruments used to assess cognitive function and QoL prevent any clear conclusions being drawn from the available literature. The potential biases inherent in this patient population and the interaction between QoL, cognitive performance and mental health warrant further investigation, as does the role of post-discharge support services in improving long-term patient outcomes. 
26303022	Acquisition of information can be facilitated through different learning strategies, classically associated with either declarative or procedural memory modalities. The consolidation of the acquired information has been positively associated with sleep. In addition, subsequent performance was better when acquisition was quickly followed by sleep, rather than daytime wakefulness. Prior studies with adults have indicated the viability of the alternative learning strategy of observational learning for motor skill acquisition, as well as the importance of sleep and sleep timing. However, relatively little research has been dedicated to studying the importance of sleep for the consolidation of procedural memory in children. Therefore, this study investigated whether children could encode procedural information through observational learning, and whether sleep timing could affect subsequent consolidation and performance. School-aged children aged 9-12years (N=86, 43% male, Mage=10.64years, SD=.85) were trained on a procedural fingertapping task through observation, either in the morning or evening; creating immediate wake and immediate sleep groups, respectively. Performance was evaluated the subsequent evening or morning on either a congruent or incongruent task version. Observation and task execution was conducted using an online interface, allowing for remote participation. Performance of the immediate wake group was lower for a congruent version, expressed by a higher error rate, opposed to an incongruent version; an effect not observed in the immediate sleep group. This finding showed that observational learning did not improve performance in children. Yet, immediate sleep prevented performance reduction on the previously observed task. These results support a benefit of sleep in observational learning in children, but in a way different from that seen in adults, where sleep enhanced performance after learning by observation. 
26299515	Besides its relevance for declarative memory functions, hippocampal activation has been observed during disambiguation of uncertainty and conflict. Uncertainty and conflict may arise on various levels. On the perceptual level, the hippocampus has been associated with signaling of contextual deviance and disambiguation of similar items (i.e., pattern separation). Furthermore, conflicts can occur on the response level. Animal experiments showed a role of the hippocampus for inhibition of prevailing response tendencies and suppression of automatic stimulus-response mappings, potentially related to increased theta oscillations (3-8 Hz). In humans, a recent fMRI study demonstrated hippocampal involvement in approach-avoidance conflicts. However, the more general significance of hippocampal activity for dealing with response conflicts also on a cognitive level is still unknown. Here, we investigated the role of the hippocampus for response conflict in the Stroop task by combining intracranial electroencephalography (iEEG) recordings from the hippocampus of epilepsy patients with region of interest-based fMRI in healthy participants. Both methods revealed converging evidence that the hippocampus is recruited in a regionally specific manner during response conflict. Moreover, our iEEG data show that this activation depends on theta oscillations and is relevant for successful response conflict resolution.
26284026	Limbic encephalitis is characterized by adaptive autoimmune inflammation of the gray matter structures of the limbic system. It has recently been identified as a major cause of temporal lobe epilepsy accompanied by progressive declarative - mainly episodic - -memory disturbance as well as a variety of rather poorly defined emotional and behavioral changes. While autoimmune inflammation of the hippocampus is likely to be responsible for declarative memory disturbance, consequences of autoimmune inflammation of the amygdala are largely unknown. The amygdala is central for the generation of adequate homoeostatic behavioral responses to emotionally significant external stimuli following processing in a variety of parallel neuronal circuits. Here, we hypothesize that adaptive cellular and humoral autoimmunity may target and modulate distinct inhibitory or excitatory neuronal networks within the amygdala, and thereby strongly impact processing of emotional stimuli and corresponding behavioral responses. This may explain some of the rather poorly understood neuropsychiatric symptoms in limbic encephalitis. 
26284013	What memory systems underlie grammar in children, and do these differ between typically developing (TD) children and children with specific language impairment (SLI)? Whilst there is substantial evidence linking certain memory deficits to the language problems in children with SLI, few studies have investigated multiple memory systems simultaneously, examining not only possible memory deficits but also memory abilities that may play a compensatory role. This study examined the extent to which procedural, declarative, and working memory abilities predict receptive grammar in 45 primary school aged children with SLI (30 males, 15 females) and 46 TD children (30 males, 16 females), both on average 9;10 years of age. Regression analyses probed measures of all three memory systems simultaneously as potential predictors of receptive grammar. The model was significant, explaining 51.6% of the variance. There was a significant main effect of learning in procedural memory and a significant group × procedural learning interaction. Further investigation of the interaction revealed that procedural learning predicted grammar in TD but not in children with SLI. Indeed, procedural learning was the only predictor of grammar in TD. In contrast, only learning in declarative memory significantly predicted grammar in SLI. Thus, different memory systems are associated with receptive grammar abilities in children with SLI and their TD peers. This study is, to our knowledge, the first to demonstrate a significant group by memory system interaction in predicting grammar in children with SLI and their TD peers. In line with Ullman's Declarative/Procedural model of language and procedural deficit hypothesis of SLI, variability in understanding sentences of varying grammatical complexity appears to be associated with variability in procedural memory abilities in TD children, but with declarative memory, as an apparent compensatory mechanism, in children with SLI. 
26283375	Theories of the neurobiology of episodic memory predominantly focus on the contributions of medial temporal lobe structures, based on extensive lesion, electrophysiological, and imaging evidence. Against this backdrop, functional neuroimaging data have unexpectedly implicated left posterior parietal cortex (PPC) in episodic retrieval, revealing distinct activation patterns in PPC subregions as humans make memory-related decisions. To date, theorizing about the functional contributions of PPC has been hampered by the absence of information about the temporal dynamics of PPC activity as retrieval unfolds. Here, we leveraged electrocorticography to examine the temporal profile of high gamma power (HGP) in dorsal PPC subregions as participants made old/new recognition memory decisions. A double dissociation in memory-related HGP was observed, with activity in left intraparietal sulcus (IPS) and left superior parietal lobule (SPL) differing in time and sign for recognized old items (Hits) and correctly rejected novel items (CRs). Specifically, HGP in left IPS increased for Hits 300-700 ms poststimulus onset, and decayed to baseline ∼200 ms preresponse. By contrast, HGP in left SPL increased for CRs early after stimulus onset (200-300 ms) and late in the memory decision (from 700 ms to response). These memory-related effects were unique to left PPC, as they were not observed in right PPC. Finally, memory-related HGP in left IPS and SPL was sufficiently reliable to enable brain-based decoding of the participant's memory state at the single-trial level, using multivariate pattern classification. Collectively, these data provide insights into left PPC temporal dynamics as humans make recognition memory decisions. 
26277459	Declarative memory is thought to consist of two independent systems: episodic and semantic. Episodic memory represents personal and contextually unique events, while semantic memory represents culturally-shared, acontextual factual knowledge. Personal semantics refers to aspects of declarative memory that appear to fall somewhere in between the extremes of episodic and semantic. Examples include autobiographical knowledge and memories of repeated personal events. These two aspects of personal semantics have been studied little and rarely compared to both semantic and episodic memory. We recorded the event-related potentials (ERPs) of 27 healthy participants while they verified the veracity of sentences probing four types of questions: general (i.e., semantic) facts, autobiographical facts, repeated events, and unique (i.e., episodic) events. Behavioral results showed equivalent reaction times in all 4 conditions. True sentences were verified faster than false sentences, except for unique events for which no significant difference was observed. Electrophysiological results showed that the N400 (which is classically associated with retrieval from semantic memory) was maximal for general facts and the LPC (which is classically associated with retrieval from episodic memory) was maximal for unique events. For both ERP components, the two personal semantic conditions (i.e., autobiographical facts and repeated events) systematically differed from semantic memory. In addition, N400 amplitudes also differentiated autobiographical facts from unique events. Autobiographical facts and repeated events did not differ significantly from each other but their corresponding scalp distributions differed from those associated with general facts. Our results suggest that the neural correlates of personal semantics can be distinguished from those of semantic and episodic memory, and may provide clues as to how unique events are transformed to semantic memory. 
26273794	Spatial cognition research in rodents typically employs the use of maze tasks, whose attributes vary from one maze to the next. These tasks vary by their behavioral flexibility and required memory duration, the number of goals and pathways, and also the overall task complexity. A confounding feature in many of these tasks is the lack of control over the strategy employed by the rodents to reach the goal, e.g., allocentric (declarative-like) or egocentric (procedural) based strategies. The double-H maze is a novel water-escape memory task that addresses this issue, by allowing the experimenter to direct the type of strategy learned during the training period. The double-H maze is a transparent device, which consists of a central alleyway with three arms protruding on both sides, along with an escape platform submerged at the extremity of one of these arms. Rats can be trained using an allocentric strategy by alternating the start position in the maze in an unpredictable manner (see protocol 1; §4.7), thus requiring them to learn the location of the platform based on the available allothetic cues. Alternatively, an egocentric learning strategy (protocol 2; §4.8) can be employed by releasing the rats from the same position during each trial, until they learn the procedural pattern required to reach the goal. This task has been proven to allow for the formation of stable memory traces. Memory can be probed following the training period in a misleading probe trial, in which the starting position for the rats alternates. Following an egocentric learning paradigm, rats typically resort to an allocentric-based strategy, but only when their initial view on the extra-maze cues differs markedly from their original position. This task is ideally suited to explore the effects of drugs/perturbations on allocentric/egocentric memory performance, as well as the interactions between these two memory systems. 
26271113	On the 50th anniversary of Norman Geschwind's seminal paper entitled 'Disconnexion syndrome in animal and man', we pay tribute to his ideas by applying contemporary tractography methods to understand white matter disconnection in 3 classic cases that made history in behavioral neurology. We first documented the locus and extent of the brain lesion from the computerized tomography of Phineas Gage's skull and the magnetic resonance images of Louis Victor Leborgne's brain, Broca's first patient, and Henry Gustave Molaison. We then applied the reconstructed lesions to an atlas of white matter connections obtained from diffusion tractography of 129 healthy adults. Our results showed that in all 3 patients, disruption extended to connections projecting to areas distant from the lesion. We confirmed that the damaged tracts link areas that in contemporary neuroscience are considered functionally engaged for tasks related to emotion and decision-making (Gage), language production (Leborgne), and declarative memory (Molaison). Our findings suggest that even historic cases should be reappraised within a disconnection framework whose principles were plainly established by the associationist schools in the last 2 centuries. 
26257961	Neocortical structures typically only support slow acquisition of declarative memory; however, learning through fast mapping may facilitate rapid learning-induced cortical plasticity and hippocampal-independent integration of novel associations into existing semantic networks. During fast mapping the meaning of new words and concepts is inferred, and durable novel associations are incidentally formed, a process thought to support early childhood's exuberant learning. The anterior temporal lobe, a cortical semantic memory hub, may critically support such learning. We investigated encoding of semantic associations through fast mapping using fMRI and multivoxel pattern analysis. Subsequent memory performance following fast mapping was more efficiently predicted using anterior temporal lobe than hippocampal voxels, while standard explicit encoding was best predicted by hippocampal activity. Searchlight algorithms revealed additional activity patterns that predicted successful fast mapping semantic learning located in lateral occipitotemporal and parietotemporal neocortex and ventrolateral prefrontal cortex. By contrast, successful explicit encoding could be classified by activity in medial and dorsolateral prefrontal and parahippocampal cortices. We propose that fast mapping promotes incidental rapid integration of new associations into existing neocortical semantic networks by activating related, nonoverlapping conceptual knowledge. In healthy adults, this is better captured by unique anterior and lateral temporal lobe activity patterns, while hippocampal involvement is less predictive of this kind of learning. 
26257956	The impairment in episodic memory system is the best-known cognitive deficit in patients with temporal lobe epilepsy (TLE). Recent studies have shown evidence of semantic disorders, but they have been less studied than episodic memory. The semantic dysfunction in TLE has various cognitive manifestations, such as the presence of language disorders characterized by defects in naming, verbal fluency, or remote semantic information retrieval, which affects the ability of patients to interact with their surroundings. This paper is a review of recent research about the consequences of TLE on semantic processing, considering neuropsychological, electrophysiological, and neuroimaging findings, as well as the functional role of the hippocampus in semantic processing. The evidence from these studies shows disturbance of semantic memory in patients with TLE and supports the theory of declarative memory of the hippocampus. Functional neuroimaging studies show an inefficient compensatory functional reorganization of semantic networks and electrophysiological studies show a lack of N400 effect that could indicate that the deficit in semantic processing in patients with TLE could be due to a failure in the mechanisms of automatic access to lexicon. 
26251602	Dopamine, a prominent neuromodulator, is implicated in many neuropsychiatric disorders. It has wide-ranging effects on both cortical and subcortical brain regions and on many types of cognitive tasks that rely on a variety of different learning and memory systems. As neuroscience and behavioral evidence for the existence of multiple memory systems and their corresponding neural networks accumulated, so did the notion that dopamine's role is markedly different depending on which memory system is engaged. As a result, dopamine-directed treatments will have different effects on different types of cognitive behaviors. To predict what these effects will be, it is critical to understand: which memory system is mediating the behavior; the neural basis of the mediating memory system; the nature of the dopamine projections into that system; and the time course of dopamine after its release into the relevant brain regions. Consideration of these questions leads to different predictions for how changes in brain dopamine levels will affect automatic behaviors and behaviors mediated by declarative, procedural, and perceptual representation memory systems. 
26244989	Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS. 
26241013	The integration of a novel spoken word with existing lexical items can proceed within 24 hours of learning its phonological form. However, previous studies have reported that lexical integration of new spoken words can be delayed if semantic information is provided during learning. One possibility is that this delay in lexical integration reflects reduced phonological processing during learning as a consequence of the need to learn the semantic associations. In the current study, adult participants learnt novel words via a phoneme monitoring task, in which half of the words were associated with a picture referent, and half were phonological forms only. Critically, participants were instructed to learn the forms of the novel words, with no explicit goal to learn the word-picture mappings. Results revealed significant lexical competition effects emerging one week after consolidation, which were equivalent for the picture-present and form-only conditions. Tests of declarative memory and shadowing showed equivalent performance for picture-present and form-only words, despite participants showing good knowledge of the picture associations immediately after learning. These data support the contention that provided phonological information is recruited sufficiently well during learning, the provision of semantic information does not slow the time-course of lexical integration. 
26240357	A population of human hippocampal neurons has shown responses to individual concepts (e.g., Jennifer Aniston) that generalize to different instances of the concept. However, recordings from the rodent hippocampus suggest an important function of these neurons is their ability to discriminate overlapping representations, or pattern separate, a process that may facilitate discrimination of similar events for successful memory. In the current study, we explored whether human hippocampal neurons can also demonstrate the ability to discriminate between overlapping representations and whether this selectivity could be directly related to memory performance. We show that among medial temporal lobe (MTL) neurons, certain populations of neurons are selective for a previously studied (target) image in that they show a significant decrease in firing rate to very similar (lure) images. We found that a greater proportion of these neurons can be found in the hippocampus compared with other MTL regions, and that memory for individual items is correlated to the degree of selectivity of hippocampal neurons responsive to those items. Moreover, a greater proportion of hippocampal neurons showed selective firing for target images in good compared with poor performers, with overall memory performance correlated with hippocampal selectivity. In contrast, selectivity in other MTL regions was not associated with memory performance. These findings show that a substantial proportion of human hippocampal neurons encode specific memories that support the discrimination of overlapping representations. These results also provide previously unidentified evidence consistent with a unique role of the human hippocampus in orthogonalization of representations in declarative memory. 
26240179	It is well known that formation of new episodic memories depends on hippocampus, but in real-life settings (e.g., conversation), hippocampal amnesics can utilize information from several minutes earlier. What neural systems outside hippocampus might support this minutes-long retention? In this study, subjects viewed an audiovisual movie continuously for 25 min; another group viewed the movie in 2 parts separated by a 1-day delay. Understanding Part 2 depended on retrieving information from Part 1, and thus hippocampus was required in the day-delay condition. But is hippocampus equally recruited to access the same information from minutes earlier? We show that accessing memories from a few minutes prior elicited less interaction between hippocampus and default mode network (DMN) cortical regions than accessing day-old memories of identical events, suggesting that recent information was available with less reliance on hippocampal retrieval. Moreover, the 2 groups evinced reliable but distinct DMN activity timecourses, reflecting differences in information carried in these regions when Part 1 was recent versus distant. The timecourses converged after 4 min, suggesting a time frame over which the continuous-viewing group may have relied less on hippocampal retrieval. We propose that cortical default mode regions can intrinsically retain real-life episodic information for several minutes. 
26238378	For over a century, clinicians have consistently described the paradoxical co-existence in posttraumatic stress disorder (PTSD) of sensory intrusive hypermnesia and declarative amnesia for the same traumatic event. Although this amnesia is considered as a critical etiological factor of the development and/or persistence of PTSD, most current animal models in basic neuroscience have focused exclusively on the hypermnesia, i.e., the persistence of a strong fear memory, neglecting the qualitative alteration of fear memory. The latest is characterized by an underrepresentation of the trauma in the context-based declarative memory system in favor of its overrepresentation in a cue-based sensory/emotional memory system. Combining psychological and neurobiological data as well as theoretical hypotheses, this review supports the idea that contextual amnesia is at the core of PTSD and its persistence and that altered hippocampal-amygdalar interaction may contribute to such pathologic memory. In a first attempt to unveil the neurobiological alterations underlying PTSD-related hypermnesia/amnesia, we describe a recent animal model mimicking in mice some critical aspects of such abnormal fear memory. Finally, this line of argument emphasizes the pressing need for a systematic comparison between normal/adaptive versus abnormal/maladaptive fear memory to identify biomarkers of PTSD while distinguishing them from general stress-related, potentially adaptive, neurobiological alterations. 
26233728	It is widely agreed upon that hippocampal function is linked to episodic-like and spatial memory across various species, for example, rodents. However, the interplay between hippocampal function and other types of learning and memory, like procedural stimulus-response or sequential learning, is less clear. Recently (Eckart et al. in Hippocampus 22:1202-1214, 2012), we showed that excitotoxic hippocampal lesions, which mainly affected its dorsal part, led not only to the expected deficits in a spatial and episodic-like memory task, namely the object place recognition test, but also to substantial improvements in terms of speed and accuracy in a rat adaption of the human sequential reaction time task (SRTT). The design of that experiment, however, which included fixed test durations per training day, led to the fact that lesioned animals gained more instrumental experience, which may partly have accounted for their enhanced performance. In order to rule out such a potential confound, we performed the present experiment on rats with similar ibotenic lesions aiming at the dorsal hippocampus, but we now kept the amount of correct instrumental responses and reinforcements on the same level as in controls. Our data revealed that lesioned animals were still able to complete the SRTT in a substantially smaller amount of time, when compared to control and sham-operated animals, although no differences were observable in terms of speed or accuracy. Also, the animals with lesions showed impaired extinction in a subsequent test where rewards were omitted. The former effect can primarily be attributed to shorter post-reinforcement pauses in the lesioned animals, and the possible mechanisms of this and the extinction effect will be addressed in the discussion. 
26227582	Two published datasets (Dumay & Gaskell, 2007, Psychological Science; Tamminen, Payne, Stickgold, Wamsley, & Gaskell, 2010, Journal of Neuroscience) showing a positive influence of sleep on declarative memory were re-analyzed, focusing on the "fate" of each item at the 0-h test and 12-h retest. In particular, I looked at which items were retrieved at test and "maintained" (i.e., not forgotten) at retest, and which items were not retrieved at test, but eventually "gained" at retest. This gave me separate estimates of protection against loss and memory enhancement, which the classic approach relying on net recall/recognition levels has remained blind to. In both free recall and recognition, the likelihood of maintaining an item between test and retest, like that of gaining one at retest, was higher when the retention interval was filled with nocturnal sleep, as opposed to day-time (active) wakefulness. And, in both cases, the effect of sleep was stronger on gained than maintained items. Thus, if sleep indeed protects against retroactive, unspecific interference, it also clearly promotes access to those memories initially too weak to be retrieved. These findings call for an integrated approach including both passive (cell-level) and active (systems-level) consolidation, possibly unfolding in an opportunistic fashion.
26214216	Behavioral Neuroscience published a pivotal paper by Moyer, Deyo, and Disterhoft (1990) 25 years ago that described the impaired acquisition of trace-eyeblink conditioning in rabbits with complete removal of the hippocampus. As part of the Behavioral Neuroscience celebration commemorating the 30th anniversary of the journal, we reflect upon the impact of that study on understanding the role of the hippocampus, forebrain, and forebrain-cerebellar interactions that mediate acquisition and retention of trace-conditioned responses, and of declarative memory more globally. We discuss the expansion of the conditioning paradigm to species other than the rabbit, the heterogeneity of responses among hippocampal neurons during trace conditioning, the responsivity of hippocampal neurons following consolidation of conditioning, the role of awareness in conditioning, how blink conditioning can be used as a translational tool by assaying potential therapeutics for cognitive enhancement, how trace and delay classical conditioning may be used to investigate neurological disorders including Alzheimer's disease and schizophrenia, and how the 2 paradigms may be used to understand the relationship between declarative (explicit) and nondeclarative (implicit) memory systems.
26194566	Examine the role of sleep in the consolidation of declarative memory in children with autism spectrum disorder (ASD).Case-control study.	Home-based study with sleep and wake conditions.	Twenty-two participants with ASD and 20 control participants between 9 and 16 y of age.	Participants were trained to criterion on a spatial declarative memory task and then given a cued recall test. Retest occurred after a period of daytime wake (Wake) or a night of sleep (Sleep) with home-based polysomnography; Wake and Sleep conditions were counterbalanced. Children with ASD had poorer sleep efficiency than controls, but other sleep macroarchitectural and microarchitectural measures were comparable after controlling for age and medication use. Both groups demonstrated better memory consolidation across Sleep than Wake, although participants with ASD had poorer overall memory consolidation than controls. There was no interaction between group and condition. The change in performance across sleep, independent of medication and age, showed no significant relationships with any specific sleep parameters other than total sleep time and showed a trend toward less forgetting in the control group.	This study shows that despite their more disturbed sleep quality, children with autism spectrum disorder (ASD) still demonstrate more stable memory consolidation across sleep than in wake conditions. The findings support the importance of sleep for stabilizing memory in children with and without neurodevelopmental disabilities. Our results suggest that improving sleep quality in children with ASD could have direct benefits to improving their overall cognitive functioning.	

26160426	When humans simultaneously execute multiple tasks, performance on individual tasks suffers. Complementing existing theories, this article poses a novel question to investigate interactions between memory systems supporting multi-tasking performance: When a primary and dual task both recruit declarative learning and memory systems, does simultaneous performance of both tasks impair primary task performance because learning in the declarative system is reduced, or because control of the primary task is passed to slower procedural systems? To address this question, participants were trained on either a perceptual categorization task believed to rely on procedural learning or one of three different categorization tasks believed to rely on declarative learning. Task performance was examined with and without a simultaneous dual task thought to recruit working memory and executive attention. To test whether the categories were learned procedurally or declaratively, the response keys were switched after a learning criterion had been reached. Large impairments in performance after switching the response keys are taken to indicate procedural learning, and small impairments are taken to indicate declarative learning. Our results suggest that the declarative memory categorization tasks (regardless of task difficulty) were learned by declarative systems, regardless of whether they were learned under dual-task conditions. 
26158890	This study sought to investigate the role of nocturnal sleep duration for the retrieval of oversleep consolidated memories, both prior to and after being cognitively stressed for ∼30 minutes the next morning.Participants learned object locations (declarative memory task comprising 15 card pairs) and a finger tapping sequence (procedural memory task comprising 5 digits) in the evening. After learning, participants either had a sleep opportunity of 8 hours (between ∼23:00 and ∼07:00, full sleep condition) or they could sleep between ∼03:00 and ∼07:00 (short sleep condition). Retrieval of both memory tasks was tested in the morning after each sleep condition, both before (∼08:30) and after being stressed (∼09:50).	Sleep laboratory.	15 healthy young men.	The analyses demonstrated that oversleep memory changes did not differ between sleep conditions. However, in their short sleep condition, following stress hallmarked by increased subjective stress feelings, the men were unable to maintain their pre-stress performance on the declarative memory task, whereas their performance on the procedural memory task remained unchanged. While men felt comparably subjectively stressed by the stress intervention, overall no differences between pre- and post-stress recalls were observed following a full night of sleep.	The findings suggest that 8-h sleep duration, within the range recommended by the US National Sleep Foundation, may not only help consolidate newly learned procedural and declarative memories, but also ensure full access to both during periods of subjective stress.	
26144545	In this study, we investigated motor and cognitive procedural learning in typically developing children aged 8-12 years with a serial reaction time (SRT) task and a probabilistic classification learning (PCL) task. The aims were to replicate and extend the results of previous SRT studies, to investigate PCL in school-aged children, to explore the contribution of declarative knowledge to SRT and PCL performance, to explore the strategies used by children in the PCL task via a mathematical model, and to see whether performances obtained in motor and cognitive tasks correlated. The results showed similar learning effects in the three age groups in the SRT and in the first half of the PCL tasks. Participants did not develop explicit knowledge in the SRT task whereas declarative knowledge of the cue-outcome associations correlated with the performances in the second half of the PCL task, suggesting a participation of explicit knowledge after some time of exposure in PCL. An increasing proportion of the optimal strategy use with increasing age was observed in the PCL task. Finally, no correlation appeared between cognitive and motor performance. In conclusion, we extended the hypothesis of age invariance from motor to cognitive procedural learning, which had not been done previously. The ability to adopt more efficient learning strategies with age may rely on the maturation of the fronto-striatal loops. The lack of correlation between performance in the SRT task and the first part of the PCL task suggests dissociable developmental trajectories within the procedural memory system.
26136107	Drawing inferences from past experiences enables adaptive behavior in future situations. Inference has been shown to depend on hippocampal processes. Usually, inference is considered a deliberate and effortful mental act which happens during retrieval, and requires the focus of our awareness. Recent fMRI studies hint at the possibility that some forms of hippocampus-dependent inference can also occur during encoding and possibly also outside of awareness. Here, we sought to further explore the feasibility of hippocampal implicit inference, and specifically address the temporal evolution of implicit inference using intracranial EEG. Presurgical epilepsy patients with hippocampal depth electrodes viewed a sequence of word pairs, and judged the semantic fit between two words in each pair. Some of the word pairs entailed a common word (e.g., "winter-red," "red-cat") such that an indirect relation was established in following word pairs (e.g., "winter-cat"). The behavioral results suggested that drawing inference implicitly from past experience is feasible because indirect relations seemed to foster "fit" judgments while the absence of indirect relations fostered "do not fit" judgments, even though the participants were unaware of the indirect relations. A event-related potential (ERP) difference emerging 400 ms post-stimulus was evident in the hippocampus during encoding, suggesting that indirect relations were already established automatically during encoding of the overlapping word pairs. Further ERP differences emerged later post-stimulus (1,500 ms), were modulated by the participants' responses and were evident during encoding and test. Furthermore, response-locked ERP effects were evident at test. These ERP effects could hence be a correlate of the interaction of implicit memory with decision-making. Together, the data map out a time-course in which the hippocampus automatically integrates memories from discrete but related episodes to implicitly influence future decision making.
26136052	We investigated theoretically and empirically a range of training schedules on tasks with three knowledge types: declarative, procedural, and perceptual-motor. We predicted performance for 6435 potential eight-block training schedules with ACT-R's declarative memory equations. Hybrid training schedules (schedules consisting of distributed and massed practice) were predicted to produce better performance than purely distributed or massed training schedules. The results of an empirical study (N = 40) testing four exemplar schedules indicated a more complex picture. There were no statistical differences among the groups in the declarative and procedural tasks. We also found that participants in the hybrid practice groups produced reliably better performance than ones in the distributed practice group for the perceptual-motor task--the results indicate training schedules with some spacing and some intensiveness may lead to better performance, particularly for perceptual-motor tasks, and that tasks with mixed types of knowledge might be better taught with a hybrid schedule.We explored distributed and massed training schedules as well as hybrids between them with respect to three knowledge types based on theories and an empirical study. The results suggest that industrial and operator training in complex tasks need not and probably should not be done on a distributed training schedule.	
26116933	We examined the intriguing but controversial idea that disrupted sleep-dependent consolidation contributes to age-related memory decline. Slow-wave activity during sleep may help strengthen neural connections and provide memories with long-term stability, in which case decreased slow-wave activity in older adults could contribute to their weaker memories. One prediction from this account is that age-related memory deficits should be reduced by artificially enhancing slow-wave activity. In young adults, applying transcranial current oscillating at a slow frequency (0.75 Hz) during sleep improves memory. Here, we tested whether this procedure can improve memory in older adults. In 2 sessions separated by 1 week, we applied either slow-oscillatory stimulation or sham stimulation during an afternoon nap in a double-blind, crossover design. Memory tests were administered before and after sleep. A larger improvement in word-pair recall and higher slow-wave activity was observed with slow-oscillatory stimulation than with sham stimulation. This is the first demonstration that this procedure can improve memory in older adults, suggesting that declarative memory performance in older adults is partly dependent on slow-wave activity during sleep.
26103422	The mechanism by which the hippocampus facilitates declarative memory formation appears to involve, among other things, restructuring of the actin cytoskeleton within neuronal dendrites. One protein involved in this process is cortactin, which is an important link between extracellular signaling and cytoskeletal reorganization. In this paper, we demonstrate that total hippocampal cortactin, as well as Y421-phosphorylated cortactin are transiently reduced following spatial working memory formation in the radial arm maze (RAM). Because cortactin is a substrate of the cysteine protease calpain, we also assessed the effect of chronic calpain inhibition on RAM performance and cortactin expression. Calpain inhibition impaired spatial working memory and blocked the reduction in hippocampal cortactin levels following RAM training. These findings add to a growing body of research implicating cortactin and calpain in hippocampus-dependent memory formation. 
26097451	Individuals with a history of traumatic brain injury (TBI) often report sleep disturbances, which may be caused by changes in sleep architecture or reduced sleep quality (greater time awake after sleep onset, poorer sleep efficiency, and sleep stage proportion alterations). Sleep is beneficial for memory formation, and herein we examine whether altered sleep physiology following TBI has deleterious effects on sleep-dependent declarative memory consolidation. Participants learned a list of word pairs in the morning or evening, and recall was assessed 12-h later, following an interval awake or with overnight sleep. Young adult participants (18-22 years) were assigned to one of four experimental groups: TBI Sleep (n = 14), TBI Wake (n = 12), non-TBI Sleep (n = 15), non-TBI Wake (n = 15). Each TBI participant was >1 year post-injury. Sleep physiology was measured with polysomnography. Memory consolidation was assessed by comparing change in word-pair recall over 12-h intersession intervals. The TBI group spent a significantly greater proportion of the night in SWS than the non-TBI group at the expense of NREM1. The TBI group also had marginally lower EEG delta power during SWS in the central region. Intersession changes in recall were greater for intervals with sleep than without sleep in both groups. However, despite abnormal sleep stage proportions for individuals with a TBI history, there was no difference in the intersession change in recall following sleep for the TBI and non-TBI groups. In both Sleep groups combined, there was a positive correlation between Intersession Change and the proportion of the night in NREM2 + SWS. Overall, sleep composition is altered following TBI but such deficits do not yield insufficiencies in sleep-dependent memory consolidation. 
26084621	Early clinical descriptions of and research with people with schizophrenia described apparent difficulties in moral judgement and sensitivity. However, this research failed to take into account the effect of cognitive deficits and symptoms on task performance.We assessed people with schizophrenia on the Moral Judgement Interview, a task used in the earlier literature, alongside a battery of neuro- and social-cognitive tasks.	Whereas people with schizophrenia perform more poorly on this task than controls, this is mediated by memory and declarative theory of mind, and also impacted by negative symptoms.	These results indicate that performance deficits on moral judgement tasks are not a universal feature of schizophrenia, but rather due to associated difficulties such as those in social cognition.	
26071676	Recent research has used context cues (odor or auditory cues) to target memories during sleep and has demonstrated that they can enhance declarative and procedural memories. However, the effects of external cues re-presented during sleep on emotional memory are still not fully understood. In the present study, we conducted a Pavlovian fear conditioning/extinction paradigm and examined the effects of re-exposure to extinction memory associated contextual tones during slow-wave sleep (SWS) and wakefulness on fear expression. The participants underwent fear conditioning on the first day, during which colored squares served as the conditioned stimulus (CS) and a mild shock served as the unconditioned stimulus (US). The next day, they underwent extinction, during which the CSs were presented without the US but accompanied by a contextual tone (pink noise). Immediately after extinction, the participants were required to take a nap or remain awake and randomly assigned to six groups. Four of the groups were separately exposed to the associated tone (i.e. SWS-Tone group and Wake-Tone group) or an irrelevant tone (control tone, CtrT) (i.e. SWS-CtrT group and Wake-CtrT group), while the other two groups were not (i.e. SWS-No Tone group and Wake-No Tone group). Subsequently, the conditioned responses to the CSs were tested to evaluate the fear expression. All of the participants included in the final analysis showed successful levels of fear conditioning and extinction. During the recall test, the fear responses were significantly higher in the SWS-Tone group than that in the SWS-No Tone group or the SWS-CtrT group, while the Wake-Tone group exhibited more attenuated fear responses than either the Wake-No Tone group or Wake-CtrT group. Otherwise, re-exposure to auditory tones during SWS did not affect sleep profiles. These results suggest that distinct conditions during which re-exposure to an extinction memory associated contextual cue contributes to differential effects on fear expression. 
26071087	Maneuvering safely through the environment is central to survival of all animals. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and sometimes proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures (e.g., subiculum); in humans this system encodes declarative memory (allocentric, semantic, and episodic, i.e., memory for people, places, things, and events). This form of memory is assessed in laboratory animals by many methods, but predominantly the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and when over-learned becomes implicit or procedural memory. Several allocentric methods for rodents are reviewed and compared with the MWM with particular focus on the Cincinnati water maze (CWM). MWM advantages include minimal training, no food deprivation, ease of testing, reliable learning, insensitivity to differences in body weight and appetite, absence of non-performers, control methods for performance effects, repeated testing capability and other factors that make this test well-suited for regulatory studies. MWM limitations are also reviewed. Evidence-based MWM design and testing methods are presented. On balance, the MWM is arguably the preferred test for assessing learning and memory in basic research and regulatory studies and the CWM is recommended if two tests can be accommodated so that both allocentric (MWM) and egocentric (CWM) learning and memory can be effectively and efficiently assessed. 
26063773	Emerging human, animal, and computational evidence suggest that, within the hippocampus, stored memories are compared with current sensory input to compute novelty, i.e., detecting when inputs deviate from expectations. Hippocampal subfield CA1 is thought to detect mismatches between past and present, and detected novelty is thought to modulate encoding processes, providing a mechanism for gating the entry of information into memory. Using high-resolution functional MRI, we examined human hippocampal subfield and medial temporal lobe cortical activation during prediction violations within a sequence of events unfolding over time. Subjects encountered sequences of four visual stimuli that were then reencountered in the same temporal order (Repeat) or a rearranged order (Violation). Prediction strength was manipulated by varying whether the sequence was initially presented once (Weak) or thrice (Strong) prior to the critical Repeat or Violation sequence. Analyses of blood oxygen level-dependent signals revealed that task-responsive voxels in anatomically defined CA1, CA23/dentate gyrus, and perirhinal cortex were more active when expectations were violated than when confirmed. Additionally, stronger prediction violations elicited greater activity than weaker violations in CA1, and CA1 contained the greatest proportion of voxels displaying this prediction violation pattern relative to other medial temporal lobe regions. Finally, a memory test with a separate group of subjects showed that subsequent recognition memory was superior for items that had appeared in prediction violation trials than in prediction confirmation trials. These findings indicate that CA1 responds to temporal order prediction violations, and that this response is modulated by prediction strength. 
26053402	Memory-based decisions are often accompanied by an assessment of choice certainty, but the mechanisms of such confidence judgments remain unknown. We studied the response of 1,065 individual neurons in the human hippocampus and amygdala while neurosurgical patients made memory retrieval decisions together with a confidence judgment. Combining behavioral, neuronal and computational analysis, we identified a population of memory-selective (MS) neurons whose activity signaled stimulus familiarity and confidence, as assessed by subjective report. In contrast, the activity of visually selective (VS) neurons was not sensitive to memory strength. The groups further differed in response latency, tuning and extracellular waveforms. The information provided by MS neurons was sufficient for a race model to decide stimulus familiarity and retrieval confidence. Together, our results indicate a trial-by-trial relationship between a specific group of neurons and declared memory strength in humans. We suggest that VS and MS neurons are a substrate for declarative memories. 
26047664	Korsakoff's syndrome (KS) is a chronic neuropsychiatric disorder caused by alcohol abuse and thiamine deficiency. Patients with KS show restricted autonomy due to their severe declarative amnesia and executive disorders. Recently, it has been suggested that procedural learning and memory are relatively preserved in KS and can effectively support autonomy in KS. In the present review we describe the available evidence on procedural learning and memory in KS and highlight advances in memory rehabilitation that have been demonstrated to support procedural memory. The specific purpose of this review was to increase insights in the available tools for successful memory rehabilitation and give suggestions how to apply these tools in clinical practice to increase procedural learning in KS. Current evidence suggests that when memory rehabilitation is adjusted to the specific needs of KS patients, this will increase their ability to learn procedures and their typically compromised autonomy gets enhanced. 
26029150	The last decade has witnessed a spurt of new publications documenting sleep's essential contribution to the brains ability to form lasting memories. For the declarative memory domain, slow wave sleep (the deepest sleep stage) has the greatest beneficial effect on the consolidation of memories acquired during preceding wakefulness. The finding that newly encoded memories become reactivated during subsequent sleep fostered the idea that reactivation leads to the strengthening and transformation of the memory trace. According to the active system consolidation account, trace reactivation leads to the redistribution of the transient memory representations from the hippocampus to the long-lasting knowledge networks of the cortex. Apart from consolidating previously learned information, sleep also facilitates the encoding of new memories after sleep, which probably relies on the renormalization of synaptic weights during sleep as suggested by the synaptic homeostasis theory. During wakefulness overshooting potentiation causes an imbalance in synaptic weights that is countered by synaptic downscaling during subsequent sleep. This review briefly introduces the basic concepts and central findings of the research on sleep and memory, and discusses implications of this lab-based work for everyday applications to make the best possible use of sleep's beneficial effect on learning and memory. 
26005417	While it is well accepted that motor performance declines with age, the ability to learn simple procedural motor tasks appears to remain intact to some extent in normal aging. Here we examined the impact of aging on the acquisition of a simple sequence of bimanual actions. We further asked whether such learning results from an overall decrease in response time or is also associated with improved coordination between the hands. Healthy young and old individuals performed a bimanual version of the classic serial reaction time task. We found no learning deficit in older adults and noted that older subjects were able to learn as much as young participants. We also observed that learning in both groups was associated with an overall decrease in response time, but switch cost, the increase in response time when a switch in hands was required during sequence execution, did not decrease with learning. Surprisingly however, overall switch cost was lower in the older group compared to the younger subjects. These findings are discussed in the context of interactions between procedural and declarative memory, reduced interhemispheric inhibition and more symmetric cortical activation during motor performance in normal aging. 
25988227	Memory formation for newly acquired associations typically depends on hippocampal-neocortical interactions. Through the process of system-consolidation, the mnemonic binding role of the hippocampus is subsequently replaced by cortical hubs, such as the ventromedial prefrontal cortex (vmPFC) or the anterior temporal lobe (ATL). Here, using BOLD-fMRI, we compared retrieval of semantic associations acquired through Fast Mapping (FM), an incidental, exclusion-based learning procedure, to retrieval of similar associations that were intentionally acquired through Explicit Encoding (EE). Despite an identical retrieval task, the encoding histories of the retrieved semantic associations (FM vs. EE) induced distinct neural substrates and disparate related neural dynamics in time. Retrieval of associations acquired through EE engaged the expected hippocampal and vmPFC related networks. Furthermore, retrieval intentionally encoded associations gave rise to a typical overnight increase in engagement of the vmPFC and increased vmPFC-hippocampal-neocortical functional connectivity. On the other hand, retrieval of associations acquired through FM immediately engaged an ATL related network that typically supports well-established semantic knowledge, a network that did not engage the hippocampus and the vmPFC. Moreover, FM learning was associated with minimal overnight changes in the BOLD responses and in the functional connectivity. Our findings indicate that FM may induce a direct, ATL-mediated acquisition and retention of novel arbitrary associations, bypassing the initial hippocampal-cortical representation phase. A direct, ATL-mediated vocabulary acquisition through FM could support the learning and retention of new associations in young children with presumably an immature hippocampal system, and possibly even in amnesic adults with hippocampal lesions. 
25987365	Declarative verbal learning and memory are known to be lateralised to the dominant hemisphere and to be subserved by a network of structures, including those located in frontal and temporal regions. These structures support critical components of verbal memory, including working memory, encoding, and retrieval. Their relative functional importance in facilitating declarative verbal learning and memory, however, remains unclear.To investigate the different functional roles of these structures in subserving declarative verbal learning and memory performance by applying a more focal form of transcranial direct current stimulation, "High Definition tDCS" (HD-tDCS). Additionally, we sought to examine HD-tDCS effects and electrical field intensity distributions using computer modelling.	HD-tDCS was administered to the left dorsolateral prefrontal cortex (LDLPFC), planum temporale (PT), and left medial temporal lobe (LMTL) to stimulate the hippocampus, during learning on a declarative verbal memory task. Sixteen healthy participants completed a single blind, intra-individual cross-over, sham-controlled study which used a Latin Square experimental design. Cognitive effects on working memory and sustained attention were additionally examined.	HD-tDCS to the LDLPFC significantly improved the rate of verbal learning (p=0.03, η(2)=0.29) and speed of responding during working memory performance (p=0.02, η(2)=0.35), but not accuracy (p=0.12, η(2)=0.16). No effect of tDCS on verbal learning, retention, or retrieval was found for stimulation targeted to the LMTL or the PT. Secondary analyses revealed that LMTL stimulation resulted in increased recency (p=0.02, η(2)=0.31) and reduced mid-list learning effects (p=0.01, η(2)=0.39), suggesting an inhibitory effect on learning.	HD-tDCS to the LDLPFC facilitates the rate of verbal learning and improved efficiency of working memory may underlie performance effects. This focal method of administrating tDCS has potential for probing and enhancing cognitive functioning.	
25977084	Declarative Memory consists of memory for events (episodic memory) and facts (semantic memory). Methods to test declarative memory are key in investigating effects of potential cognition-enhancing substances--medicinal drugs or nutrients. A number of cognitive performance tests assessing declarative episodic memory tapping verbal learning, logical memory, pattern recognition memory, and paired associates learning are described. These tests have been used as outcome variables in 34 studies in humans that have been described in the literature in the past 10 years. Also, the use of episodic tests in animal research is discussed also in relation to the drug effects in these tasks. The results show that nutritional supplementation of polyunsaturated fatty acids has been investigated most abundantly and, in a number of cases, but not all, show indications of positive effects on declarative memory, more so in elderly than in young subjects. Studies investigating effects of registered anti-Alzheimer drugs, cholinesterase inhibitors in mild cognitive impairment, show positive and negative effects on declarative memory. Studies mainly carried out in healthy volunteers investigating the effects of acute dopamine stimulation indicate enhanced memory consolidation as manifested specifically by better delayed recall, especially at time points long after learning and more so when drug is administered after learning and if word lists are longer. The animal studies reveal a different picture with respect to the effects of different drugs on memory performance. This suggests that at least for episodic memory tasks, the translational value is rather poor. For the human studies, detailed parameters of the compositions of word lists for declarative memory tests are discussed and it is concluded that tailored adaptations of tests to fit the hypothesis under study, rather than "off-the-shelf" use of existing tests, are recommended.
25959547	Metal ions, i.e., Zn(2+) and Cu(2+), are released from neuron terminals in the hippocampus, which plays important roles in spatial and declarative memory, and may serve as a signal factor. Synaptic homeostasis of metal ions is critical for cognitive activity in the hippocampus. Amyloid-β (Aβ) is a causative candidate for the pathogenesis of Alzheimer's disease (AD) and Aβ-induced synapse dysfunction is easy to emerge along with normal aging and leads to the cognitive decline and memory loss in the pre-dementia stage of AD. Because Aβ interacts with Zn(2+) and Cu(2+), it is likely that these metal ions are involved in the Aβ-induced modification of the synaptic function. There is evidence to indicate that the inhibition of the interaction of Aβ with Zn(2+) and Cu(2+) may ameliorate the pathophysiology of AD. Interaction of extracellular Zn(2+) with Aβ in the hippocampus is involved in transiently Aβ-induced cognition deficits, while the interaction of extracellular Cu(2+) reduces bioavailability of intracellular Cu(2+), followed by an increase in oxidative stress, which may lead to cognitive deficits. It is likely that Zn(2+) and Cu(2+) play as a key-mediating factor in pathophysiology of the synaptic dysfunction in which Aβ is involved. Based on the idea that understating Aβ-induced changes in synaptic plasticity is important to prevent AD, the present paper summarizes the interaction of Aβ with metal ions in cognition. 
25943422	Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning. 
25928684	This article summarizes the state-of-science knowledge regarding the associations between hypnosis and brain oscillations. Brain oscillations represent the combined electrical activity of neuronal assemblies, usually measured as specific frequencies representing slower (delta, theta, alpha) and faster (beta, gamma) oscillations. Hypnosis has been most closely linked to power in the theta band and changes in gamma activity. These oscillations are thought to play a critical role in both the recording and recall of declarative memory and emotional limbic circuits. The authors propose that this role may be the mechanistic link between theta (and perhaps gamma) oscillations and hypnosis, specifically, that the increases in theta oscillations and changes in gamma activity observed with hypnosis may underlie some hypnotic responses. If these hypotheses are supported, they have important implications for both understanding the effects of hypnosis and for enhancing response to hypnotic treatments.
25926443	The <1 Hz EEG slow oscillation (SO) is a hallmark of slow-wave sleep (SWS) and is critically involved in sleep-associated memory formation. Previous studies showed that SOs and associated memory function can be effectively enhanced by closed-loop auditory stimulation, when clicks are presented in synchrony with upcoming SO up states. However, increasing SOs and synchronized excitability also bear the risk of emerging seizure activity, suggesting the presence of mechanisms in the healthy brain that counter developing hypersynchronicity during SOs. Here, we aimed to test the limits of driving SOs through closed-loop auditory stimulation in healthy humans. Study I tested a "Driving stimulation" protocol (vs "Sham") in which trains of clicks were presented in synchrony with SO up states basically as long as an ongoing SO train was identified on-line. Study II compared Driving stimulation with a "2-Click" protocol where the maximum of stimuli delivered in a train was limited to two clicks. Stimulation was applied during SWS in the first 210 min of nocturnal sleep. Before and after sleep declarative word-pair memories were tested. Compared with the Sham control, Driving stimulation prolonged SO trains and enhanced SO amplitudes, phase-locked spindle activity, and overnight retention of word pairs (all ps < 0.05). Importantly, effects of Driving stimulation did not exceed those of 2-Click stimulation (p > 0.180), indicating the presence of a mechanism preventing the development of hypersynchronicity during SO activity. Assessment of temporal dynamics revealed a rapidly fading phase-locked spindle activity during repetitive click stimulation, suggesting that spindle refractoriness contributes to this protective mechanism. 
25925692	Early detection of Alzheimer's disease (AD) has become one of the principal focuses of research in medicine, particularly when the disease is incipient or even prodromic, because treatments are more effective in these stages. Lexical-semantic-conceptual deficit (LSCD) in the oral definitions of semantic categories for basic objects is an important early indicator in the evaluation of the cognitive state of patients.The objective of this research is to define an economic procedure for cognitive impairment (CI) diagnosis, which may be associated with early stages of AD, by analysing cognitive alterations affecting declarative semantic memory. Because of its low cost, it could be used for routine clinical evaluations or screenings, leading to more expensive and selective tests that confirm or rule out the disease accurately. It should necessarily be an explanatory procedure, which would allow us to study the evolution of the disease in relation to CI, the irregularities in different semantic categories, and other neurodegenerative diseases. On the basis of these requirements, we hypothesise that Bayesian networks (BNs) are the most appropriate tool for this purpose.	We have developed a BN for CI diagnosis in mild and moderate AD patients by analysing the oral production of semantic features. The BN causal model represents LSCD in certain semantic categories, both of living things (dog, pine, and apple) and non-living things (chair, car, and trousers), as symptoms of CI. The model structure, the qualitative part of the model, uses domain knowledge obtained from psychology experts and epidemiological studies. Further, the model parameters, the quantitative part of the model, are learnt automatically from epidemiological studies and Peraita and Grasso's linguistic corpus of oral definitions. This corpus was prepared with an incidental sampling and included the analysis of the oral linguistic production of 81 participants (42 cognitively healthy elderly people and 39 mild and moderate AD patients) from Madrid region's hospitals. Experienced neurologists diagnosed these cases following the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)'s Alzheimer's criteria, performing, among other explorations and tests, a minimum neuropsychological exploration that included the Mini-Mental State Examination test.	BN's classification performance is remarkable compared with other machine learning methods, achieving 91% accuracy and 94% precision in mild and moderate AD patients. Apart from this, the BN model facilitates the explanation of the reasoning process and the validation of the conclusions and allows the study of uncommon declarative semantic memory impairments.	Our method is able to analyse LSCD in a wide set of semantic categories throughout the progression of CI, being a valuable first screening method in AD diagnosis in its early stages. Because of its low cost, it can be used for routine clinical evaluations or screenings to detect AD in its early stages. Besides, due to its knowledge-based structure, it can be easily extended to provide an explanation of the diagnosis and to the study of other neurodegenerative diseases. Further, this is a key advantage of BNs over other machine learning methods with similar performance: it is a recognisable and explanatory model that allows one to study irregularities in different semantic categories.	
25915711	Caring for offspring diagnosed with a chronic psychological disorder such as autism spectrum disorder (ASD) is used in research as a model of chronic stress. This chronic stress has been reported to have deleterious effects on caregivers' cognition, particularly in verbal declarative memory. Moreover, such cognitive decline may be mediated by testosterone (T) levels and negative affect, understood as depressive mood together with high anxiety and anger. This study aimed to compare declarative memory function in middle-aged women who were caregivers for individuals with ASD (n = 24; mean age = 45) and female controls (n = 22; mean age = 45), using a standardised memory test (Rey's Auditory Verbal Learning Test). It also sought to examine the role of care recipient characteristics, negative mood and T levels in memory impairments. ASD caregivers were highly sensitive to proactive interference and verbal forgetting. In addition, they had higher negative affect and T levels, both of which have been associated with poorer verbal memory performance. Moreover, the number of years of caregiving affected memory performance and negative affect, especially, in terms of anger feelings. On the other hand, T levels in caregivers had a curvilinear relationship with verbal memory performance; that is, increases in T were associated with improvements in verbal memory performance up to a certain point, but subsequently, memory performance decreased with increasing T. Chronic stress may produce disturbances in mood and hormonal levels, which in turn might increase the likelihood of developing declarative memory impairments although caregivers do not show a generalised decline in memory. These findings should be taken into account for understanding the impact of cognitive impairments on the ability to provide optimal caregiving. 
25912599	Deficits in declarative memory performance are among the most severe neuropsychological impairments in schizophrenia and contribute to poor clinical outcomes. The importance of sleep for brain plasticity and memory consolidation is widely accepted, and sleep spindles seem to play an important role in these processes. The aim of this study was to test the associations of sleep spindles and picture memory consolidation in patients with schizophrenia and healthy controls.We studied 16 patients with schizophrenia on stable antipsychotic medication (mean age ± standard deviation, 29.4 ± 6.4 years) and 16 healthy controls matched for age and educational level. Sleep was recorded and scored according to American Academy of Sleep Medicine (AASM) standard criteria. We performed a picture recognition paradigm and compared recognition performance for neutral and emotional pictures in sleep and wake conditions.	Recognition accuracy was better in healthy controls than in patients with schizophrenia in the sleep and wake conditions. However, the memory-promoting effect of sleep was significantly lower in schizophrenia patients than in controls. Sleep spindle activity was reduced in patients, and sleep spindle density was correlated with sleep-associated facilitation of recognition accuracy for neutral pictures.	Reduced sleep spindles seem to play an important role as a possible mechanism or biomarker for impaired sleep-related memory consolidation in patients with schizophrenia, and are a new target for treatment to improve memory functions and clinical outcomes in these patients.	
25904779	Individuals value the opportunity to make choices and exert control over their environment. This perceived sense of agency has been shown to have broad influences on cognition, including preference, decision-making, and valuation. However, it is unclear whether perceived control influences memory. Using a combined behavioral and functional magnetic resonance imaging approach, we investigated whether imbuing individuals with a sense of agency over their learning experience influences novel memory encoding. Participants encoded objects during a task that manipulated the opportunity to choose. Critically, unlike previous work on active learning, there was no relationship between individuals' choices and the content of memoranda. Despite this, we found that the opportunity to choose resulted in robust, reliable enhancements in declarative memory. Neuroimaging results revealed that anticipatory activation of the striatum, a region associated with decision-making, valuation, and exploration, correlated with choice-induced memory enhancements in behavior. These memory enhancements were further associated with interactions between the striatum and hippocampus. Specifically, anticipatory signals in the striatum when participants are alerted to the fact that they will have to choose one of two memoranda were associated with encoding success effects in the hippocampus on a trial-by-trial basis. The precedence of the striatal signal in these interactions suggests a modulatory relationship of the striatum over the hippocampus. These findings not only demonstrate enhanced declarative memory when individuals have perceived control over their learning but also support a novel mechanism by which these enhancements emerge. Furthermore, they demonstrate a novel context in which mesolimbic and declarative memory systems interact. 
25894546	Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning, and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. Rapid eye movement (REM) may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction, and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep's effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. (PsycINFO Database Record 
25890819	In a recent study, we demonstrated that sleep-dependent consolidation of declarative memories is preserved in older adults. The present study examined whether this benefit of sleep for declarative learning in older adults reflects a passive role of sleep in protecting memories from decay or an active role in stabilizing them. Young and older adults learned a visuospatial task, and recall was probed after sleep or wake. Although a reduction in performance was observed after sleep and wake, task-related interference before recall had a larger detriment on performance in the wake condition. This was true for young and high performing older adults only. Low performing older adults did not receive a benefit of sleep on the visuospatial task. Performance changes were associated with early night nonrapid eye movement sleep in young adults and with early night rapid eye movement sleep in high performing older adults. These results demonstrate that performance benefits from sleep in older adults as a result of an active memory stabilization process; importantly, the extent of this benefit of sleep is closely linked to the level of initial acquisition of the episodic information in older adults. 
25888454	This article is part of a Special Issue "SBN 2014". Stress is a potential etiology contributor to both post-traumatic stress disorders (PTSD) and major depression. One stress-related neuropeptide that is hypersecreted in these disorders is corticotropin releasing factor (CRF). Dysregulation of CRF has long been linked to the emotion and mood symptoms that characterize PTSD and depression. However, the idea that CRF also mediates the cognitive disruptions observed in patients with these disorders has received less attention. Here we review literature indicating that CRF can alter cognitive functions. Detailed are anatomical studies revealing that CRF is poised to modulate regions required for learning and memory. We also describe preclinical behavioral studies that demonstrate CRF's ability to alter fear conditioning, impair memory consolidation, and alter a number of executive functions, including attention and cognitive flexibility. The implications of these findings for the etiology and treatment of the cognitive impairments observed in stress-related psychiatric disorders are described. 
25880710	To investigate changes of cognitive performances in female elderly patients with osteoporosis and to determine whether any impairments can be attributed to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.This cross-sectional study included 277 postmenopausal women, who were divided into an osteoporosis patients group (n = 170) and an age, gender and educational history matching control group (n = 107). All the subjects completed a set of neuropsychological tests for the elderly for cognitive assessment, which included measures of executive function, episodic memory, attention and processing speed, semantic memory, and visuospatial construction. Blood biomarkers for osteoporosis, as well as diurnal rhythms of cortisol levels were used as cognitive performance correlation parameters in linear multivariate regression analyses.	Individuals with osteoporosis had poorer cognitive scores (P < 0.001). When dividing the osteoporosis patients according to their Mini-Mental State Examination scores into mild cognitive impairment (MCI) and normal cognitive (NC) performance groups, Auditory Verbal Learning trial 1-5 scores were lower (P = 0.006) and Trail Making Test-A scores were higher (P = 0.05) in the MCI compared to the NC group. Further comparison of the MCI and NC groups revealed that declarative memory was inversely associated with cortisol levels (P < 0.001), but this association became marginal when 25-hydroxy vitamin D was included in the linear multivariate regression analyses (P = 0.06).	Patients with osteoporosis are prone to cognitive impairments especially declarative memory deficits. The cognitive impairment may be the result of HPA axis dysregulation but 25-hydroxy vitamin D serum concentrations might be compensatory or even a potent contributing factor.	
25862600	Temporal lobe epilepsy (TLE) is often associated with memory deficits. Given the putative role for sleep spindles memory consolidation, spindle generators skewed toward the affected lobe in TLE subjects may be a neurophysiological marker of defective memory. Slow-oscillatory transcranial direct current stimulation (sotDCS) during slow waves sleep (SWS) has previously been shown to enhance sleep-dependent memory consolidation by increasing slow-wave sleep and modulating sleep spindles.To test if anodal sotDCS over the affected TL prior to a nap affects sleep spindles and whether this improves memory consolidation.	Randomized controlled cross-over study. 12 people with TLE underwent sotDCS (0.75 Hz; 0-250 μV, 30 min) or sham before daytime nap. Declarative verbal and visuospatial learning were tested. Fast and slow spindle signals were recorded by 256-channel EEG during sleep. In both study arms, electrical source imaging (ESI) localized cortical generators. Neuropsychological data were analyzed with general linear model statistics or the Kruskal-Wallis test (P or Z < 0.05), and neurophysiological data tested with the Mann-Whitney t test and binomial distribution test (P or Z < 0.05).	An improvement in declarative (P = 0.05) and visuospatial memory performance (P = 0.048) emerged after sotDCS. SotDCS increased slow spindle generators current density (Z = 0.001), with a shift to the anterior cortical areas.	Anodal sotDCS over the affected temporal lobe improves declarative and visuospatial memory performance by modulating slow sleep spindles cortical source generators. SotDCS appears a promising tool for memory rehabilitation in people with TLE.	
25845686	Several studies proposed a link between sleep spindles and sleep dependent memory consolidation in declarative learning tasks. In addition to these state-like aspects of sleep spindles, they have also trait-like characteristics, i.e., were related to general cognitive performance, an important distinction that has often been neglected in correlative studies. Furthermore, from the multitude of different sleep spindle measures, often just one specific aspect was analyzed. Thus, we aimed at taking multidimensional aspects of sleep spindles into account when exploring their relationship to word-pair memory consolidation.Each subject underwent 2 study nights with all-night high-density electroencephalographic (EEG) recordings. Sleep spindles were automatically detected in all EEG channels. Subjects were trained and tested on a word-pair learning task in the evening, and retested in the morning to assess sleep related memory consolidation (overnight retention). Trait-like aspects refer to the mean of both nights and state-like aspects were calculated as the difference between night 1 and night 2.	Sleep laboratory.	Twenty healthy male subjects (age: 23.3 ± 2.1 y).	Overnight retention was negatively correlated with trait-like aspects of fast sleep spindle density and positively with slow spindle density on a global level. In contrast, state-like aspects were observed for integrated slow spindle activity, which was positively related to the differences in overnight retention in specific regions.	Our results demonstrate the importance of a multidimensional approach when investigating the relationship between sleep spindles and memory consolidation and thereby provide a more complete picture explaining divergent findings in the literature.	
25834038	Following a change in the environment or motor apparatus, human subjects are able to rapidly compensate their movements to recover accurate performance. This ability to adapt is thought to be achieved through multiple, qualitatively distinct learning processes acting in parallel. It is unclear, however, what the relative contributions of these multiple processes are during learning. In particular, long-term memories in such paradigms have been extensively studied through the phenomenon of savings-faster adaptation to a given perturbation the second time it is experienced-but it is unclear which components of learning contribute to this effect. Here we show that distinct components of learning in an adaptation task can be dissociated based on the amount of preparation time they require. During adaptation, we occasionally forced subjects to generate movements at very low preparation times. Early in learning, subjects expressed only a limited amount of their prior learning in these trials, though performance improved gradually with further practice. Following washout, subjects exhibited a strong and persistent aftereffect in trials in which preparation time was limited. When subjects were exposed to the same perturbation twice in successive days, they adapted faster the second time. This savings effect was, however, not seen in movements generated at low preparation times. These results demonstrate that preparation time plays a critical role in the expression of some components of learning but not others. Savings is restricted to those components that require prolonged preparation to be expressed and might therefore reflect a declarative rather than procedural form of memory. 
25824306	Previous studies on the neurocognitive impact of cannabis use have found working and declarative memory deficits that tend to normalize with abstinence. An unexplored aspect of cognitive function in chronic cannabis users is the ability to distinguish between veridical and illusory memories, a crucial aspect of reality monitoring that relies on adequate memory function and cognitive control. Using functional magnetic resonance imaging, we show that abstinent cannabis users have an increased susceptibility to false memories, failing to identify lure stimuli as events that never occurred. In addition to impaired performance, cannabis users display reduced activation in areas associated with memory processing within the lateral and medial temporal lobe (MTL), and in parietal and frontal brain regions involved in attention and performance monitoring. Furthermore, cannabis consumption was inversely correlated with MTL activity, suggesting that the drug is especially detrimental to the episodic aspects of memory. These findings indicate that cannabis users have an increased susceptibility to memory distortions even when abstinent and drug-free, suggesting a long-lasting compromise of memory and cognitive control mechanisms involved in reality monitoring. 
25818846	The hippocampus plays an important role in spatial and declarative memory. Zn(2+) is released from glutamatergic (zincergic) neuron terminals in the hippocampus and serves as a signal factor. Synaptic Zn(2+) homeostasis is critical for cognitive activity in the hippocampus. Amyloid-β (Aβ) is a candidate for the pathogenesis of Alzheimer's disease (AD) and interacts with Zn(2+).This paper gives an overview of the interaction between Aβ and Zn(2+) in the extracellular compartment in the pathophysiology of AD. Aβ is aggregated with Zn(2+) and the aggregation of Aβ-peptides is widely considered to be the critical step in the pathogenesis of AD. The reader will gain an understanding of recent studies on the importance of the interaction of Aβ with Zn(2+) in the pathophysiology and therapeutic strategy of AD. Extracellular Zn(2+) in the hippocampus is a therapeutic target for AD.	Recent studies show that the inhibition of the interaction of Aβ with extracellular Zn(2+) ameliorates the pathophysiology of AD and that extracellular Zn(2+) in the hippocampus is involved in transiently Aβ-induced cognition deficits. Zn(2+) may play as a key-mediating factor in pathophysiology in which Aβ is involved and is a targeting molecule to prevent the pathogenesis of AD.	
25817848	Two experiments investigated effects of sleep on consolidation and integration of novel form-meaning mappings using size congruity and semantic distance paradigms. Both paradigms have been used in previous studies to measure automatic access to word meanings. When participants compare semantic or physical font size of written word-pairs (e.g. BEE-COW), judgments are typically faster if relative sizes are congruent across both dimensions. Semantic distance effects are also found for wellestablished words, with semantic size judgements faster for pairs that differ substantially on this dimension. English-speaking participants learned novel form-meaning mappings with Mandarin (Experiment 1) or Malay (Experiment 2) words and were tested following overnight sleep or a similar duration awake. Judgements on English words controlled for circadian effects. The sleep group demonstrated selective stronger size congruity and semantic distance effects for novel word-pairs. This benefit occurred in Experiment 1 for semantic size comparisons of novel words, and in Experiment 2 on comparisons where novel pairs had large distances and font differences (for congruity effects) or in congruent trials (for semantic distance effects). Conversely, these effects were equivalent across sleep and wake for English words. Experiment 2 included polysomnography data and revealed that changes in the strength of semantic distance and congruity effects were positively correlated with slow-wave sleep and sleep spindles respectively. These findings support systems consolidation accounts of declarative learning and suggest that sleep plays an active role in integrating new words with existing knowledge, resulting in increased automatic access of the acquired knowledge. 
25816233	There is emerging evidence from imaging studies that parietal and temporal cortices act together to achieve successful recognition of declarative information; nevertheless, the precise role of these regions remains elusive. To evaluate the role of these brain areas in declarative memory retrieval, we applied bilateral tDCS, with anode over the left and cathode over the right parietal or temporal cortices separately, during the recognition phase of a verbal learning paradigm using a balanced old-new decision task. In a parallel group design, we tested three different groups of healthy adults, matched for demographic and neurocognitive status: two groups received bilateral active stimulation of either the parietal or the temporal cortex, while a third group received sham stimulation. Accuracy, discriminability index (d') and reaction times of recognition memory performance were measurements of interest. The d' sensitivity index and accuracy percentage improved in both active stimulation groups, as compared with the sham one, while reaction times remained unaffected. Moreover, the analysis of accuracy revealed a different effect of tDCS for old and new item recognition. While the temporal group showed enhanced performance for old item recognition, the parietal group was better at correctly recognising new ones. Our results support an active role of both of these areas in memory retrieval, possibly underpinning different stages of the recognition process. 
25805323	Memory plays a critical role in time estimation, yet detailed mechanisms underlying temporal memory have not been fully understood. The current functional magnetic resonance imaging (fMRI) study investigated memory phenomena in absolute identification of time durations and line lengths. In both time and length identification, participants responded faster to end-of-range stimuli (e.g., the shortest or longest items of the stimulus set) than to middle stimuli. Participants performed worse in the incongruent condition (mismatch between time and length in the stimulus position) than in the congruent condition, indicating cross-dimensional interference between time and length. Both phenomena reflect increased difficulty of retrieving information relevant to the current context in the presence of context-irrelevant information. A region in the lateral inferior prefrontal cortex showed a greater response to the middle stimuli and in the incongruent condition suggesting greater demands for controlled memory retrieval. A cognitive model based on the ACT-R (Adaptive Control of Thought - Rational) declarative memory mechanisms accounted for the major behavioral and imaging results. The results suggest that contextual effects in temporal memory can be understood in terms of domain-general memory principles established outside the time estimation domain. 
25797834	Novelty and appropriateness have been recognized as the fundamental features of creative thinking. However, the brain mechanisms underlying these features remain largely unknown. In this study, we used event-related functional magnetic resonance imaging (fMRI) to dissociate these mechanisms in a revised creative chunk decomposition task in which participants were required to perform different types of chunk decomposition that systematically varied in novelty and appropriateness. We found that novelty processing involved functional areas for procedural memory (caudate), mental rewarding (substantia nigra, SN), and visual-spatial processing, whereas appropriateness processing was mediated by areas for declarative memory (hippocampus), emotional arousal (amygdala), and orthography recognition. These results indicate that non-declarative and declarative memory systems may jointly contribute to the two fundamental features of creative thinking.
25796966	To examine the effects of online Cognitive Behavior Therapy for Insomnia (CBTI) on adolescents' sleep and cognitive functioning.32 adolescents (13-19 years, M = 15.9, SD = 1.6) with DSM-5 insomnia disorder, were randomly assigned to a treatment group (n = 18) or a waiting list (n = 14). Treatment consisted of six guided self-help online CBTI sessions. Both groups were assessed at baseline and post-treatment. Sleep was measured with actigraphy, sleep logs, and questionnaires. Cognitive functioning was assessed with a battery of standard cognitive tests.	After CBTI the treatment group showed significant improvements compared to the waiting list group in sleep efficiency from actigraphy and sleep logs. This finding was confirmed by improvements in other sleep variables from sleep logs, and in symptoms of chronic sleep reduction and insomnia. Most participants from the treatment group improved to sub clinical levels of insomnia. Cognitive functioning of the treatment group showed more improvement compared to the waiting list in visuospatial processing, selective attention and phonological working memory, and a trend of improvement in response inhibition and set shifting, letter fluency and sustained attention, but not in declarative memory, visuospatial working memory, category fluency, and general cognitive speed. Changes in sleep appeared to be related to changes in cognitive functioning.	These results indicate that CBTI can have positive effects on cognitive functions in adolescents, with notable improvements in visuospatial processing and phonological working memory but not in visuospatial working memory.	
25795621	A 2006 trial in healthy medical students found that anodal slow oscillating tDCS delivered bi-frontally during slow wave sleep had an enhancing effect in declarative, but not procedural memory. Although there have been supporting animal studies, and similar findings in pathological groups, this study has not been replicated, or refuted, in the intervening years. We therefore tested these earlier results for replication using similar methods with the exception of current waveform (square in our study, nearly sinusoidal in the original).Our objective was to test the findings of a 2006 trial suggesting bi-frontal anodal tDCS during slow wave sleep enhances declarative memory.	Twelve students (mean age 25, 9 women) free of medical problems underwent two testing conditions (active, sham) in a randomized counterbalanced fashion. Active stimulation consisted of oscillating square wave tDCS delivered during early Non-Rapid Eye Movement (NREM) sleep. The sham condition consisted of setting-up the tDCS device and electrodes, but not turning it on during sleep. tDCS was delivered bi-frontally with anodes placed at F3/F4, and cathodes placed at mastoids. Current density was 0.517 mA/cm(2), and oscillated between zero and maximal current at a frequency of 0.75 Hz. Stimulation occurred during five-five minute blocks with 1-min inter-block intervals (25 min total stimulation). The primary outcomes were both declarative memory consolidation measured by a paired word association test (PWA), and non-declarative memory, measured by a non-dominant finger-tapping test (FTT). We also recorded and analyzed sleep EEG.	There was no difference in the number of paired word associations remembered before compared to after sleep [(active = 3.1 ± 3.0 SD more associations) (sham = 3.8 ± 3.1 SD more associations)]. Finger tapping improved, (non-significantly) following active stimulation [(3.6 ± 2.7 SD correctly typed sequences) compared to sham stimulation (2.3 ± 2.2 SD correctly typed sequences)].	In this study, we failed to find improvements in declarative or performance memory and could not replicate an earlier study using nearly identical settings. Specifically we failed to find a beneficial effect on either overnight declarative or non-declarative memory consolidation via square-wave oscillating tDCS intervention applied bi-frontally during early NREM sleep. It is unclear if the morphology of the tDCS pulse is critical in any memory related improvements.	
25795599	Multiple sclerosis (MS) is a progressive inflammatory autoimmune disease that is characterized by demyelination and axonal damage in the nervous system. One obvious consequence is a cumulative loss of muscle control. However, cognitive dysfunction affects roughly half of MS sufferers, sometimes already early in the disease course. Although long-term (remote) memory is typically unaffected, the ability to form new declarative memories becomes compromised. A major structure for the encoding of new declarative memories is the hippocampus. Encoding is believed to be mediated by synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength. Here, in an animal model of MS we explored whether disease symptoms are accompanied by a loss of functional neuronal integrity, synaptic plasticity, or hippocampus-dependent learning ability. In mice that developed MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), passive properties of CA1 pyramidal neurons were unaffected, although the ability to fire action potentials became reduced in the late phase of EAE. LTP remained normal in the early phase of MOG35-55-induced EAE. However, in the late phase, LTP was impaired and LTP-related spatial memory was impaired. In contrast, LTD and hippocampus-dependent object recognition memory were unaffected. These data suggest that in an animal model of MS hippocampal function becomes compromised as the disease progresses. 
25793291	It has been reported that reality evaluation and recognition are impaired in patients with schizophrenia and these impairments are related to the severity of psychotic symptoms. The current study aimed to investigate the neural basis of impairments in reality evaluation and recognition and their relationships with cognitive insight in schizophrenia. During functional magnetic resonance imaging, 20 patients with schizophrenia and 20 healthy controls performed a set of reality evaluation and recognition tasks, in which subjects judged whether scenes in a series of drawings were real or unreal and whether they were familiar or novel. During reality evaluation, patients showed decreased activity in various regions including the inferior parietal lobule, retrosplenial cortex and parahippocampal gyrus, compared with controls. Particularly, parahippocampal gyrus activity was correlated with the severity of positive symptoms in patients. During recognition, patients also exhibited decreased activity in various regions, including the dorsolateral prefrontal cortex, inferior parietal lobule and posterior cingulate cortex. Particularly, inferior parietal lobule activity and posterior cingulate cortex activity were correlated with cognitive insight in patients. These findings provide evidence that neural impairments in reality evaluation and recognition are related to psychotic symptoms. Anomalous appraisal of context by dysfunctions in the context network may contribute to impairments in the reality processing in schizophrenia, and abnormal declarative memory processes may be involved in cognitive insight in patients with schizophrenia. 
25792761	In this article, we summarize the state-of-science knowledge regarding the associations between hypnosis and brain oscillations. Brain oscillations represent the combined electrical activity of neuronal assemblies, and are usually measured as specific frequencies representing slower (delta, theta, alpha) and faster (beta, gamma) oscillations. Hypnosis has been most closely linked to power in the theta band and changes in gamma activity. These oscillations are thought to play a critical role in both the recording and recall of declarative memory and emotional limbic circuits. Here we propose that it is this role that may be the mechanistic link between theta (and perhaps gamma) oscillations and hypnosis; specifically that theta oscillations may facilitate, and that changes in gamma activity observed with hypnosis may underlie, some hypnotic responses. If these hypotheses are supported, they have important implications for both understanding the effects of hypnosis, and for enhancing response to hypnotic treatments.
25788454	A longstanding debate in hippocampus research has revolved around how to reconcile spatial mapping functions of the hippocampus with the global amnesia produced by hippocampal damage in humans. Is the hippocampus primarily a cognitive map used to support spatial learning, or does it support more general types of learning necessary for declarative memory? In recent years, a general consensus has emerged that the hippocampus receives both spatial and nonspatial inputs from the entorhinal cortex. The hippocampus creates representations of experience in a particular spatial and temporal context. This process allows the individual components of experience to be stored in such a way that they can be retrieved together as a conscious recollection.
25788434	Analysis sought to determine whether Wechsler Memory Scale-Logical Memory (LM)-correct responses and errors were related to magnetic resonance imaging (MRI) brain volume measurements.The LM immediate (LM-I) and LM delay (LM-D) free recall correct responses and related and unrelated errors were scored. Principal components analysis yielded a 3-factor solution: LM-I and LM-D correct responses, LM-I and LM-D-unrelated errors, and LM-I/-D-related errors. The MRI total cerebral brain volume, frontal brain volume, temporal horn volume (THV), and white matter hyperintensities volume (WMHIV) were obtained.	Increasing THV (suggesting greater regional atrophy) was associated with lower scores on the LM-correct responses factor. Extensive WMHIV was associated with higher scores on the LM-related errors factor.	These results suggest that LM-correct responses could relate to emerging brain alterations. Longitudinal research might enhance the sensitivity of this test to identify preclinical impairment and persons at risk of mild cognitive impairment and dementia.	
25786428	Artificial intelligence (IA) is the subject of much research, but also many fantasies. It aims to reproduce human intelligence in its learning capacity, knowledge storage and computation. In 2014, the Defense Advanced Research Projects Agency (DARPA) started the restoring active memory (RAM) program that attempt to develop implantable technology to bridge gaps in the injured brain and restore normal memory function to people with memory loss caused by injury or disease. In another IA's field, computational ontologies (a formal and shared conceptualization) try to model knowledge in order to represent a structured and unambiguous meaning of the concepts of a target domain. The aim of these structures is to ensure a consensual understanding of their meaning and a univariant use (the same concept is used by all to categorize the same individuals). The first representations of knowledge in the AI's domain are largely based on model tests of semantic memory. This one, as a component of long-term memory is the memory of words, ideas, concepts. It is the only declarative memory system that resists so remarkably to the effects of age. In contrast, non-specific cognitive changes may decrease the performance of elderly in various events and instead report difficulties of access to semantic representations that affect the semantics stock itself. Some dementias, like semantic dementia and Alzheimer's disease, are linked to alteration of semantic memory. We propose in this paper, using the computational ontologies model, a formal and relatively thin modeling, in the service of neuropsychology: 1) for the practitioner with decision support systems, 2) for the patient as cognitive prosthesis outsourced, and 3) for the researcher to study semantic memory.
25780564	It has been proposed that children with Specific Language Impairment (SLI) have a selective deficit in procedural learning, with relatively spared declarative learning. In previous studies we and others confirmed deficits in procedural learning of sequences, using both verbal and nonverbal materials. Here we studied the same children using a task that implicates the declarative system, auditory-visual paired associate learning. There were parallel tasks for verbal materials (vocabulary learning) and nonverbal materials (meaningless patterns and sounds).Participants were 28 children with SLI aged 7-11 years, 28 younger typically-developing children matched for raw scores on a test of receptive grammar, and 20 typically-developing children matched on chronological age. Children were given four sessions of paired-associate training using a computer game adopting an errorless learning procedure, during which they had to select a picture from an array of four to match a heard stimulus. In each session they did both vocabulary training, where the items were eight names and pictures of rare animals, and nonverbal training, where stimuli were eight visual patterns paired with complex nonverbal sounds. A total of 96 trials of each type was presented over four days.	In all groups, accuracy improved across the four sessions for both types of material. For the vocabulary task, the age-matched control group outperformed the other two groups in the starting level of performance, whereas for the nonverbal paired-associate task, there were no reliable differences between groups. In both tasks, rate of learning was comparable for all three groups.	These results are consistent with the Procedural Deficit Hypothesis of SLI, in finding spared declarative learning on a nonverbal auditory-visual paired associate task. On the verbal version of the task, the SLI group had a deficit in learning relative to age-matched controls, which was evident on the first block in the first session. However, the subsequent rate of learning was consistent across all three groups. Problems in vocabulary learning in SLI could reflect the procedural demands of remembering novel phonological strings; declarative learning of crossmodal links between auditory and visual information appears to be intact.	
25780085	The ability to remember life's events, and to leverage memory to guide behavior, defines who we are and is critical for everyday functioning. The neural mechanisms supporting such mnemonic experiences are multiprocess and multinetwork in nature, which creates challenges for studying them in humans and animals. Advances in noninvasive neuroimaging techniques have enabled the investigation of how specific neural structures and networks contribute to human memory at its many cognitive and mechanistic levels. In this review, we discuss how functional and anatomical imaging has provided novel insights into the types of information represented in, and the computations performed by, specific medial temporal lobe (MTL) regions, and we consider how interactions between the MTL and other cortical and subcortical structures influence what we learn and remember. By leveraging imaging, researchers have markedly advanced understanding of how the MTL subserves declarative memory and enables navigation of our physical and mental worlds. 
25776507	Methylphenidate (MPH) is a central nervous system stimulant that is widely used to treat attention deficit hyperactivity disorder (ADHD) and has been shown to improve attention, cognitive function and behaviors in both patients and animal models of ADHD. Even among normal healthy people, MPH can facilitate the consolidation of memories and improve declarative memory. Using microarray techniques, we aimed to find new pharmacology profile of MPH. A Làt maze experiment showed that locomotor activity and non-selective attention were affected by 2 weeks of exposure to MPH. Then, we identified long non-coding RNA (lncRNA) signatures in the prefrontal cortex of rats; 461 up-regulated lncRNAs and 97 down-regulated lncRNAs were found in the MPH-exposed group compared with the control group using fold-change >1.5. GO and KEGG pathway analyses indicated biological functions related to the metabolism of neural chemical compounds and nerve cell development. Furthermore, we reported changes in uc.173+ related to the UBE2B gene, which may affect neurite outgrowth and axonal regeneration. At the same time, MRAK081997 associated with the DHFR gene may be involved in axon regeneration in the rodent central nervous system through DNA methylation. Our study showed distinct expression profiles of lncRNAs in the normal rat prefrontal cortex after exposure to MPH, offering information for further research of MPH and may suggesting a new therapeutic target for ADHD. 
25770921	The medial temporal lobe is a key region in the formation and consolidation of conscious or declarative memories. In this review, we will first consider the role of the hippocampus and its surrounding medial temporal lobe structures in recognition memory from a historical perspective. According to the dual process model of recognition memory, recognition judgments can be based on the recollection of details about previous presented stimuli or on the feeling of familiarity. Studies in humans, primates and rodents suggest that the hippocampus, the parahippocampal cortex and the perirhinal cortex play different roles in recollection and familiarity. Then, we will describe the role of the hippocampus and neocortex in memory consolidation: a process in which novel memories become integrated into long-term memory. After presenting possible mechanisms underlying sleep-dependent declarative memory consolidation, we will discuss the phenomenon of accelerated long-term forgetting. This type of memory deficit is often observed in epileptic patients with a hippocampal lesion, and provides a novel opportunity to investigate post-encoding and memory consolidation processes. 
25768336	Sleep has been shown to improve the retention of newly learned words. However, most methodologies have used artificial or foreign language stimuli, with learning limited to word/novel word or word/image pairs. Such stimuli differ from many word-learning scenarios in which definition strings are learned with novel words. Thus, we examined sleep's benefit on learning new words within a native language by using very low-frequency words. Participants learned 45 low-frequency English words and, at subsequent recall, attempted to recall the words when given the corresponding definitions. Participants either learned in the morning with recall in the evening (wake group), or learned in the evening with recall the following morning (sleep group). Performance change across the delay was significantly better in the sleep than the wake group. Additionally, the Levenshtein distance, a measure of correctness of the typed word compared with the target word, became significantly worse following wake, whereas sleep protected correctness of recall. Polysomnographic data from a subsample of participants suggested that rapid eye movement (REM) sleep may be particularly important for this benefit. These results lend further support for sleep's function on semantic learning even for word/definition pairs within a native language. 
25751131	There is now abundant evidence that human learning and memory are governed by multiple systems. As a result, research is now turning to the next question of how these putative systems interact. For instance, how is overall control of behavior coordinated, and does learning occur independently within systems regardless of what system is in control? Behavioral, neuroimaging, and neuroscience data are somewhat mixed with respect to these questions. Human neuroimaging and animal lesion studies suggest independent learning and are mostly agnostic with respect to control. Human behavioral studies suggest active inhibition of behavioral output but have little to say regarding learning. The results of two perceptual category-learning experiments are described that strongly suggest that procedural learning does occur while the explicit system is in control of behavior and that this learning might be just as good as if the procedural system was controlling the response. These results are consistent with the idea that declarative memory systems inhibit the ability of the procedural system to access motor output systems but do not prevent procedural learning.
25750853	Aging is characterized by a decline in cognitive functions, particularly in the domains of executive function, processing speed and episodic memory. These age-related declines are exacerbated by cardiovascular disease (CVD) and cardiovascular risk factors (hypertension, diabetes, obesity, elevated total cholesterol). Structural and functional alterations in brain regions, including the fronto-parietal and medial temporal lobes, have been linked to age- and CVD-related cognitive decline. Multiple recent studies indicate that aerobic exercise programs may slow the progression of age-related neural changes and reduce the risk for mild cognitive impairment as well as dementia. We review age- and CVD-related decline in cognition and the underlying changes in brain morphology and function, and then clarify the impact of aerobic exercise on moderating these patterns.
25731765	The idea that memory is not a single mental faculty has a long and interesting history but became a topic of experimental and biologic inquiry only in the mid-20th century. It is now clear that there are different kinds of memory, which are supported by different brain systems. One major distinction can be drawn between working memory and long-term memory. Long-term memory can be separated into declarative (explicit) memory and a collection of nondeclarative (implicit) forms of memory that include habits, skills, priming, and simple forms of conditioning. These memory systems depend variously on the hippocampus and related structures in the parahippocampal gyrus, as well as on the amygdala, the striatum, cerebellum, and the neocortex. This work recounts the discovery of declarative and nondeclarative memory and then describes the nature of declarative memory, working memory, nondeclarative memory, and the relationship between memory systems. 
25727677	Impaired learning and memory are common symptoms of neurodegenerative and neuropsychiatric diseases. Present, there are several behavioural test employed to assess cognitive functions in animal models, including the frequently used novel object recognition (NOR) test. However, although atypical functional brain lateralization has been associated with neuropsychiatric conditions, spanning from schizophrenia to autism, few animal models are available to study this phenomenon in learning and memory deficits. Here we present a visual lateralization NOR model (VLNOR) in zebrafish larvae as an assay that combines brain lateralization and NOR. In zebrafish larvae, learning and memory are generally assessed by habituation, sensitization, or conditioning paradigms, which are all representatives of nondeclarative memory. The VLNOR is the first model for zebrafish larvae that studies a memory similar to the declarative memory described for mammals. We demonstrate that VLNOR can be used to study memory formation, storage, and recall of novel objects, both short and long term, in 10-day-old zebrafish. Furthermore we show that the VLNOR model can be used to study chemical modulation of memory formation and maintenance using dizocilpine (MK-801), a frequently used non-competitive antagonist of the NMDA receptor, used to test putative antipsychotics in animal models. 
25720656	Many young females take exogenous hormones as oral contraceptive (OC), a condition rarely controlled for in studies on sleep and memory consolidation even though sex hormones influence consolidation. This study investigated the effects of OCs on sleep-related consolidation of a motor and declarative task, utilizing a daytime nap protocol. Fifteen healthy, young females taking OCs came to the sleep lab for three different conditions: nap with previous learning, wake with previous learning and nap without learning. They underwent each condition twice, once during the "pill-active" weeks and once during the "pill-free" week, resulting in 6 visits. In all conditions, participants showed a significant off-line consolidation effect, independent of pill week or nap/wake condition. There were no significant differences in sleep stage duration, spindle activity or spectral EEG frequency bands between naps with or without the learning condition. The present data showed a significant off-line enhancement in memory irrespective of potential beneficial effects of a nap. In comparison to previous studies, this may suggest that the use of OCs may enhance off-line memory consolidation in motor and verbal tasks per se. These results stress the importance to control for the use of OCs in studies focusing on memory performance.
25715882	Older patients may be more vulnerable to the deleterious effect of depressive episodes on delayed narrative memory, a cognitive task which reflects hippocampal activity. We aimed to disentangle which factors could explain such increased vulnerability in the elderly, including the poorer response to treatment, a longer lifetime exposure to past depressive episodes, and lower baseline memory skills.From an initial sample of 8,229 depressed outpatients, we focused on the 2,424 treatment responders, and compared older (65 years old and over, N = 233) to younger (N = 2,191) ones. These patients were included through general practitioners' assessment and tested for the Wechsler delayed paragraph recall index, a valid and sensitive test assessing verbal declarative memory (and a marker of the hippocampal function), at baseline and after six weeks of treatment.	As expected, older patients after response to antidepressants showed decreased narrative memory abilities compared to younger ones. As baseline memory performance and residual depressive symptoms were also found in excess in this sample, they could act as confounders. Indeed, after controlling for these two factors, the role of age in memory performance after treatment response was ruled out.	The potential "toxicity" of a depressive episode to cognitive functions related to the hippocampus may not be more critical in older patients compared to younger ones. Limiting remaining depressive symptoms in older depressed patients might be a way to counteract the observed worsening of memory functions in depressed patients.	
25709571	Reactivation of long-term memory can render the memory item temporarily labile, offering an opportunity to modify it via behavioral or pharmacological intervention. Declarative memory reactivation is accompanied by a metamemory ability to subjectively assess the knowledge available concerning the target item (Feeling of knowing, FOK). We set out to examine whether FOK can predict the extent of change of long-term episodic memories by post-retrieval manipulations. To this end, participants watched a short movie and were immediately thereafter tested on their memory for it. A day later, they were reminded of that movie, and either immediately or 1 day later, were presented with a second movie. The reminder phase consisted of memory cues to which participants were asked to judge their FOK regarding the original movie. The memory performance of participants to whom new information was presented immediately after reactivating the original episode corresponded to the degree of FOK ratings upon reactivation such that the lower their FOK, the less their memory declined. In contrast, no relation was found between FOK and memory strength for those who learned new information 1 day after the reminder phase. Our findings suggest that the subjective accessibility of reactivated memories may determine the extent to which new information might modify those memories. 
25708092	Emotion boosts the consolidation of events in the declarative memory system. Rapid eye movement (REM) sleep is believed to foster the memory consolidation of emotional events. On the other hand, REM sleep is assumed to reduce the emotional tone of the memory. Here, we investigated the effect of selective REM-sleep deprivation, SWS deprivation, or wake on the affective evaluation and consolidation of emotional and neutral pictures. Prior to an 9-h retention interval, sixty-two healthy participants (23.5 ± 2.5 years, 32 female, 30 male) learned and rated their affect to 80 neutral and 80 emotionally negative pictures. Despite rigorous deprivation of REM sleep or SWS, the residual sleep fostered the consolidation of neutral and negative pictures. Furthermore, emotional arousal helped to memorize the pictures. The better consolidation of negative pictures compared to neutral ones was most pronounced in the SWS-deprived group where a normal amount of REM sleep was present. This emotional memory bias correlated with REM sleep only in the SWS-deprived group. Furthermore, emotional arousal to the pictures decreased over time, but neither sleep nor wake had any differential effect. Neither the comparison of the affective ratings (arousal, valence) during encoding and recognition, nor the affective ratings of the recognized targets and rejected distractors supported the hypothesis that REM sleep dampens the emotional reaction to remembered stimuli. The data suggest that REM sleep fosters the consolidation of emotional memories but has no effect on the affective evaluation of the remembered contents.
25697588	Slow Wave Activity (SWA), the low frequency (<4 Hz) oscillations that characterize Slow Wave Sleep (SWS) are thought to relate causally to declarative memory consolidation during nocturnal sleep. Evidence is conflicting relating SWA to memory consolidation during nap however.We applied transcranial alternating current stimulation (tACS) - which, with a cross-hemispheric electrode montage (F3 and F4 - International 10:20 EEG system), is able to disrupt brain oscillations-to determine if disruption of low frequency oscillation generation during afternoon nap is causally related to disruption in declarative memory consolidation.	Eight human subjects each participated in stimulation and sham nap sessions. A verbal paired associate learning (PAL) task measured memory changes. During each nap period, five 5-min stimulation (0.75 Hz cross-hemispheric frontal tACS) or sham intervals were applied with 1-min post-stimulation intervals (PSI's). Spectral EEG power for Slow (0.7-0.8 Hz), Delta (1.0-4.0 Hz), Theta (4.0-8.0 Hz), Alpha (8.0-12.0 Hz), and Spindle-range (12.0-14.0) frequencies was analyzed during the 1-min preceding the onset of stimulation and the 1-min PSI's.	As hypothesized, power reduction due to stimulation positively correlated with reduction in word-pair recall post-nap specifically for Slow (P < 0.0022) and Delta (P < 0.037) frequency bands.	These results provide preliminary evidence suggesting a causal and specific role of SWA in declarative memory consolidation during nap.	
25682549	Although many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements.The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands (n=83), their nonpsychotic siblings (n=151), and community comparison subjects (n=209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR.	Analyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction).	Neurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia.	
25660053	This study examined verbal declarative memory functioning in SLI and its relationship to working memory. Encoding, recall, and recognition of verbal information was examined in children with SLI who had below average working memory (SLILow WM), children with SLI who had average working memory (SLIAvg. WM) and, a group of non-language impaired children with average working memory (TDAvg. WM). The SLILow WM group was significantly worse than both the SLIAvg. WM and TDAvg. WM groups at encoding verbal information and at retrieving verbal information following a delay. In contrast, the SLIAvg. WM group showed no verbal declarative memory deficits. The study demonstrates that verbal declarative memory deficits in SLI only occur when verbal working memory is impaired. Thus SLI declarative memory is largely intact and deficits are likely to be related to working memory impairments. 
25653598	Learning novel sequences constitutes an example of declarative memory formation, involving conscious recall of temporal events. Performance in sequence learning tasks improves with repetition and involves forming temporal associations over scales of seconds to minutes. To further understand the neural circuits underlying declarative sequence learning over trials, we tracked changes in intracranial field potentials (IFPs) recorded from 1142 electrodes implanted throughout temporal and frontal cortical areas in 14 human subjects, while they learned the temporal-order of multiple sequences of images over trials through repeated recall. We observed an increase in power in the gamma frequency band (30-100 Hz) in the recall phase, particularly in areas within the temporal lobe including the parahippocampal gyrus. The degree of this gamma power enhancement decreased over trials with improved sequence recall. Modulation of gamma power was directly correlated with the improvement in recall performance. When presenting new sequences, gamma power was reset to high values and decreased again after learning. These observations suggest that signals in the gamma frequency band may play a more prominent role during the early steps of the learning process rather than during the maintenance of memory traces. 
25648963	Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.	rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.	This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.	
25646382	The hippocampal system is critical for storage and retrieval of declarative memories, including memories for locations and events that take place at those locations. Spatial memories place high demands on capacity. Memories must be distinct to be recalled without interference and encoding must be fast. Recent studies have indicated that hippocampal networks allow for fast storage of large quantities of uncorrelated spatial information. The aim of the this article is to review and discuss some of this work, taking as a starting point the discovery of multiple functionally specialized cell types of the hippocampal-entorhinal circuit, such as place, grid, and border cells. We will show that grid cells provide the hippocampus with a metric, as well as a putative mechanism for decorrelation of representations, that the formation of environment-specific place maps depends on mechanisms for long-term plasticity in the hippocampus, and that long-term spatiotemporal memory storage may depend on offline consolidation processes related to sharp-wave ripple activity in the hippocampus. The multitude of representations generated through interactions between a variety of functionally specialized cell types in the entorhinal-hippocampal circuit may be at the heart of the mechanism for declarative memory formation. 
25642186	The fornix is a part of the limbic system and constitutes the major efferent and afferent white matter tracts from the hippocampi. The underdevelopment of or injuries to the fornix are strongly associated with memory deficits. Its role in memory impairments was suggested long ago with cases of surgical forniceal transections. However, recent advances in brain imaging techniques, such as diffusion tensor imaging, have revealed that macrostructural and microstructural abnormalities of the fornix correlated highly with declarative and episodic memory performance. This structure appears to provide a robust and early imaging predictor for memory deficits not only in neurodegenerative and neuroinflammatory diseases, such as Alzheimer's disease and multiple sclerosis, but also in schizophrenia and psychiatric disorders, and during neurodevelopment and "typical" aging. The objective of the manuscript is to present a systematic review regarding published brain imaging research on the fornix, including the development of its tracts, its role in various neurological diseases, and its relationship to neurocognitive performance in human studies. 
25628556	Hand gesture, a ubiquitous feature of human interaction, facilitates communication. Gesture also facilitates new learning, benefiting speakers and listeners alike. Thus, gestures must impact cognition beyond simply supporting the expression of already-formed ideas. However, the cognitive and neural mechanisms supporting the effects of gesture on learning and memory are largely unknown. We hypothesized that gesture's ability to drive new learning is supported by procedural memory and that procedural memory deficits will disrupt gesture production and comprehension. We tested this proposal in patients with intact declarative memory, but impaired procedural memory as a consequence of Parkinson's disease (PD), and healthy comparison participants with intact declarative and procedural memory. In separate experiments, we manipulated the gestures participants saw and produced in a Tower of Hanoi (TOH) paradigm. In the first experiment, participants solved the task either on a physical board, requiring high arching movements to manipulate the discs from peg to peg, or on a computer, requiring only flat, sideways movements of the mouse. When explaining the task, healthy participants with intact procedural memory displayed evidence of their previous experience in their gestures, producing higher, more arching hand gestures after solving on a physical board, and smaller, flatter gestures after solving on a computer. In the second experiment, healthy participants who saw high arching hand gestures in an explanation prior to solving the task subsequently moved the mouse with significantly higher curvature than those who saw smaller, flatter gestures prior to solving the task. These patterns were absent in both gesture production and comprehension experiments in patients with procedural memory impairment. These findings suggest that the procedural memory system supports the ability of gesture to drive new learning. 
25628150	The Procedural Deficit Hypothesis (PDH) proposes that individuals with primary developmental language impairment (DLI) have a deficient procedural memory, compromising their syntactic abilities. Individuals with DLI may compensate for procedural memory deficits by engaging declarative memory for syntactic tasks. Arguments are part of the lexicon whereas adjuncts rely on syntactic processing. As a result, individuals with DLI may have unusual difficulty processing adjuncts. Alternatively, processing for adjuncts may be typical for individuals with DLI but show frequency effects, indicating compensatory use of declarative memory.Our goal was to test the predictions of the PDH by comparing argument and adjunct processing times for adults with and without DLI, and to seek evidence of compensatory use of declarative memory for adjunct processing. We further evaluated group performance on measures of visual procedural and declarative memory.	Forty-four adults, 21 with DLI, completed a self-paced listening task, a procedural memory task, and a declarative memory task. The self-paced listening task tracked the word-by-word processing time for sentences that included prepositional phrases acting as arguments or adjuncts. We used regression analysis to determine effects of group membership and argument or adjunct status on processing times. Correlation analyses evaluated relationships between argument and adjunct frequency on processing times by group.	We found no effect of group membership on the processing time for arguments and adjuncts in the self-paced listening task. Argument phrases were processed more easily by both groups. There were frequency effects for adjunct processing for the group with DLI, but not the group with typical language. We did not find the expected frequency effects for argument processing. The group with DLI also performed more poorly in both the procedural and declarative memory tasks. Secondary analyses found that non-verbal intelligence was related to outcomes on the declarative memory but not the procedural memory task.	We found mixed evidence on the predictions of the PDH. Adults with DLI may compensate for procedural memory deficits but it is unclear whether this depends on declarative memory or language processing experience. Compensatory processing is an important element of the language profile for adults with DLI.	The readers will be able to describe how processing arguments and adjuncts in sentences may depend on different memory systems, and how adults with developmental language impairment may compensate for syntactic processing deficits.	
25620921	Owing to a similar cerebral neuro-anatomy, non-human primates are viewed as the most valid models for understanding cognitive deficits. This study evaluated psychomotor and mnesic functions of 41 young to old mouse lemurs (Microcebus murinus). Psychomotor capacities and anxiety-related behaviors decreased abruptly from middle to late adulthood. However, mnesic functions were not affected in the same way with increasing age. While results of the spontaneous alternation task point to a progressive and widespread age-related decline of spatial working memory, both spatial reference and novel object recognition (NOR) memory tasks did not reveal any tendency due to large inter-individual variability in the middle-aged and old animals. Indeed, some of the aged animals performed as well as younger ones, whereas some others had bad performances in the Barnes maze and in the object recognition test. Hierarchical cluster analysis revealed that declarative-like memory was strongly impaired only in 7 out of 25 middle-aged/old animals. These results suggest that this analysis allows to distinguish elder populations of good and bad performers in this non-human primate model and to closely compare this to human aging. 
25620526	Although hippocampus unequivocally supports explicit/declarative memory, fewer findings have demonstrated its role in implicit expressions of memory. We tested for hippocampal contributions to an implicit expression of configural/relational memory for complex scenes using eye-movement tracking during functional magnetic resonance imaging (fMRI) scanning. Participants studied scenes and were later tested using scenes that resembled study scenes in their overall feature configuration but comprised different elements. These configurally similar scenes were used to limit explicit memory, and were intermixed with new scenes that did not resemble studied scenes. Scene configuration memory was expressed through eye movements reflecting exploration overlap (EO), which is the viewing of the same scene locations at both study and test. EO reliably discriminated similar study-test scene pairs from study-new scene pairs, was reliably greater for similarity-based recognition hits than for misses, and correlated with hippocampal fMRI activity. In contrast, subjects could not reliably discriminate similar from new scenes by overt judgments, although ratings of familiarity were slightly higher for similar than new scenes. Hippocampal fMRI correlates of this weak explicit memory were distinct from EO-related activity. These findings collectively suggest that EO was an implicit expression of scene configuration memory associated with hippocampal activity. Visual exploration can therefore reflect implicit hippocampal-related memory processing that can be observed in eye-movement behavior during naturalistic scene viewing.
25619550	Spatial learning and memory in rodents represent close equivalents of human episodic declarative memory, which is especially sensitive to cerebral aging, neurodegeneration, and various neuropsychiatric disorders. Many tests and protocols are available for use in laboratory rodents, but Morris water maze and radial-arm maze remain the most widely used as well as the most valid and reliable spatial tests. Telencephalic neurocircuitry that plays functional roles in spatial learning and memory includes hippocampus, dorsal striatum and medial prefrontal cortex. Prefrontal-hippocampal circuitry comprises the major associative system in the rodent brain, and is critical for navigation in physical space, whereas interconnections between prefrontal cortex and dorsal striatum are probably more important for motivational or goal-directed aspects of spatial learning. Two major forms of synaptic plasticity, namely long-term potentiation, a lasting increase in synaptic strength between simultaneously activated neurons, and long-term depression, a decrease in synaptic strength, have been found to occur in hippocampus, dorsal striatum and medial prefrontal cortex. These and other phenomena of synaptic plasticity are probably crucial for the involvement of telencephalic neurocircuitry in spatial learning and memory. They also seem to play a role in the pathophysiology of two brain pathologies with episodic declarative memory impairments as core symptoms, namely Alzheimer's disease and schizophrenia. Further research emphasis on rodent telencephalic neurocircuitry could be relevant to more valid and reliable preclinical research on these most devastating brain disorders. This article is part of a Special Issue entitled SI: Brain and Memory. 
25618326	Recognition memory--affected early in the course of Alzheimer Disease (AD)--is supposed to rely on two processes: recollection (i.e., retrieval of details from the encoding episode) and familiarity (i.e., acontextual sense of prior exposure). Recollection has repeatedly been shown to be impaired in patients with amnestic Mild Cognitive Impairment (aMCI)--known to be at high risk for AD. However, studies that evaluated familiarity in these patients have reported conflicting results. Here, we assessed familiarity in single-domain aMCI patients (n = 19) and healthy matched controls (n = 22). All participants underwent a classic yes/no recognition memory paradigm with confidence judgements, allowing an estimation of familiarity and recollection similar to the approach used in previous studies. In addition, they underwent a novel speeded recognition memory task, the Speed and Accuracy Boosting procedure, based on the idea that familiarity is fast and hence that fast answers rely on familiarity. On the classic yes/no task, aMCI patients were found to have impaired performance, reaction times, recollection and familiarity. However, performance and reaction times of aMCI patients did not differ from that of controls in the speeded task. This is noteworthy since this task was comparatively difficult for control subjects. This dissociation within familiarity suggests that a very basic component of declarative memory, probably at the interface between implicit and explicit memory, may be preserved, or possibly released, in patients with aMCI. It is suggested that early subprocesses (e.g., fluency based familiarity) could be preserved in aMCI patients, while delayed ones (e.g., conceptual fluency, post-retrieval monitoring, confidence assessment, or even access to awareness) may be impaired. These findings may provide support for recent suggestions that familiarity may result from the combination of a set of subprocesses, each with its specific temporal signature.
25604917	Cognitive deficits are common symptom presentations in neurology and psychiatry. Cognitive symptoms during major depressive episodes cause subjective distress as well as difficulties during therapy and psychosocial reintegration. Depression-associated cognitive symptoms are characterized by a mood-congruent information processing bias as well as by cognitive performance deficits. A diagnostically relevant profile of neuropsychological impairments specific to depression has not yet been identified. Nevertheless, deficits of executive and declarative memory functions have repeatedly been reported. The time course of cognitive deficits after remission of mood is not entirely clear. Depending on the point of time of the reinvestigation, patients may still exhibit pronounced cognitive deficits. This article presents the current knowledge about cognitive symptoms in major depression, including the pathophysiology and treatment options. 
25597655	Most research on neurodevelopmental disorders has focused on their abnormalities. However, what remains intact may also be important. Increasing evidence suggests that declarative memory, a critical learning and memory system in the brain, remains largely functional in a number of neurodevelopmental disorders. Because declarative memory remains functional in these disorders, and because it can learn and retain numerous types of information, functions, and tasks, this system should be able to play compensatory roles for multiple types of impairments across the disorders. Here, we examine this hypothesis for specific language impairment, dyslexia, autism spectrum disorder, Tourette syndrome, and obsessive-compulsive disorder. We lay out specific predictions for the hypothesis and review existing behavioral, electrophysiological, and neuroimaging evidence. Overall, the evidence suggests that declarative memory indeed plays compensatory roles for a range of impairments across all five disorders. Finally, we discuss diagnostic, therapeutic and other implications. 
25596441	The basal ganglia, typically associated with motor function, are involved in human cognitive processes, as demonstrated in behavioral, lesion, and noninvasive functional neuroimaging studies. Here we report task-contingent changes in concentrations of the neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) in the globus pallidus internus (GPi) of two patients with Parkinson's disease undergoing deep brain stimulation surgery by utilizing in-vivo microdialysis measurements during performance of implicit and declarative memory tasks. Performance of an implicit memory task (weather prediction task-WPT) was associated with increased levels of glutamate and GABA in the GPi compared to their concentrations at baseline. On the other hand, performance of a declarative memory task (verbal learning task-VLT) was associated with decreased levels of glutamate and GABA in GPi compared to baseline during the encoding and immediate recall phase with less conclusive results during the delayed recall phase. These results are in line with hypothesized changes in these neurotransmitter levels: an increase of excitatory (Glu) input from subthalamic nucleus (STN) to GPi during implicit memory task performance and a decrease of inhibitory inputs (GABA) from globus pallidus externus (GPe) and striatum to GPi during declarative memory performance. Consistent with our previous report on in-vivo neurotransmitter changes during tasks in STN, these data provide corroborative evidence for the direct involvement of basal ganglia in cognitive functions and complements our model of the functional circuitry of basal ganglia in the healthy and Parkinson's disease affected brain. 
25585032	In schizophrenia, hippocampal perfusion is increased and declarative memory function is degraded. Based on an a priori model of hippocampal dysfunction in schizophrenic psychosis, the authors postulated molecular and cellular changes in CA3 consistent with increased NMDA receptor signaling.Postmortem hippocampal subfield tissue (CA3, CA1) from subjects with schizophrenia and nonpsychiatric comparison subjects was analyzed using Western blotting and Golgi histochemistry to examine the hypothesized outcomes.	The GluN2B-containing NMDA receptors (GluN2B/GluN1) and their associated postsynaptic membrane protein PSD95 were both increased in schizophrenia in CA3 tissue, but not in CA1 tissue. Quantitative analyses of Golgi-stained hippocampal neurons showed an increase in spine density on CA3 pyramidal cell apical dendrites (stratum radiatum) and an increase in the number of thorny excrescences.	The hippocampal data are consistent with increased excitatory signaling in CA3 and/or with an elevation in silent synapses in CA3, a state that may contribute to an increase in long-term potentiation in CA3 with subsequent stimulation and "unsilencing." These changes are plausibly associated with increased associational activity in CA3, with degraded declarative memory function, and with formation of false memories with psychotic content. The influence of these hyperactive hippocampal projections on targets in the limbic neocortex could contribute to components of schizophrenia manifestations in other cerebral regions.	
25583469	Human infants devote the majority of their time to sleeping. However, very little is known about the role of sleep in early memory processing. Here we test 6- and 12-mo-old infants' declarative memory for novel actions after a 4-h [Experiment (Exp.) 1] and 24-h delay (Exp. 2). Infants in a nap condition took an extended nap (≥30 min) within 4 h after learning, whereas infants in a no-nap condition did not. A comparison with age-matched control groups revealed that after both delays, only infants who had napped after learning remembered the target actions at the test. Additionally, after the 24-h delay, memory performance of infants in the nap condition was significantly higher than that of infants in the no-nap condition. This is the first experimental evidence to our knowledge for an enhancing role of sleep in the consolidation of declarative memories in the first year of life. 
25581223	Studies of the testing effect have shown that retrieval significantly improves learning. However, most of these studies have been restricted to simple types of declarative verbal knowledge. Five experiments were designed to explore whether testing improves acquisition of route knowledge, which has a procedural component consisting of actions to be performed at decision points (Golledge, 1991). Participants learned a route through a series of connected rooms in a virtual building. Each room contained multiple doors, only one of which led to the next room. During encoding, participants were shown the correct sequence of doors in a manner similar to global positioning system (GPS) navigation guidance. During subsequent exposures to the route, participants were either shown the correct sequence again or had to recall the sequence from memory. Participants later completed a final test in which they traversed the route without guidance or feedback. Testing improved route memory compared to studying, but only when participants were given feedback about the correct door prior to moving through the room. When feedback occurred after moving to an incorrect door, testing resulted in worse performance compared to studying. These findings parallel work on errorless learning, in which procedural skills are acquired more quickly when errors are minimized during learning.
25562828	The hippocampus has traditionally been thought to be critical for conscious explicit memory but not necessary for unconscious implicit memory processing. In a recent study of a group of mild amnesia patients with evidence of MTL damage limited to the hippocampus, subjects were tested on a direct test of item recognition confidence while electroencephalogram (EEG) was acquired, and revealed intact measures of explicit memory from 400 to 600 ms (mid-frontal old-new effect, FN400). The current investigation re-analyzed this data to study event-related potentials (ERPs) of implicit memory, using a recently developed procedure that eliminated declarative memory differences. Prior ERP findings from this technique were first replicated in two independent matched control groups, which exhibited reliable implicit memory effects in posterior scalp regions from 400 to 600 ms, which were topographically dissociated from the explicit memory effects of familiarity. However, patients were found to be dramatically impaired in implicit memory effects relative to control subjects, as quantified by a reliable condition × group interaction. Several control analyses were conducted to consider alternative factors that could account for the results, including outliers, sample size, age, or contamination by explicit memory, and each of these factors was systematically ruled out. Results suggest that the hippocampus plays a fundamental role in aspects of memory processing that are beyond conscious awareness. The current findings therefore indicate that both memory systems of implicit and explicit memory may rely upon the same neural structures - but function in different physiological ways.
25552573	Based on studies in rodents, the basolateral amygdala (BLA) is considered a key site for experience-dependent neural plasticity underlying the acquisition of conditioned fear responses. In humans, very few studies exist of subjects with selective amygdala lesions and those studies have only implicated the amygdala more broadly leaving the role of amygdala sub-regions underexplored. We tested a rare sample of subjects (N = 4) with unprecedented focal bilateral BLA lesions due to a genetic condition called Urbach-Wiethe disease. In a classical delay fear conditioning experiment, these subjects showed impaired acquisition of conditioned fear relative to a group of matched control subjects (N = 10) as measured by fear-potentiation of the defensive eye-blink startle reflex. After the experiment, the BLA-damaged cases showed normal declarative memory of the conditioned association. Our findings provide new evidence that the human BLA is essential to drive fast classically conditioned defensive reflexes. 
25550227	The aesthetic experience, in particular the experience of beauty in the visual arts, should have neural correlates in the human brain. Neuroesthetics is principally implemented by functional studies in normal subjects, but the neuropsychology of the aesthetic experience, that is, the impact of brain damage on the appreciation of works of art, is a neglected field. Here, 16 mild to moderate Alzheimer's disease patients and 15 caregivers expressed their preference on 16 works of art (eight representational and eight abstract) during programmed visits to an art gallery. A week later, all subjects expressed a preference rate on reproductions of the same works presented in the gallery. Both patients and caregivers were consistent in assigning preference ratings, and in patients consistency was independent of the ability to recognize the works on which the preference rate had been given in an explicit memory task. Caregivers performed at ceiling in the memory task. Both patients and caregivers assigned higher preference ratings for representational than for abstract works and preference consistency was comparable in representational and abstract works. Furthermore, in the memory task, patients did not recognize better artworks they had assigned higher preference ratings to, suggesting that emotional stimuli (as presumably visual works of art are) cannot enhance declarative memory in this pathology. Our data, which were gathered in an ecological context and with real-world stimuli, confirm previous findings on the stability of aesthetic preference in patients with Alzheimer's disease and on the independence of aesthetic preference from cognitive abilities such as memory. 
25549103	The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a β-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders. 
25546732	Declarative memory is consolidated during sleep in healthy children. We tested the hypothesis that consolidation processes are impaired in idiopathic focal epilepsies (IFE) of childhood in association with frequent interictal epileptiform discharges (IEDs) during sleep.A verbal (word-pair association) and a nonverbal (2D object location) declarative memory task were administrated to 15 children with IFEs and 8 control children 6-12 years of age. Patients had either centrotemporal (11 patients) or occipital (4 patients) IEDs. All but 3 patients had a history of unprovoked seizures, and 6 of them were treated with valproate (VPA). The learning procedure (location of object pairs presented on a grid; association of word pairs) was executed in the evening. Retrieval was tested immediately after learning and on the next morning after a night of sleep. Participants were tested twice, once in natural home conditions and one month later in the unfamiliar conditions of the sleep unit under EEG monitoring.	Overnight recall performance was lower in children with IFE than in control children on both tasks (ps<0.05). Performance in home conditions was similar to that in hospital conditions. Higher spike-wave index (SWI) during nonrapid eye movement (NREM) sleep was associated with poorer performance in the nonverbal task (p<0.05). Valproate treatment was not associated with overnight recall performance for both tasks (ps>0.05).	Memory consolidation is impaired in IFE of childhood. The association between higher SWI during NREM sleep and poorer nonverbal declarative memory consolidation supports the hypothesis that interictal epileptic activity could disrupt sleep memory consolidation.	
25541365	Although memory recall is known to be reduced with normal aging, little is known about the patterns of brain activity that accompany these recall failures. By assessing faulty memory, we can identify the brain regions engaged during retrieval attempts in the absence of successful memory and determine the impact of aging on this functional activity. We used functional magnetic resonance imaging to examine age differences in brain activity associated with memory failure in three memory retrieval tasks: autobiographical (AM), episodic (EM) and semantic (SM). Compared to successful memory retrieval, both age groups showed more activity when they failed to recall a memory in regions consistent with the salience network (SLN), a brain network also associated with non-memory errors. Both groups also showed strong functional coupling among SLN regions during incorrect trials and in intrinsic patterns of functional connectivity. In comparison to young adults, older adults demonstrated (1) less activity within the SLN during unsuccessful AM trials; (2) weaker intrinsic functional connectivity between SLN nodes and dorsolateral prefrontal cortex; and (3) less differentiation of SLN functional connectivity during incorrect trials across memory conditions. These results suggest that the SLN is engaged during recall failures, as it is for non-memory errors, which may be because errors in general have particular salience for adapting behavior. In older adults, the dedifferentiation of functional connectivity within the SLN across memory conditions and the reduction of functional coupling between it and prefrontal cortex may indicate poorer inter-network communication and less flexible use of cognitive control processes, either while retrieval is attempted or when monitoring takes place after retrieval has failed. This article is part of a Special Issue entitled SI: Memory & Aging. 
25535859	Pro-inflammatory cytokines like interleukin-1 beta (IL-1) are major players in the interaction between the immune system and the central nervous system. Various animal studies report a sleep-promoting effect of IL-1 leading to enhanced slow wave sleep (SWS). Moreover, this cytokine was shown to affect hippocampus-dependent memory. However, the role of IL-1 in human sleep and memory is not yet understood. We administered the synthetic IL-1 receptor antagonist anakinra (IL-1ra) in healthy humans (100mg, subcutaneously, before sleep; n=16) to investigate the role of IL-1 signaling in sleep regulation and sleep-dependent declarative memory consolidation. Inasmuch monocytes have been considered a model for central nervous microglia, we monitored cytokine production in classical and non-classical blood monocytes to gain clues about how central nervous effects of IL-1ra are conveyed. Contrary to our expectation, IL-1ra increased EEG slow wave activity during SWS and non-rapid eye movement (NonREM) sleep, indicating a deepening of sleep, while sleep-associated memory consolidation remained unchanged. Moreover, IL-1ra slightly increased prolactin and reduced cortisol levels during sleep. Production of IL-1 by classical monocytes was diminished after IL-1ra. The discrepancy to findings in animal studies might reflect species differences and underlines the importance of studying cytokine effects in humans. 
25515308	A contentious point in memory research is whether or not the hippocampus plays a time-limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long-term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single-neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo-conditioned control rabbits. Results reveal continued learning-specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories.
25514786	The relation between preschoolers' theory of mind (ToM) and declarative metamemory (DM) was investigated in two studies. The first study focused on 4-year-old children's (N=106) cognitive and affective ToM and their DM. The data showed a significant association between cognitive (but not affective) ToM and DM, independent of verbal ability, non-verbal ability, and working memory. The second study involved 83 children tested at 4 years 6 months of age (and 6 months later) for cognitive ToM and DM. Here, results showed that early cognitive ToM, in particular false-belief understanding, predicts later DM independent of early verbal ability. These data support a view considering cognitive ToM as a precursor of children's DM.
25504458	It has recently been suggested that working memory could be conceived as two symmetrical subsystems with analogous structure and processing principles: a declarative working memory storing objects of thought available for cognitive operations, and a procedural working memory holding representations of what to do with these objects (Oberauer, Psychology of learning and motivation 51: 45-100, 2009). Within this theoretical framework, the two subsystems are thought to be independent and fueled by their own capacity. The present study tested this hypothesis through two experiments using a complex span task in which participants were asked to maintain consonants for further recall while performing response selection tasks. In line with Oberauer's conception, the load of the procedural working memory was varied by manipulating the number of stimulus-response mappings of the response selection task. Increasing the number of these mappings had a strong detrimental effect on recall performance. Besides contradicting Oberauer's proposal, this finding supports models that assume a resource-sharing between processing and storage in working memory. 
25497222	Declarative memory (DM) impairments are reported in schizophrenia and in unaffected biological relatives of patients. However, the neural correlates of successful and unsuccessful encoding, mediated by the medial temporal lobe (MTL) memory system, and the influence of disease-related genetic liability remain under explored. This study employed an event-related functional MRI paradigm to compare activations for successfully and unsuccessfully encoded associative face-name stimuli between 26 schizophrenia patients (mean age: 33, 19m/7f), 30 controls (mean age: 29, 24m/6f), and 14 unaffected relatives of patients (mean age: 40, 5m/9f). Compared to controls or unaffected relatives, patients showed hyper-activations in ventral visual stream and temporo-parietal cortical association areas when contrasting successfully encoded events to fixation. Follow-up hippocampal regions-of-interest analysis revealed schizophrenia-related hyper-activations in the right anterior hippocampus during successful encoding; contrasting successful versus unsuccessful events produced schizophrenia-related hypo-activations in the left anterior hippocampus. Similar hippocampal hypo-activations were observed in unaffected relatives during successful versus unsuccessful encoding. Post hoc analyses of hippocampal volume showed reductions in patients, but not in unaffected relatives compared to controls. Findings suggest that DM encoding deficits are attributable to both disease-specific and genetic liability factors that impact different components of the MTL memory system. Hyper-activations in temporo-occipital and parietal regions observed only in patients suggest the influence of disease-related factors. Regional hyper- and hypo-activations attributable to successful encoding occurring in both patients and unaffected relatives suggest the influence of schizophrenia-related genetic liability factors. 
25496759	Bipolar disorder (BD) is a psychiatric disorder accompanied by deficits in declarative memory. Given the importance of the hippocampus in declarative memory, it is not surprising that BD patients have been reported to show hippocampal abnormalities.Review evidence about structural and functional hippocampal abnormalities in BD.	Systematic review of studies comparing BD patients and healthy controls with respect to hippocampal structure or function.	Twenty-five studies were included, together involving 1043 patients, 21 of which compared patients to controls. Decrease in hippocampal volume was found in four of 18 studies using adult samples, and two of three samples using adolescents. Four studies revealed localized hippocampal deficits. Meta-analysis revealed a significant but small effect with lower hippocampal volumes when comparing all BD patients with controls. Lithium treatment was associated with larger hippocampal volumes across studies. The three functional studies yielded contradictory evidence.	Studies were only cross-sectional in nature and all used MRI or fMRI to investigate hippocampal volume or function. Heterogeneous patients groups and different methodologies for hippocampal segmentation, may have contributed to difficulties when comparing the different studies.	There seems to be a small reduction in hippocampal volume in BD, which perhaps is more pronounced in early-onset BD and is counteracted by a neuroprotective effect of lithium treatment. However, how these structural abnormalities relate to functional deficits is largely unclear. Given the few functional neuroimaging studies and given the lack of congruence in these results, further investigation of especially hippocampal function in BD is recommended.	
25490073	The progressive loss of memory and autonomy of Alzheimer's Disease (AD) patients, together with their characteristic behavioral and psychological symptoms, subjects their family caregivers to chronic stress. Several studies indicate that these caregivers are predisposed to cognitive impairments, but the physiological correlates of these alterations remain to be elucidated.Analyze the effects of chronic stress of family caregivers of AD patients on cognition, cortisol/DHEA ratios and BDNF levels and investigate the relation between these variables.	Seventeen family caregivers (64.83 ± 3.64 years) of patients with AD and eighteen non-caregivers (58.29 ± 3.16 years) completed stress, depression and anxiety inventories. Exclusion criteria were current neurological disorders, major unstable medical illnesses, use of medications that could interfere with cognitive or HPA axis function and dementia. Attention, working memory and executive function were assessed with Digit Span and Trail Making tests, and declarative memory was analyzed with the Logical Memory test. Saliva was collected at 8 AM and 10 PM and its cortisol and DHEA levels determined by radioimmunoassay. Serum BDNF levels were measured by sandwich-ELISA. Results were analyzed with independent samples t test, covariance analysis and linear regressions. The statistical significance was set at p<0.05 and all p values were adjusted with Holm's Method.	Caregivers showed more stress, depression and anxiety symptoms than non-caregivers, as well as significantly worse performances on attention, working memory and executive function tests. Caregivers also had higher cortisol/DHEA ratios and lower BDNF levels than non-caregivers. Cortisol/DHEA ratios, especially at 10 PM, were negatively related with all cognitive tasks in which caregivers showed impaired performance. On the other hand, the only cognitive task that related with the BDNF level was digit span.	This study showed that caregivers' cognitive impairment is related with alterations on cortisol/DHEA ratios, and that chronic stress experienced by these subjects has the potential to alter their BDNF levels.	
25470729	The severity and number of reexperiencing symptoms (e.g., flashbacks) show considerable variability across individuals with posttraumatic stress disorder (PTSD). One interpretation of reexperiencing symptoms invokes generalization: Specifically, the traumatic memory may be stored in such a way that neutral stimuli that only vaguely resemble some feature of the traumatic event are sufficient to trigger the memory. If this is the case, then individuals with higher levels of reexperiencing symptoms might show greater generalization, even in contexts unrelated to trauma. In the current study, an acquired equivalence test was used to assess associative learning and generalization in 114 U.S. veterans who were also given a test of declarative memory. PTSD symptoms were rated by the veteran. After adjusting for demographic variables, psychoactive medication use, and initial learning, regression analyses showed that the number of PTSD reexperiencing symptoms significantly improved the model for generalization (β = -.23, R(2) = .34) but not associative learning or declarative memory. The results support the idea that generalization is linked to reexperiencing symptoms, is not limited to learning about traumatic events, and can emerge even in a relatively innocuous computer-based learning task. 
25462901	Stress hormones influence a wide range of cognitive functions, including memory performance and executive function. It is well established that glucocorticoids enhance memory consolidation but impair memory retrieval. While most of the effects have been attributed to glucocorticoid receptors (GR), the importance of mineralocorticoid receptors (MR) has been also emphasized. Dysfunctions in hypothalamic-pituitary-adrenal (HPA) axis have been reported for several mental disorders. While major depressive disorder (MDD) as well as borderline personality disorder (BPD) seem to be characterized by enhanced cortisol release in concert with a reduced feedback sensitivity of the HPA axis, in posttraumatic stress disorder (PTSD) a contrary picture has been reported. Despite the fact that altered GR function has been discussed for these disorders only very few studies have investigated the effects of glucocorticoids on cognitive performance in these patients so far. In a series of studies, we investigated the effects of glucocorticoids on cognition (i.e. declarative memory, working memory and response inhibition) in different mental disorders such as MDD, PTSD and BPD. While in patients with MDD cortisol administration failed to effect memory retrieval, patients with PTSD and BPD showed enhanced rather than impaired memory retrieval after cortisol administration. These results indicate an altered sensitivity to cortisol in these disorders. Results from one of our recent studies in the field of social cognition underline the importance of the MR. We found that emotional empathy was enhanced through stimulation of the MR via fludrocortisone in healthy participants and women with BPD. This review aims to integrate these findings and discuss potential mechanisms and implications. 
25462476	This study compared implicit and explicit learning instructions in hand writing. Implicit learning is the ability to acquire a new skill without a corresponding increase in knowledge about the skill. In contrast, explicit learning uses declarative knowledge to build up a set of performance rules that guide motor performance or skills. Explicit learning is dependent on working memory, implicit learning is not. Therefore, implicit learning was expected to be easier than explicit learning in children in special education, given their expected compromised working memory. Two groups of children (5-12 years) participated, children in special education with physical or multiple disabilities (study group, n=22), and typically developing controls (n=32). Children learned to write letter-like patterns on a digitizer by tracking a moving target (implicitly) and verbal instruction (explicitly). We further tested visual working memory, visual-motor integration, and gross manual dexterity. Learning curves were similar for both groups in both conditions; children in the study group did learn both implicitly and explicitly. Motor performance was related to the writing task. In contrast to our hypothesis, visual working memory was not an important factor in the explicit condition. These results shed new light on the conceptual difference between implicit and explicit learning, and the role of working memory therein.
25455867	Based on common pharmacodynamic mechanisms, recent efforts to develop second generation alternatives for organophosphate (OP) prophylaxis have expanded to include cholinesterase (ChE) inhibiting compounds traditionally approved for use in the treatment of Alzheimer's disease (AD). The primary purpose of this study was to determine the extent to which low-dose huperzine A, galantamine, or donepezil selectively inhibited acetylcholinesterase (AChE) versus butyrylcholinesterase (BChE) activity in healthy adults and whether such inhibition impacted neurobehavioral performance.In addition to hourly red blood cell cholinesterase sampling, neurobehavioral function was assessed before and after a single oral dose of huperzine A (100 or 200 μg), galantamine (4 or 8 mg), donepezil (2.5 or 5mg), or placebo (n=12 subjects per drug/dose).	Compared to placebo, both dosages of huperzine A and galantamine inhibited circulating AChE but not BChE. With the exception of huperzine A (200 μg), which maintained declarative recall performance across sessions, compounds did not improve neurobehavioral performance. Some aspects of neurobehavioral performance correlated with AChE activity, although associations may have reflected time of day effects.	Although huperzine A and galantamine significantly inhibited AChE (and likely increased central acetylcholine levels), neither compound improved neurobehavioral performance. The latter was likely due to ceiling effects in this young, healthy test population. Under conditions of reduced cholinergic activity (e.g., Alzheimer's disease), AChE inhibition (and corresponding maintenance of cholinergic tone) could potentially maintain/augment some aspects of neurobehavioral function.	
25451763	We summarize anatomical, electrophysiological and behavioral evidence that the rostral intralaminar (ILN) and the reuniens and rhomboid (ReRh) nuclei that belong to the nonspecific thalamus, might be part of a hippocampo-cortico-thalamic network underlying consolidation of enduring declarative(-like) memories at systems level. The first part of this review describes the anatomical and functional organization of these thalamic nuclei. The second part presents the theoretical models supporting the active systems-level consolidation, a process that relies upon sleep specific field-potential oscillations occurring during both slow-wave sleep (SWS) and rapid eye movement (REM) sleep. The last part presents data in the rat showing that the lesion of the rostral ILN or of the ReRh specifically hinders the formation of remote spatial memories without affecting task acquisition or retrieval of a recent memory. These results showing a critical role of the ILN and ReRh nuclei in the transformation of a recent memory into a remote one are discussed in the context of their control of cortical arousal (ARAS) and of thalamo-cortico-thalamic synchronization. 
25448858	Previous research suggests that different aspects of tool knowledge are mediated by different memory systems. It is believed that tool attributes (e.g., function, color) are represented as declarative memory while skill learning is supported by procedural memory. It has been proposed that other aspects (e.g., skilled tool use) may rely on an interaction of both declarative and procedural memory. However, the specific form of procedural memory underlying skilled tool use and the nature of interaction between declarative and procedural memory systems remain unclear. In the current study, individuals with Parkinson's disease (PD) and healthy controls were trained over 2 sessions, 3 weeks apart, to use a set of novel complex tools. They were also tested on their ability to recall tool attributes as well as their ability to demonstrate grasp and use of the tools to command. Results showed that, compared to controls, participants with PD showed intact motor skill acquisition and tool use to command within sessions, but failed to retain performance across sessions. In contrast, people with PD showed equivalent recall of tool attributes and tool grasping relative to controls, both within and across sessions. Current findings demonstrate that the frontal-striatal network, compromised in PD, mediates long-term retention of motor skills. Intact initial skill learning raises the possibility of compensation from declarative memory for frontal-striatal dysfunction. Lastly, skilled tool use appears to rely on both memory systems which may reflect a cooperative interaction between the two systems. Current findings regarding memory representations of tool knowledge and skill learning may have important implications for delivery of rehabilitation programs for individuals with PD. 
25420127	Age-related cognitive impairments are particularly prevalent in forms of learning that require a functionally intact hippocampal formation, such as spatial and declarative learning. However, there is notable heterogeneity in the cognitive abilities of aged subjects. To date, few studies have determined whether age-related impairments on one learning task relate to impairments on different learning tasks that engage overlapping cognitive processes. Here, we hypothesized that aged animals that were impaired on 1 hippocampal-dependent behavioral procedure would be impaired on a second hippocampal-dependent procedure. Conversely, aged animals that were unimpaired on 1 hippocampal-dependent task would be unimpaired with a subsequent hippocampal-dependent form of learning. To test these hypotheses, we trained young (2-3 months old) and aged (28-29 months old) F344XBN male rats with trace eyeblink conditioning, followed by the Morris water maze. Half of aged rats were impaired during trace conditioning. Nearly half of aged animals were also impaired during water maze probe testing. Performance during trace conditioning correlated with performance during water maze testing in aged animals. Further analyses revealed that, as a group, aged animals that were impaired on 1 hippocampal-dependent task were impaired on both tasks. Conversely, aged animals that were unimpaired on 1 task were unimpaired on both tasks. Together, these results suggest that aged-related impairments on 1 hippocampal-dependent task predict age-related impairments on a second hippocampal-dependent procedure. These results have implications for assigning personalized therapeutics to ameliorate age-related cognitive decline.
25395537	Chronic circadian dysfunction impairs declarative memory in humans but has little effect in common rodent models of arrhythmia caused by clock gene knockouts or surgical ablation of the suprachiasmatic nucleus (SCN). An important problem overlooked in these translational models is that human dysrhythmia occurs while SCN circuitry is genetically and neurologically intact. Siberian hamsters (Phodopus sungorus) are particularly well suited for translational studies because they can be made arrhythmic by a one-time photic treatment that severely impairs spatial and recognition memory. We found that once animals are made arrhythmic, subsequent SCN ablation completely rescues memory processing. These data suggest that the inhibitory effects of a malfunctioning SCN on cognition require preservation of circuitry between the SCN and downstream targets that are lost when these connections are severed. 
25394655	Structures of the medial temporal lobe (MTL) are known to be involved in declarative memory processes. However, little is known about how age-related changes in MTL structures, white matter integrity, and functional connectivity affect pattern separation processes in the MTL. In this study, we used magnetic resonance imaging (MRI) to measure the volumes of MTL regions of interest, including hippocampal subfields (dentate gyrus, CA3, CA1, and subiculum) in healthy older and younger adults. Additionally, we used diffusion tensor imaging to measure white matter integrity for both groups. Finally, we used functional MRI to acquire resting functional connectivity measures for both groups. We show that, along with age, the volume of left CA3/dentate gyrus predicts memory performance. Differences in fractional anisotropy and the strength of resting functional connections between the hippocampus and other cortical structures implicated in memory processing were not significant predictors of performance. As previous studies have only hinted, it seems that the size of left CA3/dentate gyrus contributes more to successful discrimination between similar mnemonic representations than other hippocampal sub-fields, MTL structures, and other neuroimaging correlates. Accordingly, the implications of aging and atrophy on lure discrimination capacities are discussed.
25392199	The temporal lobes play a prominent role in declarative memory function, including episodic memory (memory for events) and semantic memory (memory for facts and concepts). Surgical resection for medication-resistant and well-localized temporal lobe epilepsy has good prognosis for seizure freedom, but is linked to memory difficulties in adults, especially when the removal is on the left side. Children may benefit most from surgery, because brain plasticity may facilitate post-surgical reorganization, and seizure cessation may promote cognitive development. However, the long-term impact of this intervention in children is not known. We examined memory function in 53 children (25 males, 28 females) who were evaluated for epilepsy surgery: 42 underwent unilateral temporal lobe resections (25 left, 17 right, mean age at surgery 13.8 years), 11 were treated only pharmacologically. Average follow-up was 9 years (range 5-15). Post-surgical change in visual and verbal episodic memory, and semantic memory at follow-up were examined. Pre- and post-surgical T1-weighted MRI brain scans were analysed to extract hippocampal and resection volumes, and evaluate post-surgical temporal lobe integrity. Language lateralization indices were derived from functional magnetic resonance imaging. There were no significant pre- to postoperative decrements in memory associated with surgery. In contrast, gains in verbal episodic memory were seen after right temporal lobe surgery, and visual episodic memory improved after left temporal lobe surgery, indicating a functional release in the unoperated temporal lobe after seizure reduction or cessation. Pre- to post-surgical change in memory function was not associated with any indices of brain structure derived from MRI. However, better verbal memory at follow-up was linked to greater post-surgical residual hippocampal volumes, most robustly in left surgical participants. Better semantic memory at follow-up was associated with smaller resection volumes and greater temporal pole integrity after left temporal surgery. Results were independent of post-surgical intellectual function and language lateralization. Our findings indicate post-surgical, hemisphere-dependent material-specific improvement in memory functions in the intact temporal lobe. However, outcome was linked to the anatomical integrity of the temporal lobe memory system, indicating that compensatory mechanisms are constrained by the amount of tissue which remains in the operated temporal lobe. Careful tailoring of resections for children undergoing epilepsy surgery may enhance long-term memory outcome. 
25368566	The capacity for semantic memory-the ability to acquire and store knowledge of the world-is highly developed in the human brain. In particular, semantic memory assimilated through an auditory route may be a uniquely human capacity. One method of obtaining neurobiological insight into memory mechanisms is through the study of experts. In this work, we study a group of Hindu Vedic priests, whose religious training requires the memorization of vast tracts of scriptural texts through an oral tradition, recalled spontaneously during a lifetime of subsequent spiritual practice. We demonstrate focal increases of cortical thickness in regions of the left prefrontal lobe and right temporal lobe in Vedic priests, in comparison to a group of matched controls. The findings are relevant to current hypotheses regarding cognitive processes underlying storage and recall of long-term declarative memory. 
25360112	Background music refers to any music played while the listener is performing another activity. Most studies on this effect have been conducted on young adults, while little attention has been paid to the presence of this effect in older adults. Hence, this study aimed to address this imbalance by assessing the impact of different types of background music on cognitive tasks tapping declarative memory and processing speed in older adults. Overall, background music tended to improve performance over no music and white noise, but not always in the same manner. The theoretical and practical implications of the empirical findings are discussed. 
25358393	Skill learning deficits in Parkinson's disease (PD) at an early stage are not well known, and findings in behavioral studies with mirror reading and prism adaptation tasks are mixed. Moreover, skill learning over several days in PD patients has not been studied.A total of 12 nondemented early-stage PD patients and 12 age-matched normal control subjects participated in this study. The Wechsler Memory Scale-Revised (WMS-R) was applied to all subjects to assess declarative memory. The mirror reading task of horizontally presented kana letters and the reversed vision task using a prism were performed throughout 3 consecutive days.	For the mirror reading skill, the early-stage PD patients showed significantly increased mirror reading time on days 2 and 3. For the prism adaptation, the PD patients performed significantly more slowly in reversed vision than the normal controls, specifically at blocks 1 and 2, over 3 days. The WMS-R subscores did not show a significant correlation with the reaction times in reversed vision or with the mirror reading times.	Using two tasks with different modalities, the present study revealed visuomotor adaptation deficits and acquisition/retention deficits, especially in the later phase of perceptual skill learning, in early-stage PD patients.	


25331094	The cultivation of mindfulness has received increasing attention over the past 2 decades because of its association with increased psychological well-being and reduced stress-related health disorders. Given the robust positive association between perceived stress and cognitive impairment in late life, the current study evaluated the association between trait mindfulness, psychological well-being, and cognitive function in 73 healthy community-dwelling older adults. Controlling for a priori covariates, multivariate regression analyses showed a significant association between trait mindfulness and measures of psychological well-being, including self-reported depressive symptoms, quality of life, and stress profile. Analyses further showed a significant association between trait mindfulness and executive function, namely set shifting. No association was found for declarative memory. Mediation analyses showed that the association between mindfulness and cognitive function is mediated by perceived stress. This research supports the importance of cultivating mindfulness in late life to ensure cognitive and emotional well-being. 
25325490	Many studies have found that sleep benefits declarative memory consolidation. However, fundamental questions on the specifics of this effect remain topics of discussion. It is not clear which forms of memory are affected by sleep and whether this beneficial effect is partly mediated by passive protection against interference. Moreover, a putative correlation between the structure of sleep and its memory-enhancing effects is still being discussed.In three experiments, we tested whether sleep differentially affects various forms of declarative memory. We varied verbal content (verbal/nonverbal), item type (single/associate), and recall mode (recall/recognition, cued/free recall) to examine the effect of sleep on specific memory subtypes. We compared within-subject differences in memory consolidation between intervals including sleep, active wakefulness, or quiet meditation, which reduced external as well as internal interference and rehearsal.	Forty healthy adults aged 18-30 y, and 17 healthy adults aged 24-55 y with extensive meditation experience participated in the experiments.	All types of memory were enhanced by sleep if the sample size provided sufficient statistical power. Smaller sample sizes showed an effect of sleep if a combined measure of different declarative memory scales was used. In a condition with reduced external and internal interference, performance was equal to one with high interference. Here, memory consolidation was significantly lower than in a sleep condition. We found no correlation between sleep structure and memory consolidation.	Sleep does not preferentially consolidate a specific kind of declarative memory, but consistently promotes overall declarative memory formation. This effect is not mediated by reduced interference.	
25325488	Sleep and memory are stable and heritable traits that strongly differ between individuals. Sleep benefits memory consolidation, and the amount of slow wave sleep, sleep spindles, and rapid eye movement sleep have been repeatedly identified as reliable predictors for the amount of declarative and/or emotional memories retrieved after a consolidation period filled with sleep. These studies typically encompass small sample sizes, increasing the probability of overestimating the real association strength. In a large sample we tested whether individual differences in sleep are predictive for individual differences in memory for emotional and neutral pictures.Between-subject design.	Cognitive testing took place at the University of Basel, Switzerland. Sleep was recorded at participants' homes, using portable electroencephalograph-recording devices.	Nine hundred-twenty-nine healthy young participants (mean age 22.48 ± 3.60 y standard deviation).	None.	In striking contrast to our expectations as well as numerous previous findings, we did not find any significant correlations between sleep and memory consolidation for pictorial stimuli.	Our results indicate that individual differences in sleep are much less predictive for pictorial memory processes than previously assumed and suggest that previous studies using small sample sizes might have overestimated the association strength between sleep stage duration and pictorial memory performance. Future studies need to determine whether intraindividual differences rather than interindividual differences in sleep stage duration might be more predictive for the consolidation of emotional and neutral pictures during sleep.	
25315025	Emotional and traumatic experiences lead to the development of particularly strong memories that can drive neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD) and drug addiction. Disruption of these memories would therefore serve as a powerful treatment option, and targeting the pathologic emotional, but not declarative, component of a memory would be ideal for clinical intervention. Research reveals that after retrieval of a consolidated memory, the memory can be destabilized, and must then be reconsolidated through synaptic plasticity to allow subsequent retrieval. Disruption of reconsolidation-related plasticity would therefore impair specific, reactivated memories. Noradrenergic signaling strengthens synaptic plasticity and is essential for encoding the emotional components of memory. Consistent with this, investigations have now revealed that noradrenergic signaling is a critical mechanism for reconsolidation of emotional memories in rodent and human models. Here, we discuss these investigations and promising clinical trials indicating that disruption of noradrenergic signaling during reconsolidation may abolish the pathologic emotional, but not declarative, component of memories allowing alleviation of neuropsychiatric disorders including PTSD and drug addiction. 
25312348	Over time, regular exercise can lower the risk for age-related decline in cognition. However, the immediate effects of exercise on memory consolidation in younger adults have not been fully investigated. In two experiments, the effects of exercise were assessed on three different memory tasks. These included paired-associate learning, procedural learning and text memory. Results indicate that performance on procedural learning and situation model memory was increased with exercise, regardless of if participants exercised before or after encoding. No benefit of exercise was found for paired-associate learning. These findings suggest that intense exercise may benefit certain types of memory consolidation. 
25309387	We tested a densely amnesic patient (P9), with bilateral hippocampal damage resulting from an autoimmune disorder, and 12 age- and sex-matched controls on a series of memory tasks designed to characterize allocentric spatial learning and memory abilities. We compared P9's ability to perform spatial memory tasks with her ability to perform non-spatial, color memory tasks. First, P9's performance was impaired as compared to controls even in the simplest versions of an allocentric spatial memory task, in which she had to find repeatedly over 10 trials the same location(s) of one, two or three illuminating foot pad(s) among 23 pads distributed in an open-field arena. In contrast, she performed as well as controls when she had to find repeatedly over 10 trials the same one, two or three pad(s) marked by color cue(s), whose locations varied between trials. Second, P9's performance was severely impaired in working memory tasks, when she had to learn on a trial-unique basis and remember the location(s) or the color(s) of one, two or three pad(s), while performing an interfering task during the 1-min interval separating encoding and retrieval. Without interference during the retention interval of the trial-unique tasks, P9's performance was partially preserved in the color tasks, whereas it remained severely impaired in the allocentric spatial tasks. Detailed behavioral analyses indicate that P9's memory representations are more limited than those of controls both in their precision (metric coding) and in the number of items that can be maintained in memory (capacity). These findings are consistent with the theory that the hippocampus contributes to the integration or binding of multiple items, in order to produce high-resolution/high-capacity representations of spatial and non-spatial information in the service of short-term/working and long-term memory. 
25308330	Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c-fos-based genetic tagging system to selectively express the channelrhodopsin variant, ChEF, and optogenetically reactivate a specific neural ensemble in retrosplenial cortex (RSC) engaged by context fear conditioning. Artificial stimulation of RSC was sufficient to produce both context-specific behavior and downstream cellular activity commensurate with natural experience. Moreover, optogenetically but not contextually elicited responses were insensitive to hippocampal inactivation, suggesting that although the hippocampus is needed to coordinate activation by sensory cues, a higher-order cortical framework can independently subserve learned behavior, even shortly after learning. 
25291047	Repetition priming is a prominent example of non-declarative memory, and it increases the accuracy and speed of responses to repeatedly processed stimuli. Major long-hold memory theories posit that repetition priming results from facilitation within perceptual and conceptual networks for stimulus recognition and categorization. Stimuli can also be bound to particular responses, and it has recently been suggested that this rapid response learning, not network facilitation, provides a sound theory of priming of object recognition. Here, we addressed the relevance of network facilitation and rapid response learning for priming of person recognition with a view to advance general theories of priming. In four experiments, participants performed conceptual decisions like occupation or nationality judgments for famous faces. The magnitude of rapid response learning varied across experiments, and rapid response learning co-occurred and interacted with facilitation in perceptual and conceptual networks. These findings indicate that rapid response learning and facilitation in perceptual and conceptual networks are complementary rather than competing theories of priming. Thus, future memory theories need to incorporate both rapid response learning and network facilitation as individual facets of priming. 
25278876	Eating behavior depends on associations between the sensory and energetic properties of foods. Healthful balance of these factors is a challenge for industrialized societies that have an abundance of food, food choices and food-related cues. Here, we were interested in whether appetitive conditioning changes as a function of age. Operant and pavlovian conditioning experiments (rewarding stimulus was a palatable food) in male mice (aged 3, 6, and 15 months) showed that implicit (non-declarative) memory remains intact during aging. Two other essential components of eating behavior, motivation and hedonic preference for rewarding foods, were also found not to be altered in aging mice. Specifically, hedonic responding by satiated mice to isocaloric foods of differing sensory properties (sucrose, milk) was similar in all age groups; importantly, however, this paradigm disclosed that older animals adjust their energy intake according to energetic need. Based on the assumption that the mechanisms that control feeding are conserved across species, it would appear that overeating and obesity in humans reflects a mismatch between ancient physiological mechanisms and today's cue-laden environment. The implication of the present results showing that aging does not impair the ability to learn stimulus-food associations is that the risk of overeating in response to food cues is maintained through to old age. 
25278459	Different lines of research suggest that the consolidation of emotional memories is influenced by (a) endogenous levels of sex hormones, and (b) individual differences in the capacity to use vivid mental imagery. No studies to date have investigated how these factors may interact to influence declarative emotional memories. This study examined the interacting influence of progesterone and mental imagery strength on emotional memory consolidation. Twenty-four men, 20 women from the low progesterone (follicular) menstrual phase, and 20 women from the high progesterone (mid-luteal) phase of the cycle were assessed using an objective performance-based measure of mental imagery strength, and then shown a series of aversive and neutral images. Half of the images were accompanied by instructions to process sensory features, and the remaining half to process the conceptual characteristics of the images. Two days later, all participants returned for a surprise free recall memory test. The interaction of progesterone and mental imagery strength significantly predicted recall of visually processed, but not verbally processed, negative images. These data suggest that mental imagery strength may be one mechanism underlying the documented association between endogenous progesterone and enhanced emotional memory performance in the literature. 
25264352	The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age×BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p<.07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory - in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). This article is part of a Special Issue entitled Memory & Aging. 
25247611	The aim of the present study was to assess the validity of a 12-word Czech version of the Philadelphia (repeatable) Verbal Learning Test [czP(r)VLT-12]. The construction of the czP(r)VLT-12 was modeled after the California Verbal Learning Test (CVLT) and the nine-word Philadelphia (repeatable) Verbal Learning Test [P(r)VLT]. The czP(r)VLT-12 was constructed from a large corpus of old (60-74) and very old (75-96) Czech adults (n = 540). Participants met strict inclusion criteria for the absence of any active or past neurodegenerative disorders and performed within normal limits on other neuropsychological measures. Principal component analysis (PCA) and correlations between czP(r)VLT-12 factor structure and other memory tests were conducted. The czP(r)VLT-12 produced a four-factor solution, accounting for 70.90% of variance, with factors related to: (1) recall, (2) extra-list intrusion errors/recognition foils, (3) interference, and (4) acquisition rate; a solution similar to the CVLT and P(r)VLT. Increasing age resulted in a decline in most czP(r)VLT-12 indices, women outperformed men, and higher education led to higher scores. Memory performance in normal aging did not correlate with instrumental activities of daily living. Low, but significant, correlations were seen with other tests of cognitive performance (divergent validity). Appendices are available that provide normed percentile estimates of individual czP(r)VLT-12 performance stratified by age, education, and gender. In accordance with previous studies, these results demonstrate the usefulness of czP(r)VLT-12 in assessing declarative memory in older adults.
25237742	Patients with Alzheimer disease (AD) typically have impaired declarative memory as a result of hippocampal damage early in the disease. Far less is understood about AD's effect on emotion.We investigated whether feelings of emotion can persist in patients with AD, even after their declarative memory for what caused the feelings has faded.	A sample of 17 patients with probable AD and 17 healthy comparison participants (case-matched for age, sex, and education) underwent 2 separate emotion induction procedures in which they watched film clips intended to induce feelings of sadness or happiness. We collected real-time emotion ratings at baseline and at 3 post-induction time points, and we administered a test of declarative memory shortly after each induction.	As expected, the patients with AD had severely impaired declarative memory for both the sad and happy films. Despite their memory impairment, the patients continued to report elevated levels of sadness and happiness that persisted well beyond their memory for the films. This outcome was especially prominent after the sadness induction, with sustained elevations in sadness lasting for more than 30 minutes, even in patients with no conscious recollection for the films.	These findings indicate that patients with AD can experience prolonged states of emotion that persist well beyond the patients' memory for the events that originally caused the emotion. The preserved emotional life evident in patients with AD has important implications for their management and care, and highlights the need for caretakers to foster positive emotional experiences.	
25232312	Damage to the hippocampus impairs the ability to acquire new declarative memories, but not the ability to learn simple motor tasks. An unresolved question is whether hippocampal damage affects learning for music performance, which requires motor processes, but in a cognitively complex context. We studied learning of novel musical pieces by sight-reading in a newly identified amnesic, LSJ, who was a skilled amateur violist prior to contracting herpes simplex encephalitis. LSJ has suffered virtually complete destruction of the hippocampus bilaterally, as well as extensive damage to other medial temporal lobe structures and the left anterior temporal lobe. Because of LSJ's rare combination of musical training and near-complete hippocampal destruction, her case provides a unique opportunity to investigate the role of the hippocampus for complex motor learning processes specifically related to music performance. Three novel pieces of viola music were composed and closely matched for factors contributing to a piece's musical complexity. LSJ practiced playing two of the pieces, one in each of the two sessions during the same day. Relative to a third unpracticed control piece, LSJ showed significant pre- to post-training improvement for the two practiced pieces. Learning effects were observed both with detailed analyses of correctly played notes, and with subjective whole-piece performance evaluations by string instrument players. The learning effects were evident immediately after practice and 14 days later. The observed learning stands in sharp contrast to LSJ's complete lack of awareness that the same pieces were being presented repeatedly, and to the profound impairments she exhibits in other learning tasks. Although learning in simple motor tasks has been previously observed in amnesic patients, our results demonstrate that non-hippocampal structures can support complex learning of novel musical sequences for music performance. 
25229457	Nocturnal sleep and daytime napping facilitate memory consolidation for semantically related and unrelated word pairs. We contrasted forgetting of both kinds of materials across a 12-hour interval involving either nocturnal sleep or daytime wakefulness (experiment 1) and a 2-hour interval involving either daytime napping or wakefulness (experiment 2). Beneficial effects of post-learning nocturnal sleep and daytime napping were greater for unrelated word pairs (Cohen's d=0.71 and 0.68) than for related ones (Cohen's d=0.58 and 0.15). While the size of nocturnal sleep and daytime napping effects was similar for unrelated word pairs, for related pairs, the effect of nocturnal sleep was more prominent. Together, these findings suggest that sleep preferentially facilitates offline memory processing of materials that are more susceptible to forgetting.
25227928	Through a variety of methods, researchers have begun unraveling the mystery of why humans spend one-third of their lives asleep. Though sleep likely serves multiple functions, it has become clear that the sleeping brain offers an ideal environment for solidifying newly learned information in the brain. Sleep , which comprises a complex collection of brain states, supports the consolidation of many different types of information. It not only promotes learning and memory stabilization, but also memory reorganization that can lead to various forms of insightful behavior. As this chapter will describe, research provides ample support for these crucial cognitive functions of sleep . Focusing on the declarative memory system in humans, we review the literature regarding the benefits of sleep for both neutral and emotionally salient declarative memory. Finally, we discuss the literature regarding the impact of sleep on emotion regulation.
25225474	Memory reactivations in hippocampal brain areas are critically involved in memory consolidation processes during sleep. In particular, specific firing patterns of hippocampal place cells observed during learning are replayed during subsequent sleep and rest in rodents. In humans, experimentally inducing hippocampal memory reactivations during slow-wave sleep (but not during wakefulness) benefits consolidation and immediately stabilizes declarative memories against future interference. Importantly, spontaneous hippocampal replay activity can also be observed during rapid eye movement (REM) sleep and some authors have suggested that replay during REM sleep is related to processes of memory consolidation. However, the functional role of reactivations during REM sleep for memory stability is still unclear. Here, we reactivated memories during REM sleep and examined its consequences for the stability of declarative memories. After 3 h of early, slow-wave sleep (SWS) rich sleep, 16 healthy young adults learned a 2-D object location task in the presence of a contextual odor. During subsequent REM sleep, participants were either re-exposed to the odor or to an odorless vehicle, in a counterbalanced within subject design. Reactivation was followed by an interference learning task to probe memory stability after awakening. We show that odor-induced memory reactivation during REM sleep does not stabilize memories against future interference. We propose that the beneficial effect of reactivation during sleep on memory stability might be critically linked to processes characterizing SWS including, e.g., slow oscillatory activity, sleep spindles, or low cholinergic tone, which are required for a successful redistribution of memories from medial temporal lobe regions to neocortical long-term stores. 
25222265	Successful learning involves integrating new material into existing memory networks. A learning procedure known as fast mapping (FM), thought to simulate the word-learning environment of children, has recently been linked to distinct neuroanatomical substrates in adults. This idea has suggested the (never-before tested) hypothesis that FM may promote rapid incorporation into cortical memory networks. We test this hypothesis here in 2 experiments. In our 1st experiment, we introduced 50 participants to 16 unfamiliar animals and names through FM or explicit encoding (EE) and tested participants on the training day, and again after sleep. Learning through EE produced strong declarative memories, without immediate lexical competition, as expected from slow-consolidation models. Learning through FM, however, led to almost immediate lexical competition, which continued to the next day. Additionally, the learned words began to prime related concepts on the day following FM (but not EE) training. In a 2nd experiment, we replicated the lexical integration results and determined that presenting an already-known item during learning was crucial for rapid integration through FM. The findings presented here indicate that learned items can be integrated into cortical memory networks at an accelerated rate through fast mapping. The retrieval of a related known concept, in order to infer the target of the FM question, is critical for this effect.
25218188	The reconsolidation hypothesis posits that the presentation of a specific cue, previously associated with a life event, makes the stored memory pass from a stable to a reactivated state. In this state, memory is again labile and susceptible to different agents, which may either damage or improve the original memory. Such susceptibility decreases over time and leads to a re-stabilization phase known as reconsolidation process. This process has been assigned two biological roles: memory updating, which suggests that destabilization of the original memory allows the integration of new information into the background of the original memory; and memory strengthening, which postulates that the labilization-reconsolidation process strengthens the original memory. The aim of this review is to analyze the strengthening as an improvement obtained only by triggering such process without any other treatment. In our lab, we have demonstrated that when triggering the labilization-reconsolidation process at least once the original memory becomes strengthened and increases its persistence. We have also shown that repeated labilization-reconsolidation processes strengthened the original memory by enlarging its precision, and said reinforced memories were more resistant to interference. Finally, we have shown that the strengthening function is not operative in older memories. We present and discuss both our findings and those of others, trying to reveal the central role of reconsolidation in the modification of stored information. 
25212397	In order to evaluate verbal memory consolidation during sleep in subjects experiencing sleepwalking or sleep terror, 19 patients experiencing sleepwalking/sleep terror and 19 controls performed two verbal memory tasks (16-word list from the Free and Cued Selective Reminding Test, and a 220- and 263-word modified story recall test) in the evening, followed by nocturnal video polysomnography (n = 29) and morning recall (night-time consolidation after 14 h, n = 38). The following morning, they were given a daytime learning task using the modified story recall test in reverse order, followed by an evening recall test after 9 h of wakefulness (daytime consolidation, n = 38). The patients experiencing sleepwalking/sleep terror exhibited more frequent awakenings during slow-wave sleep and longer wakefulness after sleep onset than the controls. Despite this reduction in sleep quality among sleepwalking/sleep terror patients, they improved their scores on the verbal tests the morning after sleep compared with the previous evening (+16 ± 33%) equally well as the controls (+2 ± 13%). The performance of both groups worsened during the daytime in the absence of sleep (-16 ± 15% for the sleepwalking/sleep terror group and -14 ± 11% for the control group). There was no significant correlation between the rate of memory consolidation and any of the sleep measures. Seven patients experiencing sleepwalking also sleep-talked during slow-wave sleep, but their sentences were unrelated to the tests or the list of words learned during the evening. In conclusion, the alteration of slow-wave sleep during sleepwalking/sleep terror does not noticeably impact on sleep-related verbal memory consolidation.
25197796	Retrieval of traumatic experiences is often accompanied by strong feelings of distress. Here, we examined in healthy participants whether post-reactivation stress experience affects the context-dependency of emotional memory. First, participants studied words from two distinctive emotional categories (i.e., war and disease) presented against a category-related background picture. One day later, participants returned to the lab and received a reminder of the words of one emotional category followed by exposure to a stress task (Stress group, n=22) or a control task (Control group, n=24). Six days later, memory contextualization was tested using a word stem completion task. Half of the word stems were presented against the encoding context (i.e., congruent context) and the other half of the word stems were presented against the other context (i.e., incongruent context). The results showed that participants recalled more words in the congruent context than in the incongruent context. Interestingly, cortisol mediated the effect of stress exposure on memory contextualization. The stronger the post-reactivation cortisol response, the more memory performance relied on the contextual embedding of the words. Taken together, the current findings suggest that a moderate cortisol response after memory reactivation might serve an adaptive function in preventing generalization of emotional memories over contexts.
25192334	Intrusive memories are a hallmark symptom of posttraumatic stress disorder (PTSD). They reflect excessive and uncontrolled retrieval of the traumatic memory. Acute elevations of cortisol are known to impair the retrieval of already stored memory information. Thus, continuous cortisol administration might help in reducing intrusive memories in PTSD. Strong perceptual priming for neutral stimuli associated with a "traumatic" context has been shown to be one important learning mechanism that leads to intrusive memories. However, the memory modulating effects of cortisol have only been shown for explicit declarative memory processes. Thus, in our double blind, placebo controlled study we aimed to investigate whether cortisol influences perceptual priming of neutral stimuli that appeared in a "traumatic" context. Two groups of healthy volunteers (N = 160) watched either neutral or "traumatic" picture stories on a computer screen. Neutral objects were presented in between the pictures. Memory for these neutral objects was tested after 24 hours with a perceptual priming task and an explicit memory task. Prior to memory testing half of the participants in each group received 25 mg of cortisol, the other half received placebo. In the placebo group participants in the "traumatic" stories condition showed more perceptual priming for the neutral objects than participants in the neutral stories condition, indicating a strong perceptual priming effect for neutral stimuli presented in a "traumatic" context. In the cortisol group this effect was not present: Participants in the neutral stories and participants in the "traumatic" stories condition in the cortisol group showed comparable priming effects for the neutral objects. Our findings show that cortisol inhibits perceptual priming for neutral stimuli that appeared in a "traumatic" context. These findings indicate that cortisol influences PTSD-relevant memory processes and thus further support the idea that administration of cortisol might be an effective treatment strategy in reducing intrusive reexperiencing. 
25182845	Investigate time-related age differences in cognitive functioning without influences of prior test experience.Cognitive scores were compared in different individuals from the same birth years who were tested in different years, when they were at different ages. These types of quasi-longitudinal comparisons were carried out on data from three large projects: the Seattle Longitudinal Study [Schaie, K. W. (2013). Developmental influences on adult intelligence: The Seattle Longitudinal Study (2nd ed.). New York, NY: Oxford University Press], the Betula Project [Ronnlund, M., & Nilsson, L-G. (2008). The magnitude, generality, and determinants of Flynn effects on forms of declarative memory and visuospatial ability: Time-sequential analyses of data from a Swedish cohort study. Intelligence, 36, 192-209], and the Virginia Cognitive Aging Project (this study).	In each data set, the results revealed that the estimates of cognitive change with no prior test experience closely resembled the estimates of age relations based on cross-sectional comparisons. Furthermore, longitudinal comparisons revealed positive changes at young ages that gradually became more negative with increased age, whereas all of the estimates of change without prior test experience were negative except those for measures of vocabulary.	The current results suggest that retest effects can distort the mean age trends in longitudinal comparisons that are not adjusted for experience. Furthermore, the findings can be considered robust because the patterns were similar across three data sets involving different samples of participants and cognitive tests, and across different methods of controlling experience effects in the new data set.	
25176349	Motivated by evidence that the dentate gyrus differentially mediates the pattern separation (PS) component of declarative memory function and that dentate gyrus harbors molecular and cellular pathologies in schizophrenia, we examined whether PS performance is altered in volunteers with schizophrenia (SZV) relative to healthy volunteers (HV). In groups of well-characterized SZV (n=14) and HV (n=15), we contrasted performance on the Behavioral Pattern Separation (BPS) Task, acquiring two outcome measures, a PS parameter and a Recognition Memory (RM) parameter, as well as specific recognition data by stimulus type. The SZVs showed a significant decrement in PS performance relative to HV (mean ± SEM, SZV: 3.1 ± 2.7%; HV: 17.1 ± 5.8%; p=0.039, d'=0.86); whereas SZV and HV did not significantly differ in RM performance (SZV: 50.1 ± 8.1%; HV: 59.3 ± 5.5%; p=0.350, d'=0.36). Moreover, the SZVs showed a selective defect in correctly identifying similar lure items (SZV: 24.0 ± 3.7%; HV: 41.2 ± 4.6%; p<0.05), but demonstrated no impairment in identifying targets and novel foils. These data suggest that the dentate gyrus is dysfunctional in schizophrenia, a feature that could contribute to declarative memory impairment in the disorder and possibly to psychosis, a conclusion consistent with the considerable molecular pathology in the dentate gyrus in schizophrenia.
25163775	Recordings from individual neurons in patients who are implanted with depth electrodes for clinical reasons have opened the possibility to narrow down the gap between neurophysiological studies in animals and non-invasive (e.g. functional magnetic resonance imaging, electroencephalogram, magnetoencephalography) investigations in humans. Here we provide a description of the main procedures for electrode implantation and recordings, the experimental paradigms used and the main steps for processing the data. We also present key characteristics of the so-called 'concept cells', neurons in the human medial temporal lobe with selective and invariant responses that represent the meaning of the stimulus, and discuss their proposed role in declarative memory. Finally, we present novel results dealing with the stability of the representation given by these neurons, by studying the effect of stimulus repetition in the strength of the responses. In particular, we show that, after an initial decay, the response strength reaches an asymptotic value after approximately 15 presentations that remains above baseline for the whole duration of the experiment. 
25154723	The human cortex can accommodate overlapping semantic information, such as synonyms, homonyms, or overlapping concepts. However, neuronal models of cortical networks predict Catastrophic Interference in conditions of overlapping information, obliterating old associations and sometimes preventing formation of new ones. It has been proposed that Catastrophic Interference in declarative memory is never observed in biological systems because of hippocampal pattern separation of competing associations. Here, we tested neocortical Catastrophic Interference during acquisition of overlapping associations through Fast Mapping; an incidental, exclusion based learning mechanism, that can support hippocampal-independent learning. Young adults acquired picture-label associations, either through explicit encoding or through Fast Mapping and were tested after 24 h. Overlapping/competing associations were presented either minutes (Early), or 22 h (Delayed) after learning. Catastrophic Interference was evident only following Fast Mapping, and only in the Delayed competition. In a follow-up experiment, Medial Temporal Lobe (MTL) amnesic patients demonstrated retroactive Catastrophic Interference after the Early competition, despite normal memory for noninterfered Fast Mapping associations. Thus, following Fast Mapping, a biological system demonstrated susceptibility to Catastrophic Interference, as predicted by the neuronal-model. Early retroactive Interference, however, can be prevented by MTL integrity.
25153776	Slow oscillations (<1 Hz) during slow wave sleep (SWS) promote the consolidation of declarative memory. Children with attention-deficit/hyperactivity disorder (ADHD) have been shown to display deficits in sleep-dependent consolidation of declarative memory supposedly due to dysfunctional slow brain rhythms during SWS.Using transcranial oscillating direct current stimulation (toDCS) at 0.75 Hz, we investigated whether an externally triggered increase in slow oscillations during early SWS elevates memory performance in children with ADHD.	12 children with ADHD underwent a toDCS and a sham condition in a double-blind crossover study design conducted in a sleep laboratory. Memory was tested using a 2D object-location task. In addition, 12 healthy children performed the same memory task in their home environment.	Stimulation enhanced slow oscillation power in children with ADHD and boosted memory performance to the same level as in healthy children.	These data indicate that increasing slow oscillation power during sleep by toDCS can alleviate declarative memory deficits in children with ADHD.	
25152723	The notion of working memory (WM) was introduced to account for the usage of short-term memory resources by other cognitive tasks such as reasoning, mental arithmetic, language comprehension, and many others. This collaboration between memory and other cognitive tasks can only be achieved by a dedicated WM system that controls task coordination. To that end, WM models include executive control. Nevertheless, other attention control systems may be involved in coordination of memory and cognitive tasks calling on memory resources. The present paper briefly reviews the evidence concerning the role of selective attention in WM activities. A model is proposed in which selective attention control is directly linked to the executive control part of the WM system. The model assumes that apart from storage of declarative information, the system also includes an executive WM module that represents the current task set. Control processes are automatically triggered when particular conditions in these modules are met. As each task set represents the parameter settings and the actions needed to achieve the task goal, it will depend on the specific settings and actions whether selective attention control will have to be shared among the active tasks. Only when such sharing is required, task performance will be affected by the capacity limits of the control system involved. 
25144874	Some argue that hippocampus supports declarative memory, our capacity to recall facts and events, whereas others view the hippocampus as part of a system dedicated to calculating routes through space, and these two contrasting views are pursued largely independently in current research. Here we offer a perspective on where these views can and cannot be reconciled and update a bridging framework that will improve our understanding of hippocampal function. 
25142558	Functional interactions between sleep spindle activity, declarative memory consolidation, and general cognitive abilities in school-aged children.Healthy, prepubertal children (n = 63; mean age 9.56 ± 0.76 y); ambulatory all-night polysomnography (2 nights); investigating the effect of prior learning (word pair association task; experimental night) versus nonlearning (baseline night) on sleep spindle activity; general cognitive abilities assessed using the Wechsler Intelligence Scale for Children-IV (WISC-IV).	Analysis of spindle activity during nonrapid eye movement sleep (N2 and N3) evidenced predominant peaks in the slow (11-13 Hz) but not in the fast (13-15 Hz) sleep spindle frequency range (baseline and experimental night). Analyses were restricted to slow sleep spindles. Changes in spindle activity from the baseline to the experimental night were not associated with the overnight change in the number of recalled words reflecting declarative memory consolidation. Children with higher sleep spindle activity as measured at frontal, central, parietal, and occipital sites during both baseline and experimental nights exhibited higher general cognitive abilities (WISC-IV) and declarative learning efficiency (i.e., number of recalled words before and after sleep).	Slow sleep spindles (11-13 Hz) in children age 8-11 y are associated with inter-individual differences in general cognitive abilities and learning efficiency.	
25141088	Much is known about sport officials' decisions (e.g., anticipation, visual search, and prior experience). Comprehension of the entire decision process, however, requires an ecologically valid examination. To address this, we implemented a 2-part study using an expertise paradigm with ice hockey referees.Study 1 explored the strategies referees indicated they used to make decisions. For Study 2, we sought to confirm the emergent codes of Study 1 and further examine referee expertise and evaluations of decision making.	In Study 1, 2 elite, 2 intermediate, and 2 novice referees wore helmet cameras for 1 game and participated in stimulated recall interviews, which were coded using theoretical and focused codes. Study 2 involved focus groups that each watched and commented on 2 helmet camera videotapes from Study 1; 1 videotape consisted of an elite referee's game and the other included an intermediate referee's game. The focus-group data were analyzed using the same coding structure from Study 1.	Combined, 3 distinct theoretical codes were identified: (a) primary referee strategies, (b) secondary referee strategies, and (c) cognitive and situational influences on refereeing. Study 1 showed that elite referees demonstrated more sophisticated knowledge of the 3 theoretical codes. In Study 2, elite referees demonstrated enhanced declarative knowledge compared with intermediate and novice participants.	Elite referees have more elaborate knowledge bases than do nonelite referees. In the discussion, we explain our results and link them with the action plan profiles framework.	
25136377	The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer's disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny. 
25116937	Maneuvering safely through the environment is central to survival of all animals. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and sometimes proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures (e.g., subiculum); in humans this system encodes declarative memory (allocentric, semantic, and episodic, i.e., memory for people, places, things, and events). This form of memory is assessed in laboratory animals by many methods, but predominantly the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and when over-learned becomes implicit or procedural memory. Several allocentric methods for rodents are reviewed and compared with the MWM with particular focus on the Cincinnati water maze (CWM). MWM advantages include minimal training, no food deprivation, ease of testing, reliable learning, insensitivity to differences in body weight and appetite, absence of non-performers, control methods for performance effects, repeated testing capability and other factors that make this test well-suited for regulatory studies. MWM limitations are also reviewed. Evidence-based MWM design and testing methods are presented. On balance, the MWM is arguably the preferred test for assessing learning and memory in basic research and regulatory studies and the CWM is recommended if two tests can be accommodated so that both allocentric (MWM) and egocentric (CWM) learning and memory can be effectively and efficiently assessed. 
25112600	Supraspan verbal list learning is widely used to assess dementia and related cognitive disorders where declarative memory deficits are a major clinical sign. While the overall learning rate is important for diagnosis, serial position patterns may give insight into more specific memory processes in patients with cognitive impairment. This study explored these patterns in a memory clinic clientele. One hundred eighty three participants took the Rey Auditory-Verbal Learning Test (RAVLT). The major groups were patients with Alzheimer's disease (AD), Vascular Dementia (VD), Mild Cognitive Impairment (MCI), and Subjective Cognitive Impairment (SCI) as well as healthy controls (HC). Raw scores for the five trials and five serial partitions were factor analysed. Three memory factors were found and interpreted as Primacy, Recency, and Resistance to Interference. AD and MCI patients had impaired scores in all factors. SCI patients were significantly impaired in the Resistance to Interference factor, and in the Recency factor at the first trial. The main conclusion is that serial position data from word list testing reflect specific memory capacities which vary with levels of cognitive impairment. 
25102126	The idea that memories are not invariable after the consolidation process has led to new perspectives about several mnemonic processes. In this framework, we review our studies on the modulation of memory expression during reconsolidation. We propose that during both memory consolidation and reconsolidation, neuromodulators can determine the probability of the memory trace to guide behavior, i.e. they can either increase or decrease its behavioral expressibility without affecting the potential of persistent memories to be activated and become labile. Our hypothesis is based on the findings that positive modulation of memory expression during reconsolidation occurs even if memories are behaviorally unexpressed. This review discusses the original approach taken in the studies of the crab Neohelice (Chasmagnathus) granulata, which was then successfully applied to test the hypothesis in rodent fear memory. Data presented offers a new way of thinking about both weak trainings and experimental amnesia: memory retrieval can be dissociated from memory expression. Furthermore, the strategy presented here allowed us to show in human declarative memory that the periods in which long-term memory can be activated and become labile during reconsolidation exceeds the periods in which that memory is expressed, providing direct evidence that conscious access to memory is not needed for reconsolidation. Specific controls based on the constraints of reminders to trigger reconsolidation allow us to distinguish between obliterated and unexpressed but activated long-term memories after amnesic treatments, weak trainings and forgetting. In the hypothesis discussed, memory expressibility--the outcome of experience-dependent changes in the potential to behave--is considered as a flexible and modulable attribute of long-term memories. Expression seems to be just one of the possible fates of re-activated memories.
25076903	Age-related memory decline has been associated with a faulty regulation of the hypothalamus-pituitary-adrenal axis (HPA-axis). The aim of this study was to investigate whether the magnitude of the stress-induced cortisol increase is related to memory performance when memory is measured in non-stressful conditions. To do so, declarative and working memory performance were measured in 31 men and 35 women between 55 and 77 years of age. On a different day, the magnitude of their cortisol response to acute psychosocial stress was measured. The relationship between the cortisol response and memory performance was U shaped: a low cortisol response to stress was related to poorer declarative and working memory performance, whereas those who did not increase their cortisol levels and those who had the largest cortisol increase had better declarative and working memory capabilities. Sex did not moderate these relationships. These results suggest that a low cortisol response to stress could reflect a defective HPA-axis response to stressors that is accompanied by poorer memory performance. Conversely, a high cortisol response seems to reflect a correct functioning of the HPA-axis and may protect against memory deficits in the later stages of human life. 
25071629	The evidence is now good that different memory systems mediate the learning of different types of category structures. In particular, declarative memory dominates rule-based (RB) category learning and procedural memory dominates information-integration (II) category learning. For example, several studies have reported that feedback timing is critical for II category learning, but not for RB category learning-results that have broad support within the memory systems literature. Specifically, II category learning has been shown to be best with feedback delays of 500 ms compared to delays of 0 and 1000 ms, and highly impaired with delays of 2.5 s or longer. In contrast, RB learning is unaffected by any feedback delay up to 10 s. We propose a neurobiologically detailed theory of procedural learning that is sensitive to different feedback delays. The theory assumes that procedural learning is mediated by plasticity at cortical-striatal synapses that are modified by dopamine-mediated reinforcement learning. The model captures the time-course of the biochemical events in the striatum that cause synaptic plasticity, and thereby accounts for the empirical effects of various feedback delays on II category learning. 
25071536	Declarative long-term memories are not created in an instant. Gradual stabilization and temporally shifting dependence of acquired declarative memories in different brain regions-called systems consolidation-can be tracked in time by lesion experiments. The observation of temporally graded retrograde amnesia (RA) following hippocampal lesions points to a gradual transfer of memory from hippocampus to neocortical long-term memory. Spontaneous reactivations of hippocampal memories, as observed in place cell reactivations during slow-wave-sleep, are supposed to drive neocortical reinstatements and facilitate this process. We propose a functional neural network implementation of these ideas and furthermore suggest an extended three-state framework that includes the prefrontal cortex (PFC). It bridges the temporal chasm between working memory percepts on the scale of seconds and consolidated long-term memory on the scale of weeks or months. We show that our three-stage model can autonomously produce the necessary stochastic reactivation dynamics for successful episodic memory consolidation. The resulting learning system is shown to exhibit classical memory effects seen in experimental studies, such as retrograde and anterograde amnesia (AA) after simulated hippocampal lesioning; furthermore the model reproduces peculiar biological findings on memory modulation, such as retrograde facilitation of memory after suppressed acquisition of new long-term memories-similar to the effects of benzodiazepines on memory. 
25068857	What is the relationship between magnitude judgments relying on directly available characteristics versus probabilistic cues? Question frame was manipulated in a comparative judgment task previously assumed to involve inference across a probabilistic mental model (e.g., "Which city is largest"--the "larger" question-vs. "Which city is smallest"--the "smaller" question). Participants identified either the largest or smallest city (Experiments 1a and 2) or the richest or poorest person (Experiment 1b) in a 3-alternative forced-choice (3-AFC) task (Experiment 1) or a 2-AFC task (Experiment 2). Response times revealed an interaction between question frame and the number of options recognized. When participants were asked the smaller question, response times were shorter when none of the options were recognized. The opposite pattern was found when participants were asked the larger question: response time was shorter when all options were recognized. These task-stimuli congruity results in judgment under uncertainty are consistent with, and predicted by, theories of magnitude comparison, which make use of deductive inferences from declarative knowledge.
25062290	Epileptic seizures caused by hypothalamic hamartomas (HHs) are highly pharmacoresistant. Resective surgical approaches have shown some efficacy in controlling seizures; however, they bear a significant risk of postoperative mnemonic deterioration due to the close anatomical proximity of the HHs to structures essential for memory functions. We report on cognitive outcome in 26 patients with structural epilepsy due to HHs one year after interstitial radiosurgery. Individually, deteriorations occurred more frequently in declarative memory functions (in 20 to 50% of the patients), whereas more than 80% of the patients revealed stable or even improved performance in attentional functions. Preoperative better memory functions were associated with higher risk of postoperative performance decline. After radiosurgery, half of the patients showed more than 50%, and some up to 90%, of seizure reduction. Hypothalamic hamartoma volumes were significantly reduced at follow-up. Transient radiogenic edema found in 10/26 patients was not associated with further cognitive decline after radiosurgery. These results are highly relevant for therapeutic decisions and patient consultation on timing and choice of nonmedical treatment options for HHs. 
25048388	Stress has been shown to have marked and divergent effects on learning and memory which involves specific brain regions, such as spatial and declarative memory involving the hippocampus, memory of emotional arousing experiences and fear involving the amygdala, and executive functions and fear extinction involving the prefrontal cortex or the PFC. Response to stress involves a coordinated activation of a constellation of physiological systems including the activation of the hypothalamic-pituitary-adrenal (HPA) axis and other modulatory neurotransmitters and signaling systems. This paper presents a concise review of the effects of stress and glucocorticoids on the glutamatergic and monoaminergic (including noradrenergic, dopaminergic, and serotonergic systems) neurotransmitter systems as well as endocannabinoid signaling. Because of the breadth of the scope of this topic, the review is limited to the effects of stress on these brain systems on the prefrontal cortex, and where relevant, the hippocampus and the amygdala. 
25046627	Sleep supports the formation of a variety of declarative and non-declarative memories, and sleep deprivation often impairs these types of memories. In human subjects, natural sleep either during a nap or overnight leads to long-lasting improvements in visuomotor and fine motor tasks, but rodent models recapitulating these findings have been scarce. Here we present evidence that 5h of acute sleep deprivation impairs mouse skilled reach learning compared to a matched period of ad libitum sleep. In sleeping mice, the duration of total sleep time during the 5h of sleep opportunity or during the first bout of sleep did not correlate with ultimate gain in motor performance. In addition, we observed that reversal learning during the skilled reaching task was also affected by sleep deprivation. Consistent with this observation, 5h of sleep deprivation also impaired reversal learning in the water-based Y-maze. In conclusion, acute sleep deprivation negatively impacts subsequent motor and reversal learning and memory. 
25032492	Anatomically, the perirhinal cortex sits at the boundary between the medial temporal lobe and the ventral visual pathway. It has prominent interconnections not only with both these systems, but also with a wide range of unimodal and polymodal association areas. Consistent with these diverse projections, neurophysiological studies reveal a multidimensional set of mnemonic signals that include stimulus familiarity, within- and between-domain associations, associative recall, and delay-based persistence. This wide range of perirhinal memory signals not only includes signals that are largely unique to the perirhinal cortex (i.e., object familiarity), consistent with dual-process theories, but also includes a range of signals (i.e., associative flexibility and recall) that are strongly associated with the hippocampus, consistent with single-process theories. These neurophysiological findings have important implications for bridging the gap between single-process and dual-process models of medial temporal lobe function. 
25027645	The number of patients with cognitive impairment after sepsis or septic shock is high. However, the underlying neurophysiological basis of sepsis induced cognitive impairment is not fully understood.This is a prospective, controlled observational study. We are in the process of recruiting 25 survivors of severe sepsis or septic shock who will be investigated with functional MRI (fMRI), T1-weighted MRI und Diffusion Tensor Imaging (DTI) as well as Magnetoencephalography (MEG). Furthermore, patients will undergo neuropsychological evaluation using the DemTect and the clock drawing tests. In addition, verbal and declarative memory is assessed by the Verbal Learning and Memory Test. The primary aim is to determine the volumetry of the amygdala and the hippocampus. The secondary aim is to analyze the relationship between cognitive tests and MEG, and the (f)MRI results. Moreover, a between-group comparison will be evaluated to an age-matched group of healthy controls.	In a previous MEG study, we observed a significant slowing of the prominent background activity in sepsis survivors and hepatic encephalopathy patients in particular shortly after discharge from the ICU. Intriguingly, the rhythmic brain activity after visual flickering stimulation was altered in sepsis survivors in comparison to age-matched healthy volunteers. We propose that this desynchronization is based on affected underlying neuronal responses between various interconnected brain regions. The current project will analyze whether the modifications are related to a damage of the fibers connecting different brain regions or to a disturbance of the functional interaction between different brain regions or even due to an atrophy of certain brain regions.	"Langzeitfolgen nach schwerer Sepsis: Kognitive Beeinträchtigungen und strukturelle Veränderungen am Gehirn, eine MRT Studie"; German Clinical Trials Register (DRKS00005484).	
25026056	We investigated the organized storage of motor sequences in memory by assuming that processes related to interference at retrieval are indicative of memory organization. Effects resulting from these processes, thus, would allow inferences on how motor sequences are represented and organized. Participants learned motor sequences that were categorized by the direction of the initial movement. The subsequent selective retrieval of a subset of sequences of one category resulted in retrieval-induced forgetting (RIF) for the non-retrieved sequences of the same category. RIF occurred in an explicit recall test (Experiment 1), as well in an implicit test assessing memory with novel cues (Experiment 2). The results suggest that RIF affected motor programmes and that other cues as the used effectors (here movement direction) can be used for the organization of procedural memory. Basic retrieval dynamics apparently operate within the declarative and procedural systems in a similar way. 
25008351	Converging evidence suggests that addiction can be considered a disease of aberrant learning and memory with impulsive decision-making. In the past decades, numerous studies have demonstrated that drug addiction is involved in multiple memory systems such as classical conditioned drug memory, instrumental learning memory and the habitual learning memory. However, most of these studies have focused on the contributions of non-declarative memory, and declarative memory has largely been neglected in the research of addiction. Based on a recent finding that hippocampus, as a core functioning region of declarative memory, was proved biased the decision-making process based on past experiences by spreading associated reward values throughout memory. Our present study focused on the hippocampus. By utilizing seed-based network analysis on the resting-state functional MRI datasets with the seed hippocampus we tested how the intrinsic hippocampal memory network altered toward drug addiction, and examined how the functional connectivity strength within the altered hippocampal network correlated with behavioral index 'impulsivity'. Our results demonstrated that HD group showed enhanced coherence between hippocampus which represents declarative memory system and non-declarative reward-guided learning memory system, and also showed attenuated intrinsic functional link between hippocampus and top-down control system, compared to the CN group. This alteration was furthered found to have behavioral significance over the behavioral index 'impulsivity' measured with Barratt Impulsiveness Scale (BIS). These results provide insights into the mechanism of declarative memory underlying the impulsive behavior in drug addiction. 
25000446	The rate of exceptionally slow reaction times (RTs), described by the long tail of the RT distribution, was found to be amplified in a variety of special populations with cognitive deficits (e.g., early-stage Alzheimer's disease, attention-deficit/hyperactivity disorder, low intelligence, elderly). Previous individual differences studies found high correlations between working memory (WM) and parameters that characterize the magnitude of the long-RT tail. However, the causal direction remains unknown. In 3 choice-reaction task experiments, we examined this relationship by directly manipulating WM availability. In Experiment 1, the stimulus-response rules were either arbitrary (WM demanding) or nonarbitrary. In Experiment 2, the arbitrary rules were either novel (demanding) or practiced. In Experiment 3, WM was loaded with either declarative (stimulus-stimulus) or procedural (stimulus-response) arbitrary rules. Using an ex-Gaussian model fitting, we found across all experiments that WM demands uniquely influenced the τ parameter, mostly responsible for the long-RT distribution tail. Evidence accumulation modeling of the choice process indicated that WM load had little influence on the decision process itself and primarily affected the duration of an exponentially distributed nondecision component, assumed to reflect the process of rule retrieval. Theoretical interpretations and implications are discussed.
24981854	Goal-direct behavior and habit learning represent two forms of instrumental learning; whereas the former is rapidly acquired and regulated by its outcome, the latter is reflexive, elicited by antecedent stimuli rather than their consequences. Habit learning can be generally defined as the acquisition of associations between stimuli and responses. Habits are acquired via experience-dependent plasticity, occurring repeatedly over the course of days or years and becoming remarkably fixed. The distinction between habit learning, as a product of a procedural learning brain system, and a declarative learning system for encoding facts and episodes is based on the hypothesis that memory is composed of multiple systems that have distinct neuroanatomy and operating principles. Here we review recent research analyzing the main behavioral and neural characteristics of habit learning. In particular, we focus on the distinction between goal-directed and habitual behavior, and describe the brain areas and neurotransmitters systems involved in habit learning. The emotional modulation of habit learning in rodents and primates is reviewed, and the implications of habit learning in psychopathology are briefly described. 
24956014	When long-term memories are reactivated, they can reenter a transient plastic state in which they are vulnerable to interference or physiological manipulations. The present study attempted to directly affect reactivated memories through a stress manipulation, and compared the effects of stress on reactivated and nonreactivated components of a declarative memory in a within-subject design. We presented image pairs that consisted of an image of an animal and an image of an unrelated object. Participants were instructed to memorize the object images. Forty-eight hours later, we presented half of the animal images again in an unrelated task to indirectly reactivate the associated object images. Immediately after reactivation, participants were exposed to cold pressor stress or a warm water control condition. Forty-eight hours later, we assessed memory for the object images with a free recall test. Reactivation boosted memory performance in the control condition, such that reactivated items were better recalled than nonreactivated items. This memory-enhancing effect of reactivation was completely abolished by cold pressor stress. Importantly, stress selectively impacted only the reactivated items while leaving memory for the nonreactivated items unaffected. The present study shows that it is possible to selectively reactivate and modulate specific parts of a declarative memory.
24954844	Compelling evidence indicates that sleep can facilitate the off-line consolidation of declarative, perceptual, emotional and procedural memories. Here we assessed the sleep-related off-line consolidation of motor skills in 13 young primary insomniacs (23.31±2.5 yrs) compared to 13 healthy sleepers (24.31±1.6 yrs) using the sequential finger tapping task. During a training session insomniacs performed less correct sequences than controls. However, both groups exhibited similar on-line motor learning in the pre-sleep evening session. After a night of sleep, healthy controls improved their performance, indicating an overnight effect of sleep on motor skills consolidation. In contrast, insomniacs failed to exhibit a sleep-related enhancement in memory performance indicating impairment in the off-line motor skills consolidation process. Our results suggest that young adults with insomnia experience impaired off-line memory consolidation which seems not to be associated with reduced ability to acquire new motor information.
24917794	Sleep helps the consolidation of declarative memories in the laboratory, but the pro-mnemonic effect of daytime naps in schools is yet to be fully characterized. While a few studies indicate that sleep can indeed benefit school learning, it remains unclear how best to use it. Here we set out to evaluate the influence of daytime naps on the duration of declarative memories learned in school by students of 10-15 years old. A total of 584 students from 6th grade were investigated. Students within a regular classroom were exposed to a 15-min lecture on new declarative contents, absent from the standard curriculum for this age group. The students were then randomly sorted into nap and non-nap groups. Students in the nap group were conducted to a quiet room with mats, received sleep masks and were invited to sleep. At the same time, students in the non-nap group attended regular school classes given by their usual teacher (Experiment I), or English classes given by another experimenter (Experiment II). These 2 versions of the study differed in a number of ways. In Experiment I (n = 371), students were pre-tested on lecture-related contents before the lecture, were invited to nap for up to 2 h, and after 1, 2, or 5 days received surprise tests with similar content but different wording and question order. In Experiment II (n = 213), students were invited to nap for up to 50 min (duration of a regular class); surprise tests were applied immediately after the lecture, and repeated after 5, 30, or 110 days. Experiment I showed a significant ~10% gain in test scores for both nap and non-nap groups 1 day after learning, in comparison with pre-test scores. This gain was sustained in the nap group after 2 and 5 days, but in the non-nap group it decayed completely after 5 days. In Experiment II, the nap group showed significantly higher scores than the non-nap group at all times tested, thus precluding specific conclusions. The results suggest that sleep can be used to enhance the duration of memory contents learned in school. 
24882163	Retrieval of negative emotional memories is often accompanied by the experience of stress. Upon retrieval, a memory trace can temporarily return into a labile state, where it is vulnerable to change. An unresolved question is whether post-retrieval stress may affect the strength of declarative memory in humans by modulating the reconsolidation process. Here, we tested in two experiments whether post-reactivation stress may affect the strength of declarative memory in humans. In both experiments, participants were instructed to learn neutral, positive and negative words. Approximately 24h later, participants received a reminder of the word list followed by exposure to the social evaluative cold pressor task (reactivation/stress group, nexp1=20; nexp2=18) or control task (reactivation/no-stress group, nexp1=23; nexp2=18). An additional control group was solely exposed to the stress task, without memory reactivation (no-reactivation/stress group, nexp1=23; nexp2=21). The next day, memory performance was tested using a free recall and a recognition task. In the first experiment we showed that participants in the reactivation/stress group recalled more words than participants in the reactivation/no-stress and no-reactivation/stress group, irrespective of valence of the word stimuli. Furthermore, participants in the reactivation/stress group made more false recognition errors. In the second experiment we replicated our observations on the free recall task for a new set of word stimuli, but we did not find any differences in false recognition. The current findings indicate that post-reactivation stress can improve declarative memory performance by modulating the process of reconsolidation. This finding contributes to our understanding why some memories are more persistent than others. 
24870365	Evidence suggests that standard learning and recall indexes are sensitive markers of verbal declarative memory ability in bipolar disorder (BD), but no study has examined performance across the full range of component process measures on the Hopkins Verbal Learning Test (HVLT-R) in a BD cohort. As the HVLT-R is part of a widely used battery of cognitive functioning backed by the U.S. Federal Drug Administration as the accepted battery for use in pro-cognitive trials assessing cognitive-enhancing drugs in the related disorder schizophrenia, estimating the utility of its measures in BD is important. Forty-nine BD patients and 51 healthy controls completed the HVLT-R, which was scored for 13 variables of interest, across 4 indices: recall and learning, recognition, strategic organization, and errors. BD patients had greater difficulty in learning the HVLT-R word list compared to controls. They also demonstrated impairment in delayed recall/recognition. There were no differences between the groups in terms of their slope of learning, retrieval index, retention percentage, semantic or serial clustering, errors, or level of retrieval. This pattern was consistent across symptomatic and euthymic patients. The HVLT-R has some utility in characterizing the component processes involved in memory function in BD, such that memory impairments appear to be attributable to deficient encoding processes during the acquisition phase of learning. In the case of planning pro-cognitive clinical trials, the encoding deficits in BD observed here may be sensitive enough to potentially respond to medications designed to enhance the verbal memory performance.
24853408	Emotional enhancement of memory (EEM) has been a well-known phenomenon which corresponds to the advantage of emotional stimuli to be better recalled than neutral ones. Previous studies suggest that aging favours recollection of positive items and this pattern is disrupted in Alzheimer's disease (AD). Emotional valence of different stimulus modalities, i.e. pictures and words, may also have an effect on each other's memory performances. However, none of these were clearly studied in AD. This study aimed to evaluate how emotional valences of simultaneously presented stimuli affected recall in healthy young (YG, n = 30), healthy elderly (HE, n = 30) participants and in patients with AD (n = 30). A battery consisting of emotional words presented on emotional pictures was developed. An analysis of a 3 (Groups) × 3 (Emotional Valence of Picture) × 3 (Emotional Valence of Word) mixed ANOVA design was carried out. Patients with AD could process emotional information similarly to healthy participants; however, they had EEM only for picture recalling. Emotional valence of the co-presented stimulus had a boosting effect both in the YG and HE, but not in AD group, especially if both of the stimuli had the same emotional valence. This study highlights the impaired EEM for verbal and preserved EEM for non-verbal declarative memory in patients with AD, the neurobiological underpinnings of which should be addressed by future studies.

24846190	It has recently become widely appreciated that value-based decision making is supported by multiple computational strategies. In particular, animal and human behavior in learning tasks appears to include habitual responses described by prominent model-free reinforcement learning (RL) theories, but also more deliberative or goal-directed actions that can be characterized by a different class of theories, model-based RL. The latter theories evaluate actions by using a representation of the contingencies of the task (as with a learned map of a spatial maze), called an "internal model." Given the evidence of behavioral and neural dissociations between these approaches, they are often characterized as dissociable learning systems, though they likely interact and share common mechanisms. In many respects, this division parallels a longstanding dissociation in cognitive neuroscience between multiple memory systems, describing, at the broadest level, separate systems for declarative and procedural learning. Procedural learning has notable parallels with model-free RL: both involve learning of habits and both are known to depend on parts of the striatum. Declarative memory, by contrast, supports memory for single events or episodes and depends on the hippocampus. The hippocampus is thought to support declarative memory by encoding temporal and spatial relations among stimuli and thus is often referred to as a relational memory system. Such relational encoding is likely to play an important role in learning an internal model, the representation that is central to model-based RL. Thus, insofar as the memory systems represent more general-purpose cognitive mechanisms that might subserve performance on many sorts of tasks including decision making, these parallels raise the question whether the multiple decision systems are served by multiple memory systems, such that one dissociation is grounded in the other. Here we investigated the relationship between model-based RL and relational memory by comparing individual differences across behavioral tasks designed to measure either capacity. Human subjects performed two tasks, a learning and generalization task (acquired equivalence) which involves relational encoding and depends on the hippocampus; and a sequential RL task that could be solved by either a model-based or model-free strategy. We assessed the correlation between subjects' use of flexible, relational memory, as measured by generalization in the acquired equivalence task, and their differential reliance on either RL strategy in the decision task. We observed a significant positive relationship between generalization and model-based, but not model-free, choice strategies. These results are consistent with the hypothesis that model-based RL, like acquired equivalence, relies on a more general-purpose relational memory system. 
24828364	Structural alterations in the hippocampus and other medial temporal lobe regions have been observed in schizophrenia. How these alterations and hippocampal subfields might differ across the psychosis spectrum remains unclear.To characterize medial temporal lobe structures, including hippocampal subfields, using magnetic resonance imaging and to examine their relation to psychosis and cognitive function across the psychosis spectrum.	Case-control, cross-sectional neuroimaging study in a large series of probands with psychotic disorders and healthy volunteers as part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Patients with psychotic disorders (schizophrenia, n = 219; schizoaffective disorder, n = 142; and psychotic bipolar disorder, n = 188) and healthy controls (n = 337) were recruited across ambulatory clinics at university health centers in the B-SNIP consortium.	Medial temporal lobe and hippocampal subfields were quantified with an automated parcellation approach using FreeSurfer software. Memory and other cognitive parameters were assessed using standardized neuropsychological tests.	Hippocampal volume reductions were seen in all 3 diagnostic groups when compared with healthy controls; alterations in the entorhinal cortex and parahippocampal regions were limited to schizophrenia and schizoaffective disorders (P < .001). Smaller volumes across the hippocampal subfields were seen in all 3 psychotic disorders, with the most prominent differences being in cornu ammonis 2/3 (P < .001). Hippocampal volumes were positively correlated with psychosis severity, declarative memory, and overall cognitive performance (P < .05).	Alterations in the hippocampus were evident across psychotic disorders. Hippocampal subfields that participate in memory-related processes supporting pattern separation and pattern completion might be abnormal and may underlie the pathophysiology of psychosis.	
24825621	Retrieval of episodic memories is a multi-component act that relies on numerous operations ranging from processing the retrieval cue, evaluating retrieved information, and selecting the appropriate response given the demands of the task. Motivated by a rich functional neuroimaging literature, recent theorizing about various computations at retrieval has focused on the role of posterior parietal cortex (PPC). In a potentially promising line of research, recent neuroimaging findings suggest that different subregions of dorsal PPC respond distinctly to different aspects of retrieval decisions, suggesting that better understanding of their contributions might shed light on the component processes of retrieval. In an attempt to understand the basic operations performed by dorsal PPC, we used functional MRI and functional connectivity analyses to examine how activation in, and connectivity between, dorsal PPC and ventral temporal regions representing retrieval cues varies as a function of retrieval decision uncertainty. Specifically, participants made a five-point recognition confidence judgment for a series of old and new visually presented words. Consistent with prior studies, memory-related activity patterns dissociated across left dorsal PPC subregions, with activity in the lateral IPS tracking the degree to which participants perceived an item to be old, whereas activity in the SPL increased as a function of decision uncertainty. Importantly, whole-brain functional connectivity analyses further revealed that SPL activity was more strongly correlated with that in the visual word-form area during uncertain relative to certain decisions. These data suggest that the involvement of SPL during episodic retrieval reflects, at least in part, the processing of the retrieval cue, perhaps in service of attempts to increase the mnemonic evidence elicited by the cue. 
24817139	To clarify the anatomical organization of human memory remains a major challenge in clinical neuroscience. Experimental data suggest dentate gyrus granule cells play a major role in memory acquisition, i.e. pattern separation and rapid pattern completion, whereas hippocampal CA1 neurons are implicated in place memory and autobiographical memory retrieval. Patients with temporal lobe epilepsy present with a broad spectrum of memory impairment, which can be assessed during clinical examination. Although long seizure histories may contribute to a pathophysiological reorganization of functional connectivity, surgical resection of the epileptic hippocampus offers a unique possibility to anatomically study the differential contribution of hippocampal subfields to compromised learning and memory in humans. Herein, we tested the hypothesis of hippocampal subfield specialization in a series of 100 consecutive patients with temporal lobe epilepsy submitted to epilepsy surgery. Memory profiles were obtained from intracarotid amobarbital testing and non-invasive verbal memory assessment before surgery, and correlated with histopathologically quantified cell loss pattern in hippocampal subfields obtained from the same patients using the new international consensus classification for hippocampal sclerosis proposed by the International League against Epilepsy (HS ILAE). Interestingly, patients with CA1 predominant cell loss (HS ILAE Type 2; n = 13) did not show declarative memory impairment and were indistinguishable from patients without any hippocampal cell loss (n = 19). In contrast, 63 patients with neuronal loss affecting all hippocampal subfields including CA1, CA4 and dentate gyrus (HS ILAE Type 1), or predominant cell loss in CA4 and partially affecting also CA3 and dentate gyrus (HS ILAE Type 3, n = 5) showed significantly reduced declarative memory capacities (intracarotid amobarbital testing: P < 0.001; verbal memory: P < 0.05). Our results suggested an alternative model of how memory processing can be organized amongst hippocampal subfields, and that CA1 pyramidal cells are less critically involved in declarative human memory acquisition compared to dentate gyrus granule cells or CA4/CA3 pyramidal cells. 
24813468	Sleep after learning promotes the quantitative strengthening of new memories. Less is known about the impact of sleep on the qualitative reorganisation of memory, which is the focus of this review. Studies have shown that, in the declarative system, sleep facilitates the abstraction of rules (schema formation), the integration of knowledge into existing schemas (schema integration) and creativity that requires the disbandment of existing patterns (schema disintegration). Schema formation and integration might primarily benefit from slow wave sleep, whereas the disintegration of a schema might be facilitated by rapid eye movement sleep. In the procedural system, sleep fosters the reorganisation of motor memory. The neural mechanisms of these processes remain to be determined. Notably, emotions have been shown to modulate the sleep-related reorganisation of memories. In the final section of this review, we propose that the sleep-related reorganisation of memories might be particularly relevant for mental disorders. Thus, sleep disruptions might contribute to disturbed memory reorganisation and to the development of mental disorders. Therefore, sleep-related interventions might modulate the reorganisation of memories and provide new inroads into treatment. 
24805082	Interference between successively learned tasks is widely investigated to study motor memory. However, how simultaneously learned motor memories interact with each other has been rarely studied despite its prevalence in daily life. Assuming that motor memory shares common neural mechanisms with declarative memory system, we made unintuitive predictions that mental rehearsal, as opposed to further practice, of one motor memory will temporarily impair the recall of another simultaneously learned memory. Subjects simultaneously learned two sensorimotor tasks, i.e., visuomotor rotation and gain. They retrieved one memory by either practice or mental rehearsal and then had their memory evaluated. We found that mental rehearsal, instead of execution, impaired the recall of unretrieved memory. This impairment was content-independent, i.e., retrieving either gain or rotation impaired the other memory. Hence, conscious recollection of one motor memory interferes with the recall of another memory. This is analogous to retrieval-induced forgetting in declarative memory, suggesting a common neural process across memory systems. Our findings indicate that motor imagery is sufficient to induce interference between motor memories. Mental rehearsal, currently widely regarded as beneficial for motor performance, negatively affects memory recall when it is exercised for a subset of memorized items. 
24796545	The hypothesis that sleep is instrumental in the process of memory consolidation is currently largely accepted. Hippocampal formation is involved in the acquisition of declarative memories and particularly of spatial memories. Nevertheless, although largely investigated in rodents, the relations between spatial memory and hippocampal EEG activity have been scarcely studied in humans. Aimed to evaluate the effects of spatial learning on human hippocampal sleep EEG activity, we recorded hippocampal Stereo-EEG (SEEG) in a group of refractory epilepsy patients undergoing presurgical clinical evaluation, after a training on a spatial navigation task. We observed that hippocampal high-delta (2-4 Hz range) activity increases during the first NREM episode after learning compared to the baseline night. Moreover, the amount of hippocampal NREM high-delta power was correlated with task performance at retest. The effect involved only the hippocampal EEG frequencies inasmuch no differences were observed at the neocortical electrodes and in the traditional polysomnographic measures. The present findings support the crucial role of hippocampal slow EEG frequencies during sleep in the memory consolidation processes. More generally, together with previous results, they suggest that slow frequency rhythms are a fundamental characteristic of human hippocampal EEG during both sleep and wakefulness, and are related to the consolidation of different types of memories.
24795618	NeuroML is an XML-based model description language, which provides a powerful common data format for defining and exchanging models of neurons and neuronal networks. In the latest version of NeuroML, the structure and behavior of ion channel, synapse, cell, and network model descriptions are based on underlying definitions provided in LEMS, a domain-independent language for expressing hierarchical mathematical models of physical entities. While declarative approaches for describing models have led to greater exchange of model elements among software tools in computational neuroscience, a frequent criticism of XML-based languages is that they are difficult to work with directly. Here we describe two Application Programming Interfaces (APIs) written in Python (http://www.python.org), which simplify the process of developing and modifying models expressed in NeuroML and LEMS. The libNeuroML API provides a Python object model with a direct mapping to all NeuroML concepts defined by the NeuroML Schema, which facilitates reading and writing the XML equivalents. In addition, it offers a memory-efficient, array-based internal representation, which is useful for handling large-scale connectomics data. The libNeuroML API also includes support for performing common operations that are required when working with NeuroML documents. Access to the LEMS data model is provided by the PyLEMS API, which provides a Python implementation of the LEMS language, including the ability to simulate most models expressed in LEMS. Together, libNeuroML and PyLEMS provide a comprehensive solution for interacting with NeuroML models in a Python environment. 
24790277	Rapid eye movement (REM) sleep is considered critical to the consolidation of procedural memory - the memory of skills and habits. Many antidepressants strongly suppress REM sleep, however, and procedural memory consolidation has been shown to be impaired in depressed patients on antidepressant therapy. As a result, it is important to determine whether antidepressive therapy can lead to amnestic impairment. We thus investigated the effects of the anticholinergic antidepressant amitriptyline on sleep-dependent memory consolidation.Double-blind, placebo-controlled, randomized, parallel-group study.	Sleep laboratory.	Twenty-five healthy men (mean age: 26.8 ± 5.6 y).	75 mg amitriptyline versus placebo.	To test memory consolidation, a visual discrimination task, a finger-tapping task, the Rey-Osterrieth Complex Figure Test, and the Rey Auditory-Verbal Learning Test were performed. Sleep was measured using polysomnography. Our findings show that amitriptyline profoundly suppressed REM sleep and impaired perceptual skill learning, but not motor skill or declarative learning.	Our study is the first to demonstrate that an antidepressant can affect procedural memory consolidation in healthy subjects. Moreover, considering the results of a recent study, in which selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors were shown not to impair procedural memory consolidation, our findings suggest that procedural memory consolidation is not facilitated by the characteristics of REM sleep captured by visual sleep scoring, but rather by the high cholinergic tone associated with REM sleep. Our study contributes to the understanding of potentially undesirable behavioral effects of amitriptyline.	
24782698	There is a strong correlation between signature EEG frequency patterns and the relative levels of distinct neuromodulators. These associations become particularly evident during the sleep-wake cycle. The monoamine-acetylcholine balance hypothesis is a theory of neurophysiological markers of the EEG and a detailed description of the findings that support this proposal are presented in this paper. According to this model alpha rhythm reflects the relative predominance of cholinergic muscarinic signals and delta rhythm that of monoaminergic receptor effects. Both high voltage synchronized rhythms are likely mediated by inhibitory Gαi/o-mediated transduction of inhibitory interneurons. Cognitively, alpha and delta EEG measures are proposed to indicate automatic and flexible strategies, respectively. Sleep is associated with marked changes in relative neuromodulator levels corresponding to EEG markers of distinct stages. Sleep studies on memory consolidation present some of the strongest evidence yet for the respective roles of monoaminergic and cholinergic projections in declarative and non-declarative memory processes, a key theoretical premise for understanding the data. Affective dysregulation is reflected in altered EEG patterns during sleep. 
24777135	Stress hormones, i.e. cortisol in human and cortisone in rodents, influence a wide range of cognitive functions, including hippocampus-based declarative memory performance. Cortisol enhances memory consolidation, but impairs memory retrieval. In this context glucocorticoid receptor sensitivity and hippocampal integrity play an important role. This review integrates findings on the relationships between the hypothalamus-pituitary-adrenal (HPA) axis, one of the main coordinators of the stress response, hippocampus, and memory. Findings obtained in healthy participants will be compared with selected mental disorders, including major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and borderline personality disorder (BPD). These disorders are characterized by alterations of the HPA axis and hippocampal dysfunctions. Interestingly, the acute effects of stress hormones on memory in psychiatric patients are different from those found in healthy humans. While cortisol administration has failed to affect memory retrieval in patients with MDD, patients with PTSD and BPD have been found to show enhanced rather than impaired memory retrieval after hydrocortisone. This indicates an altered sensitivity to stress hormones in these mental disorders.
24777133	Developments in tasks and imaging techniques applied over the last decades have yielded substantial support for the hypothesized role of the hippocampus in mnemonic processes. Human imaging research has now moved on to disentangle the contributions of the different hippocampal subregions and adjacent cortices, so as to bridge the gap between rodent and human data. Besides the importance of such studies for basic research, the investigation of hippocampal (dys)function has clinical relevance for diseases ranging from neurological disorders such as Alzheimer's disease or epilepsy to mental disorders such as schizophrenia or anxiety disorders. So far, most of the present review articles and books about the hippocampus and its functions focus on traditional declarative memory paradigms and 'encoding versus retrieval'. In this chapter we concentrate on a less travelled, but not less important, route concerning the role of the hippocampus in a well-established associative learning (encoding) paradigm: pavlovian fear conditioning. Fear conditioning is hypothesized to model aversive associative learning on a nonpathological level and is further assumed to recruit the same networks that are relevant for anxiety disorders, with the hippocampus being specific for contextual fear conditioning. We highlight the findings in humans by addressing its role in mediating spatial and temporal aspects of a context, involving different kinds of a fear-conditioning procedure (delay vs. trace conditioning), and its role in extinction, both from a theoretical and clinical perspective.
24777130	There has been a long tradition in memory research of adopting the view of a vital role of the medial temporal lobe and especially the hippocampus in declarative memory. Despite the broad support for this notion, there is an ongoing debate about what computations are performed by the different substructures. The present chapter summarizes several accounts of hippocampal functions in terms of the cognitive processes subserved by these structures, the information processed, and the underlying neural operations. Firstly, the value of the distinction between recollection and familiarity for the understanding of the role the hippocampus plays in memory is discussed. Then multiple lines of evidence for the role of the hippocampus in memory are considered. Cumulating evidence suggests that the hippocampus fosters the binding of disparate cortical representations of items and their spatiotemporal context into a coherent representation by means of a sparse conjunctive neural coding. This association of item and context will then lead to the phenomenological experience of recollection. In contrast, surrounding cortical areas have broader neural coding that provide a scalar signal of the similarity between two inputs (e.g. between the encoding and the retrieval). By this they form the basis of a feeling of familiarity, but also might encode the commonalities between these different inputs. However, a more complete picture of the importance of the hippocampus for declarative memories can only be drawn when the interactions of the medial temporal lobe with other brain areas are also taken into account.
24777128	The hippocampus expresses a variety of highly organized network states which bind its individual neurons into collective modes of activity. These patterns go along with characteristic oscillations of extracellular potential known as theta, gamma, and ripple oscillations. Such network oscillations share some important features throughout the entire central nervous system of higher animals: they are restricted to a defined behavioral state, they are mostly generated by subthreshold synaptic activity, and they entrain active neurons to fire action potentials at strictly defined phases of the oscillation cycle, thereby providing a unifying 'zeitgeber' for coordinated multineuronal activity. Recent work from the hippocampus of rodents and humans has revealed how the resulting spatiotemporal patterns support the formation of neuronal assemblies which, in our present understanding, form the neuronal correlate of spatial, declarative, or episodic memories. In this review, we introduce the major types of spatiotemporal activity patterns in the hippocampus, describe the underlying neuronal mechanisms, and illustrate the concept of memory formation within oscillating networks. Research on hippocampus-dependent memory has become a key model system at the interface between cellular and cognitive neurosciences. The next step will be to translate our increasing insight into the mechanisms and systemic functions of neuronal networks into urgently needed new therapeutic strategies.
24770677	Recognition memory is an important aspect of human declarative memory and is one of the routine memory abilities altered in patients with amnestic syndrome and Alzheimer's disease. In rodents, recognition memory has been most widely assessed using the novel object preference paradigm, which exploits the spontaneous preference that animals display for novel objects. Here, we used nose-poke units instead of objects to design a simple automated method for assessing context recognition memory in mice.In the acquisition trial, mice are exposed for the first time to an operant chamber with one blinking nose-poke unit. In the choice session, a novel nonblinking nose-poke unit is inserted into an empty spatial location and the number of nose poking dedicated to each set of nose-poke unit is used as an index of recognition memory.	We report that recognition performance varies as a function of the length of the acquisition period and the retention delay and is sensitive to conventional amnestic treatments. By manipulating the features of the operant chamber during a brief retrieval episode (3-min long), we further demonstrate that reconsolidation of the original contextual memory depends on the magnitude and the type of environmental changes introduced into the familiar spatial environment.	These results show that the nose-poke recognition task provides a rapid and reliable way for assessing context recognition memory in mice and offers new possibilities for the deciphering of the brain mechanisms governing the reconsolidation process.	
24767488	Sleep is pervasive throughout most of the animal kingdom-even jellyfish and honeybees do it. Although the precise function of sleep remains elusive, research increasingly suggests that sleep plays a key role in memory consolidation. Newly formed memories are highly labile and susceptible to interference, and the sleep period offers an optimal window in which memories can be strengthened or modified. Interestingly, a small but growing research area has begun to explore the ability of odors to modulate memories during sleep. The unique anatomical organization of the olfactory system, including its intimate overlap with limbic systems mediating emotion and memory, and the lack of a requisite thalamic intermediary between the nasal periphery and olfactory cortex, suggests that odors may have privileged access to the brain during sleep. Indeed, it has become clear that the long-held assumption that odors have no impact on the sleeping brain is no longer tenable. Here, we summarize recent studies in both animal and human models showing that odor stimuli experienced in the waking state modulate olfactory cortical responses in sleep-like states, that delivery of odor contextual cues during sleep can enhance declarative memory and extinguish fear memory, and that olfactory associative learning can even be achieved entirely within sleep. Data reviewed here spotlight the emergence of a new research area that should hold far-reaching implications for future neuroscientific investigations of sleep, learning and memory, and olfactory system function. 
24748707	This review examined the status of long-term memory systems in specific language impairment (SLI), in particular declarative memory and aspects of procedural memory. Studies included in the review were identified following a systematic search of the literature and findings combined using meta-analysis. This review showed individuals with SLI are poorer than age matched controls in the learning and retrieval of verbal information from the declarative memory. However, there is evidence to suggest that the problems with declarative learning and memory for verbal information in SLI might be due to difficulties with verbal working memory and language. The learning and retrieval of non-verbal information from declarative memory appears relatively intact. In relation to procedural learning and memory, evidence indicates poor implicit learning of verbal information. Findings pertaining to nonverbal information have been mixed. This review of the literature indicates there are now substantial grounds for suspecting that multiple memory systems may be implicated in the impairment.
24744453	To investigate the effects of post-learning sleep and sleep architecture on false memory in healthy older adults.Balanced, crossover design. False memory was induced using the Deese-Roediger-McDermott (DRM) paradigm and assessed following nocturnal sleep and following a period of daytime wakefulness. Post-learning sleep structure was evaluated using polysomnography (PSG).	Sleep research laboratory.	Fourteen healthy older adults from the Singapore-Longitudinal Aging Brain Study (mean age ± standard deviation = 66.6 ± 4.1 y; 7 males).	At encoding, participants studied lists of words that were semantically related to non-presented critical lures. At retrieval, they made "remember"/"know" and "new" judgments. Compared to wakefulness, post-learning sleep was associated with reduced "remember" responses, but not "know" responses to critical lures. In contrast, there were no significant differences in the veridical recognition of studied words, false recognition of unrelated distractors, discriminability, or response bias between the sleep and the wake conditions. More post-learning slow wave sleep was associated with greater reduction in false memory.	In healthy older adults, sleep facilitates the reduction in false memory without affecting veridical memory. This benefit correlates with the amount of slow wave sleep in the post-learning sleep episode.	
24739966	Accumulating evidence points to cortical oscillations as a mechanism for mediating interactions among functionally specialized neurons in distributed brain circuits. A brain function that may use such interactions is declarative memory--that is, memory that can be consciously recalled, such as episodes and facts. Declarative memory is enabled by circuits in the entorhinal cortex that interface the hippocampus with the neocortex. During encoding and retrieval of declarative memories, entorhinal and hippocampal circuits are thought to interact via theta and gamma oscillations, which in awake rodents predominate frequency spectra in both regions. In favour of this idea, theta-gamma coupling has been observed between entorhinal cortex and hippocampus under steady-state conditions in well-trained rats; however, the relationship between interregional coupling and memory formation remains poorly understood. Here we show, by multisite recording at successive stages of associative learning, that the coherence of firing patterns in directly connected entorhinal-hippocampus circuits evolves as rats learn to use an odour cue to guide navigational behaviour, and that such coherence is invariably linked to the development of ensemble representations for unique trial outcomes in each area. Entorhinal-hippocampal coupling was observed specifically in the 20-40-hertz frequency band and specifically between the distal part of hippocampal area CA1 and the lateral part of entorhinal cortex, the subfields that receive the predominant olfactory input to the hippocampal region. Collectively, the results identify 20-40-hertz oscillations as a mechanism for synchronizing evolving representations in dispersed neural circuits during encoding and retrieval of olfactory-spatial associative memory.
24739500	Cognitive impairment is a core feature of schizophrenia and it is considered by many researchers as one of the dimensional components of the disorder. Cognitive dysfunction occurs in 85% of schizophrenic patients and it is negatively associated with the outcome of the disorder, the psychosocial functioning of the patients, and non-compliance with treatment. Many different cognitive domains are impaired in schizophrenia, such as attention, memory, executive functions and speech. Nowadays, it is argued that apart from clinical heterogeneity of schizophrenia, there is probable heterogeneity in the accompanying neurocognitive dysfunction. Recent studies for cognitive dysfunction in schizophrenia employ computerized assessment batteries of cognitive tests, designed to assess specific cognitive impairments. Computerized cognitive testing permits for more detailed data collection (e.g. precise timing scores of responses), eliminates researcher's measurement errors and bias, assists the manipulation of data collected, and improves reliability of measurements through standardized data collection methods. The aims of the present study are: the comparison of cognitive performance of our sample of patients and that of healthy controls, on different specific cognitive tests, and the testing for possible association between patients' psychopathological symptoms and specific cognitive impairments, using the Cogtest computerized cognitive assessment battery. 71 male inpatients diagnosed with schizophrenia or other psychotic spectrum disorders (mean = 30.23 ± 7.71 years of age), admitted in a psychiatric unit of the First Department of Psychiatry, Athens University Medical School, Eginition Hospital (continuous admissions) were studied. Patients were excluded from the study if they suffered from severe neurological conditions, severe visual or hearing impairment, mental retardation, or if they abused alcohol or drugs. The patients' diagnoses were based on the semi-structured diagnostic interview "Diagnostic Interview for Psychosis" (DIP) and were clinically confirmed by two independent expert psychiatrists, according to the criteria of DSM-IVTM. Our healthy control group consisted of 20 healthy male participants (mean = 31.65 ± 5.90 years of age), who met the same inclusion criteria for the study as the patient group, as well as the same exclusion criteria from the study, having no history of psychiatric disorders. All statistical analyses were conducted using the statistical package SPSS.17. According to our results, healthy controls cognitively outperform our patient sample in all cognitive tests, with the differences between performances being statistically significant. Results concerning the association between psychotic symptoms and cognitive deficits of our patients indicated that hallucinations, highly organized delusions, persecutory delusions, agitation, catatonia and inappropriate affect did not associate with any subtype of cognitive deficit. Blunted affect associated significantly with response inhibition ("GoNoGo test", p = 0.007), and poor speech associated significantly with declarative memory of faces ("FMT test", p = 0.002). Moreover, psychomotor ability (non-dominant hand) associated significantly with generalized delusions ("TST test", p = 0.033), and with constricted affect ("TST test", p = 0.026). Furthermore, there was a tendency towards significance association between persecutory delusions and executive function ("CPT test", p = 0.053), inappropriate affect and declarative face memory ("FMT test", p = 0.056), and psychomotor ability and poor speech (p = 0.086).
24719218	The human hippocampus is widely believed to be necessary for the rapid acquisition of new declarative relational memories. However, processes supporting on-line inferential word use ("fast mapping") may also exercise a dissociable learning mechanism and permit rapid word learning without the hippocampus (Sharon et al. (2011) Proc Natl Acad Sci USA 108:1146-1151). We investigated fast mapping in severely amnesic patients with hippocampal damage (N = 4), mildly amnesic patients (N = 6), and healthy comparison participants (N = 10) using on-line measures (eye movements) that reflected ongoing processing. All participants studied unique word-picture associations in two encoding conditions. In the explicit-encoding condition, uncommon items were paired with their names (e.g., "This is a numbat."). In the fast mapping study condition, participants heard an instruction using a novel word (e.g., "Click on the numbat.") while two items were presented (an uncommon target such as a numbat, and a common distracter such as a dog). All groups performed fast mapping well at study, and on-line eye movement measures did not reveal group differences. However, while comparison participants showed robust word learning irrespective of encoding condition, severely amnesic patients showed no evidence of learning after fast mapping or explicit encoding on any behavioral or eye-movement measure. Mildly amnesic patients showed some learning, but performance was unaffected by encoding condition. The findings are consistent with the following propositions: the hippocampus is not essential for on-line fast mapping of novel words; but is necessary for the rapid learning of arbitrary relational information irrespective of encoding conditions.
24692164	The ability to encode information into long-term memory is not a passive process but can be influenced by motivational factors. While the mesolimbic system has long been associated with reward-driven memory enhancement, the precise neurobiology of processing aversive events and their effects on declarative learning remain unclear. To address this issue, human subjects encoded a series of scene images, which was combined with cues predicting an aversive electric shock with different probabilities (0.2, 0.5, 0.8). Subsequently, recognition memory for the scenes was tested using a remember/know procedure. In a behavioral experiment, shock probability had linear effects on familiarity and inverted u-shaped effects on recollection. While the behavioral effect was absent in experiment 2 (fMRI), at the neural level encoding-related activity in the hippocampus mimicked the recollection specific quadratic effect, whereas activity in the anterior parahippocampal gyrus mirrored the familiarity specific linear relationship that was evident in experiment 1. Importantly, the probability of upcoming shocks was linearly coded in the substantia nigra / ventral tegmental area, and pain associated brain regions, such as the insula, responded to shock delivery. Our results demonstrate that anticipating primary aversive events recruits the human mesolimbic system and differentially modulates declarative memory functions via medial temporal lobe structures.
24679545	Previous research exploring declarative memory in Williams syndrome (WS) has revealed impairment in the processing of episodic information accompanied by a relative strength in semantic ability. The aim of the current study was to extend this literature by examining how relatively spared semantic memory may support episodic remembering. Using a level of processing paradigm, older adults with WS (aged 35-61 years) were compared to typical adults of the same chronological age and typically developing children matched for verbal ability. In the study phase, pictures were encoded using either a deep (decide if a picture belongs to a particular category) or shallow (perceptual based processing) memory strategy. Behavioural indices (reaction time and accuracy) at retrieval were suggestive of an overall difficulty in episodic memory for WS adults. Interestingly, however, semantic support was evident with a greater recall of items encoded with deep compared to shallow processing, indicative of an ability to employ semantic encoding strategies to maximise the strength of the memory trace created. Unlike individuals with autism who find semantic elaboration strategies problematic, the pattern of findings reported here suggests in those domains that are relatively impaired in WS, support can be recruited from relatively spared cognitive processes. 
24666164	This study offers a neurophysiological examination of the relationship between feedback processing and learning. A two-choice paired-associate learning task borrowed and modified from Tricomi and Fiez [Tricomi, E., & Fiez, J. A. Feedback signals in the caudate reflect goal achievement on a declarative memory task. Neuroimage, 41, 1154-1167, 2008] was employed to examine the mediofrontal electrophysiological brain activity associated with the processing of performance feedback in a learning task and to elucidate the extent to which the processing of the initial informative feedback is related to learning outcomes. Twenty participants were tasked with learning to correctly pair 60 novel objects with their names by choosing on a trial-by-trial basis between two possible names and receiving feedback about the accuracy of their selection. The novel objects were presented in three blocks of trials (rounds), each of which presented the same set of 60 objects once. The rounds allowed the separation of the initial informative feedback in Round 1 from the other feedback stimuli in Rounds 2 and 3. The results indicated differences in the processing of initial informative and proceeding feedback stimuli. More specifically, the difference appeared to be driven by the change in the processing of positive feedback. Moreover, very first positive feedback provided in association with a particular new object was found associated with learning outcomes. The results imply that signs of successful and unsuccessful learning may be detected as early as the initial positive feedback provided in a learning task. The results suggest that the process giving rise to the feedback-related negativity is sensitive to the utility of the feedback and that the processing of the first informative positive feedback is associated with learning outcomes.
24657480	A hallmark of human speech perception is the ability to comprehend speech quickly and effortlessly despite enormous variability across talkers. However, current theories of speech perception do not make specific claims about the memory mechanisms involved in this process. To examine whether declarative memory is necessary for talker-specific learning, we tested the ability of amnesic patients with severe declarative memory deficits to learn and distinguish the accents of two unfamiliar talkers by monitoring their eye-gaze as they followed spoken instructions. Analyses of the time-course of eye fixations showed that amnesic patients rapidly learned to distinguish these accents and tailored perceptual processes to the voice of each talker. These results demonstrate that declarative memory is not necessary for this ability and points to the involvement of non-declarative memory mechanisms. These results are consistent with findings that other social and accommodative behaviors are preserved in amnesia and contribute to our understanding of the interactions of multiple memory systems in the use and understanding of spoken language. 
24652608	Sleep quality and architecture as well as sleep's homeostatic and circadian controls change with healthy aging. Changes include reductions in slow-wave sleep's (SWS) percent and spectral power in the sleep electroencephalogram (EEG), number and amplitude of sleep spindles, rapid eye movement (REM) density and the amplitude of circadian rhythms, as well as a phase advance (moved earlier in time) of the brain's circadian clock. With mild cognitive impairment (MCI) there are further reductions of sleep quality, SWS, spindles, and percent REM, all of which further diminish, along with a profound disruption of circadian rhythmicity, with the conversion to Alzheimer's disease (AD). Sleep disorders may represent risk factors for dementias (e.g., REM Behavior Disorder presages Parkinson's disease) and sleep disorders are themselves extremely prevalent in neurodegenerative diseases. Working memory , formation of new episodic memories, and processing speed all decline with healthy aging whereas semantic, recognition, and emotional declarative memory are spared. In MCI, episodic and working memory further decline along with declines in semantic memory. In young adults, sleep-dependent memory consolidation (SDC) is widely observed for both declarative and procedural memory tasks. However, with healthy aging, although SDC for declarative memory is preserved, certain procedural tasks, such as motor-sequence learning, do not show SDC. In younger adults, fragmentation of sleep can reduce SDC, and a normative increase in sleep fragmentation may account for reduced SDC with healthy aging. Whereas sleep disorders such as insomnia, obstructive sleep apnea, and narcolepsy can impair SDC in the absence of neurodegenerative changes, the incidence of sleep disorders increases both with normal aging and, further, with neurodegenerative disease. Specific features of sleep architecture, such as sleep spindles and SWS are strongly linked to SDC. Diminution of these features with healthy aging and their further decline with MCI may account for concomitant declines in SDC. Notably these same sleep features further markedly decline, in concert with declining cognitive function, with the progression to AD. Therefore, progressive changes in sleep quality, architecture, and neural regulation may constitute a contributing factor to cognitive decline that is seen both with healthy aging and, to a much greater extent, with neurodegenerative disease. 
24651468	Cocaine users consistently display cognitive impairments. However, it is still unknown whether these impairments are cocaine-induced and if they are reversible. Therefore, we examined the relation between changing intensity of cocaine use and the development of cognitive functioning within 1 year. The present data were collected as part of the longitudinal Zurich Cocaine Cognition Study (ZuCo(2)St). Forty-eight psychostimulant-naive controls and 57 cocaine users (19 with increased, 19 with decreased, and 19 with unchanged cocaine use) were eligible for analysis. At baseline and after a 1-year follow-up, cognitive performance was measured by a global cognitive index and four neuropsychological domains (attention, working memory, declarative memory, and executive functions), calculated from 13 parameters of a broad neuropsychological test battery. Intensity of cocaine use was objectively determined by quantitative 6-month hair toxicology at both test sessions. Substantially increased cocaine use within 1 year (mean +297%) was associated with reduced cognitive performance primarily in working memory. By contrast, decreased cocaine use (-72%) was linked to small cognitive improvements in all four domains. Importantly, users who ceased taking cocaine seemed to recover completely, attaining a cognitive performance level similar to that of the control group. However, recovery of working memory was correlated with age of onset of cocaine use-early-onset users showed hampered recovery. These longitudinal data suggest that cognitive impairment might be partially cocaine-induced but also reversible within 1 year, at least after moderate exposure. The reversibility indicates that neuroplastic adaptations underlie cognitive changes in cocaine users, which are potentially modifiable in psychotherapeutical or pharmacological interventions. 
24647040	Performance for skills such as a sequence of finger movements improves during sleep. This has widely been interpreted as evidence for a role of sleep in strengthening skill learning. Here we propose a different interpretation. We propose that practice and sleep form different aspects of skill. To show this, we train 80 subjects on a sequence of key-presses and test at different time points to determine the amount of skill stored in transition (that is, pressing '2' after '3' in '4-3-2-1') and ordinal (that is, pressing '2' in the third ordinal position in '4-3-2-1') forms. We find transition representations improve with practice and ordinal representations improve during sleep. Further, whether subjects can verbalize the trained sequence affects the formation of ordinal but not transition representations. Verbal knowledge itself does not increase over sleep. Thus, sleep encodes different representations of memory than practice, and may mediate conversion of memories between declarative and procedural forms. 
24639638	Until now direct neurochemical measurements during memory tasks have not been accomplished in the human basal ganglia. It has been proposed, based on both functional imaging studies and psychometric testing in normal subjects and in patients with Parkinson's disease (PD), that the basal ganglia is responsible for the performance of feedback-contingent implicit memory tasks. To measure neurotransmitters, we used in vivo microdialysis during deep brain stimulation (DBS) surgery. We show in the right subthalamic nucleus (STN) of patients with PD a task-dependent change in the concentrations of glutamate and GABA during an implicit memory task relative to baseline, while no difference was found between declarative memory tasks. The five patients studied had a significant decrease in the percent concentration of GABA and glutamate during the performance of the weather prediction task (WPT). We hypothesize, based on current models of basal ganglia function, that this decrease in the concentration is consistent with expected dysfunction in basal ganglia networks in patients with PD. 
24639411	Graph-theoretical analyses of functional networks obtained with resting-state functional magnetic resonance imaging (fMRI) have recently proven to be a useful approach for the study of the substrates underlying cognitive deficits in different diseases. We used this technique to investigate whether cognitive deficits in Parkinson's disease (PD) are associated with changes in global and local network measures. Thirty-six healthy controls (HC) and 66 PD patients matched for age, sex, and education were classified as having mild cognitive impairment (MCI) or not based on performance in the three mainly affected cognitive domains in PD: attention/executive, visuospatial/visuoperceptual (VS/VP), and declarative memory. Resting-state fMRI and graph theory analyses were used to evaluate network measures. We have found that patients with MCI had connectivity reductions predominantly affecting long-range connections as well as increased local interconnectedness manifested as higher measures of clustering, small-worldness, and modularity. The latter measures also tended to correlate negatively with cognitive performance in VS/VP and memory functions. Hub structure was also reorganized: normal hubs displayed reduced centrality and degree in MCI PD patients. Our study indicates that the topological properties of brain networks are changed in PD patients with cognitive deficits. Our findings provide novel data regarding the functional substrate of cognitive impairment in PD, which may prove to have value as a prognostic marker.
24635722	The present study aimed to explore autobiographical memories (long-lasting memories about the self) and episodic memories (memories about discrete episodes or events) within dream content. We adapted earlier episodic memory study paradigms and reinvestigated the incorporation of episodic memory sources into dreams, operationalizing episodic memory as featuring autonoetic consciousness, which is the feeling of truly re-experiencing or reliving a past event. Participants (n = 32) recorded daily diaries and dream diaries, and reported on wake-dream relations for 2 weeks. Using a new scale, dreams were rated for their episodic richness, which categorized memory sources of dreams as being truly episodic (featuring autonoetic consciousness), autobiographical (containing segregated features of experiences that pertained to waking life) or otherwise. Only one dream (0.5%) was found to contain an episodic memory. However, the majority of dreams (>80%) were found to contain low to moderate incorporations of autobiographical memory features. These findings demonstrate the inactivity of intact episodic memories, and emphasize the activity of autobiographical memory and processing within dreams. Taken together, this suggests that memories for personal experiences are experienced fragmentarily and selectively during dreaming, perhaps in order to assimilate these memories into the autobiographical memory schema.
24624075	Recent research suggests that the medial temporal lobe (MTL) is involved in perception as well as in declarative memory. Amnesic patients with focal MTL lesions and semantic dementia patients showed perceptual deficits when discriminating faces and objects. Interestingly, these two patient groups showed different profiles of impairment for familiar and unfamiliar stimuli. For MTL amnesics, the use of familiar relative to unfamiliar stimuli improved discrimination performance. By contrast, patients with semantic dementia-a neurodegenerative condition associated with anterolateral temporal lobe damage-showed no such facilitation from familiar stimuli. Given that the two patient groups had highly overlapping patterns of damage to the perirhinal cortex, hippocampus, and temporal pole, the neuroanatomical substrates underlying their performance discrepancy were unclear. Here, we addressed this question with a multivariate reanalysis of the data presented by Barense et al. (2011), using functional connectivity to examine how stimulus familiarity affected the broader networks with which the perirhinal cortex, hippocampus, and temporal poles interact. In this study, healthy participants were scanned while they performed an odd-one-out perceptual task involving familiar and novel faces or objects. Seed-based analyses revealed that functional connectivity of the right perirhinal cortex and right anterior hippocampus was modulated by the degree of stimulus familiarity. For familiar relative to unfamiliar faces and objects, both right perirhinal cortex and right anterior hippocampus showed enhanced functional correlations with anterior/lateral temporal cortex, temporal pole, and medial/lateral parietal cortex. These findings suggest that in order to benefit from stimulus familiarity, it is necessary to engage not only the perirhinal cortex and hippocampus, but also a network of regions known to represent semantic information. 
24572357	The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when. Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus to CA3 and then to CA1, the main hippocampal output. Genetic lesions of EC (ref. 3) and hippocampal dentate gyrus (ref. 4), CA3 (ref. 5) and CA1 (ref. 6) regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output. Here we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioural role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory--the ability of an animal to remember a conspecific--with no change in sociability or several other hippocampus-dependent behaviours, including spatial and contextual memory. These behavioural and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.
24564663	Spatial navigation and memory is considered to be a part of the declarative memory system and it is widely used as an animal model of human declarative memory. However, spatial tests typically involve only static settings, despite the dynamic nature of the real world. Animals, as well as people constantly need to interact with moving objects, other subjects or even with entire moving environments (flowing water, running stairway). Therefore, we design novel spatial tests in dynamic environments to study brain mechanisms of spatial processing in more natural settings with an interdisciplinary approach including neuropharmacology. We also translate data from neuropharmacological studies and animal models into development of novel therapeutic approaches to neuropsychiatric disorders and more sensitive screening tests for impairments of memory, thought, and behavior. 
24564539	Several types of converging evidence have suggested recently that skilled adults solve very simple addition problems (e.g., 2 + 1, 4 + 2) using a fast, unconscious counting algorithm. These results stand in opposition to the long-held assumption in the cognitive arithmetic literature that such simple addition problems normally are solved by fact retrieval from declarative memory. Here we tested a large sample of diversely skilled and culturally diverse men and women at the University of Saskatchewan and examined multiple categories of simple (1 digit plus 1 digit) addition problems for evidence of generalization of practice, a signature of procedure use. The procedure-based 0 + N = N problems presented clear evidence of generalization (i.e., practicing a subset of 0 + N problems lead to speed-up for a different subset of 0 + N problems), but there was no evidence of such generalization of practice for the nonzero problems, although the experiment had good power to detect small effects. Given that generalization of practice is a basic marker of procedure-based processing, its absence for the nonzero addition problems casts doubt on the compacted counting theory.
24564466	Adaptive memory retrieval requires mechanisms of cognitive control that facilitate the recovery of goal-relevant information. Frontoparietal systems are known to support control of memory retrieval. However, the mechanisms by which the brain acquires, evaluates, and adapts retrieval strategies remain unknown. Here, we provide evidence that ventral striatal activation tracks the success of a retrieval strategy and correlates with subsequent reliance on that strategy. Human participants were scanned with fMRI while performing a lexical decision task. A rule was provided that indicated the likely semantic category of a target word given the category of a preceding prime. Reliance on the rule improved decision-making, as estimated within a drift diffusion framework. Ventral striatal activation tracked the benefit that relying on the rule had on decision-making. Moreover, activation in ventral striatum correlated with a participant's subsequent reliance on the rule. Taken together, these results support a role for ventral striatum in learning and evaluating declarative retrieval strategies. 
24550865	In this event-related fMRI study we investigated the effect of 5 days of implicit acquisition on preference classification by means of an artificial grammar learning (AGL) paradigm based on the structural mere-exposure effect and preference classification using a simple right-linear unification grammar. This allowed us to investigate implicit AGL in a proper learning design by including baseline measurements prior to grammar exposure. After 5 days of implicit acquisition, the fMRI results showed activations in a network of brain regions including the inferior frontal (centered on BA 44/45) and the medial prefrontal regions (centered on BA 8/32). Importantly, and central to this study, the inclusion of a naive preference fMRI baseline measurement allowed us to conclude that these fMRI findings were the intrinsic outcomes of the learning process itself and not a reflection of a preexisting functionality recruited during classification, independent of acquisition. Support for the implicit nature of the knowledge utilized during preference classification on day 5 come from the fact that the basal ganglia, associated with implicit procedural learning, were activated during classification, while the medial temporal lobe system, associated with explicit declarative memory, was consistently deactivated. Thus, preference classification in combination with structural mere-exposure can be used to investigate structural sequence processing (syntax) in unsupervised AGL paradigms with proper learning designs. 
24522026	Depressive disorders are multifactorial diseases in which cognitive impairments are one of typical features. Thiol protein groups (TPGs) are elements of chemical structure of compounds having antioxidative properties (glutathione peroxidase, metallothioneins) and their oxidation reflects the lost of compensatory capacity of antioxidative mechanisms. The purpose of this study was to determine the level of TPGs in patients with recurrent depressive disorder (rDD) and to define relationship between plasma levels of TPGs and the cognitive performance.The study comprised 76 subjects: patients with rDD (n=43) and healthy subjects (comparison group, CG - n=33). Cognitive function assessment was based on the following 4 tests: the Trail Making Test (TMT), the Stroop Test, Verbal Fluency Test (VFT) and Auditory Verbal Learning Test (AVLT).	The level of TPGs was higher in patients with rDD. In rDD group, the elevated concentration of TPGs in plasma was associated with a decrease in efficiency of declarative-memory, working memory and verbal fluency. The higher was the concentration of plasma TPGs, the greater was the severity of depressive symptoms measured by 21-item Hamilton Depression Rating Scale (HDRS), before and after pharmacotherapy. In CG group, the elevated TPGs levels were associated with worse cognitive test performance (AVLT and VFT tests).	1) Our study confirms previous results showing increased TPGs level in depression. 2) Our data suggest relation between increased plasma TPGs level in depression and cognitive impairment. 3) The elevated levels of plasma TPGs are related to impairment of the short-term and delayed declarative memory, verbal fluency and working memory.	
24485479	Patients with major depressive disorder (MDD) often suffer from impaired declarative, episodic and working memory. Further, MDD is associated with alterations in the noradrenergic system. There is evidence that presynaptic α2 receptors that inhibit release of noradrenaline are upregulated in MDD. Results from our recent study demonstrated that increasing noradrenergic activity by blocking the α2 receptor with yohimbine leads to stronger memory consolidation in MDD patients. In the current study, we further examined the role of noradrenaline on memory in MDD by administering clonidine that activates presynaptic α2 receptors and thereby globally suppresses the noradrenergic output.In a placebo-controlled, within-subject crossover design, 20 patients with MDD and 20 healthy controls received either 0.15 mg of clonidine or placebo orally before memory testing. A word list paradigm (memory consolidation), an autobiographical memory test (retrieval) and a working memory test were applied. Salivary alpha-amylase and blood pressure were measured.	Across groups, clonidine decreased blood pressure and alpha-amylase. Clonidine impaired memory consolidation (word list learning) in depressed patients and controls. Memory retrieval and working memory were not affected by clonidine.	Reducing noradrenergic activity had a specific effect on memory consolidation in patients with MDD and healthy controls. The underlying mechanisms need further scrutiny.	
24478681	Traditionally, it has been proposed that the hippocampus and adjacent medial temporal lobe cortical structures are selectively critical for long-term declarative memory, which entails memory for inter-item and item-context relationships. Whether the hippocampus might also contribute to short-term retention of relational memory representations has remained controversial. In two experiments, we revisit this question by testing memory for relationships among items embedded in scenes using a standard working memory trial structure in which a sample stimulus is followed by a brief delay and the corresponding test stimulus. In each experimental block, eight trials using different exemplars of the same scene were presented. The exemplars contained the same items but with different spatial relationships among them. By repeating the pictures across trials, any potential contributions of item or scene memory to performance were minimized, and relational memory could be assessed more directly than has been done previously. When test displays were presented, participants indicated whether any of the item-location relationships had changed. Then, regardless of their responses (and whether any item did change its location), participants indicated on a forced-choice test, which item might have moved, guessing if necessary. Amnesic patients were impaired on the change detection test, and were frequently unable to specify the change after having reported correctly that a change had taken place. Comparison participants, by contrast, frequently identified the change even when they failed to report the mismatch, an outcome that speaks to the sensitivity of the change specification measure. These results confirm past reports of hippocampal contributions to short-term retention of relational memory representations, and suggest that the role of the hippocampus in memory has more to do with relational memory requirements than the length of a retention interval. 
24467663	Successful memory consolidation during sleep depends on healthy slow-wave and rapid eye movement sleep, and on successful transition across sleep stages. In post-traumatic stress disorder, sleep is disrupted and memory is impaired, but relations between these two variables in the psychiatric condition remain unexplored. We examined whether disrupted sleep, and consequent disrupted memory consolidation, is a mechanism underlying declarative memory deficits in post-traumatic stress disorder. We recruited three matched groups of participants: post-traumatic stress disorder (n = 16); trauma-exposed non-post-traumatic stress disorder (n = 15); and healthy control (n = 14). They completed memory tasks before and after 8 h of sleep. We measured sleep variables using sleep-adapted electroencephalography. Post-traumatic stress disorder-diagnosed participants experienced significantly less sleep efficiency and rapid eye movement sleep percentage, and experienced more awakenings and wake percentage in the second half of the night than did participants in the other two groups. After sleep, post-traumatic stress disorder-diagnosed participants retained significantly less information on a declarative memory task than controls. Rapid eye movement percentage, wake percentage and sleep efficiency correlated with retention of information over the night. Furthermore, lower rapid eye movement percentage predicted poorer retention in post-traumatic stress disorder-diagnosed individuals. Our results suggest that declarative memory consolidation is disrupted during sleep in post-traumatic stress disorder. These data are consistent with theories suggesting that sleep benefits memory consolidation via predictable neurobiological mechanisms, and that rapid eye movement disruption is more than a symptom of post-traumatic stress disorder. 
24464878	Declarative memory refers to a spatial strategy using numerous sources of sensory input information in which visual and vestibular inputs are assimilated in the hippocampus. In contrast, procedural memory refers to a response strategy based on motor skills and familiar gestures and involves the striatum. Even if vestibular loss impairs hippocampal activity and spatial memory, vestibular-lesioned rats remain able to find food rewards during complex spatial memory task. Since hippocampal lesions induce a switch from declarative memory to procedural memory, we hypothesize that vestibular-lesioned rats use a strategy other than that of hippocampal spatial response to complete the task and to counterbalance the loss of vestibular information. We test, in a reverse T-maze paradigm, the types of strategy vestibular-lesioned rats preferentially uses in a spatial task. We clearly demonstrate that all vestibular-lesioned rats shift to a response strategy to solve the spatial task, while control rats use spatial and response strategies equally. We conclude that the loss of vestibular informations leading to spatial learning impairments is not offset at the hippocampus level by integration process of other sense mainly visual informations; but favors a response strategy through procedural memory most likely involving the striatum, cerebellum, and motor learning.
24460980	Children treated for medulloblastoma (MB) exhibit long-term impairments in declarative memory, but the pathophysiology underlying this is unclear. Previous studies report declines in global white matter volume, but have failed to link this to declines in memory performance. We examined the effects of treatment on measures of global brain structure (i.e., total white and gray matter volume) and specific memory structures (i.e., hippocampus and uncinate fasciculus). We used volumetric MRI and diffusion tensor imaging in pediatric survivors of MB and one survivor of astrocytoma treated with cranial-spinal radiation (n = 20), and healthy controls (n = 13). Compared to controls, the survivor group exhibited reduced white matter volume, damage to the uncinate fasciculus, and a smaller right hippocampus. Critically, reduced hippocampal volume was not related to differences in brain volume, suggesting that the hippocampus may be especially vulnerable to treatment effects. A subset of the survivors (n = 10) also underwent memory testing using the Children's Memory Scale (CMS). Performance on the general index of the CMS was significantly correlated with measures of hippocampal volume and uncinate fasciculus. The examination of treatment effects on specific brain regions provides a better understanding of long-term cognitive outcome in children with brain tumors, particularly medulloblastoma.
24459876	Alzheimer's disease is the most common cause of the declarative memory disorder: 30-40% cases of dementia among all of age groups, and 50-60% among the people older 65 years. In addition, disorder of declarative memory is the genuine symptom of the disease, which certainly appears on early stage of the disease and it is an obligate diagnostic symptom. Proponents of the "cholinergic theory" of pathogenesis of Alzheimer's disease suggest that the basis disorder of declarative memory is cholinergic dysfunction. Several neurodynamic mechanisms associated with declarative memory depend on the level of acetylcholine in hippocampus and neocortex. It is believed that dysfunction of the basal cholinergic system in Alzheimer's disease leads to the impairment of these mechanisms. In this review, we summarize available literature data concerning the mechanisms of Alzheimer's disease.
24459411	La perte de mémoire est un des premiers symptômes rapportés par les patients souffrant de maladie d'Alzheimer (MA) et leurs soignants. La mémoire de travail et la mémoire déclarative à long terme sont touchées de façon précoce au cours de l'évolution de la maladie. Le schéma individuel de la détérioration des fonctions mnésiques correspond aux paramètres de l'intégrité cérébrale fonctionnelle ou structurelle. La pathologie de la MA interfère avec la formation de souvenirs allant du niveau moléculaire jusqu'au cadre des réseaux neuronaux. La recherche de la perte de mémoire de la MA aide à identifier les structures neuronales impliquées, comme le réseau du « mode par défaut », l'influence des facteurs épigénétiques et génétiques, comme l'état de l'ApoE4 et les aspects évolutifs de la cognition humaine. Cliniquement, l'analyse de la mémoire facilite la définition des sous-types de MA, le stade de la maladie et la prévision du pronostic. Malgré les nouveaux critères de MA permettant le diagnostic précoce de la maladie en faisant appel à des biomarqueurs dérivés du liquide céphalo-rachidien ou à l'analyse du volume de l'hippocampe, les tests neuropsychologiques restent au centre du diagnostic de la MA.La pérdida de memoria está entre los primeros síntomas referidos por los pacientes que padecen Enfermedad de Alzheimer (EA) y por sus cuidadores. La memoria de trabajo y la memoria declarativa de largo plazo se afectan precozmente durante el curso de la enfermedad. El perfil individual de deterioro de las funciones de la memoria se correlaciona con parámetros de integridad cerebral estructural o funcional. La patología de la EA interfiere con la formación de memorias desde el nivel molecular hasta el sistema de redes neurales. La investigación de la pérdida de memoria en la EA ayuda a identificar las estructuras neurales involucradas, como la red neural por defecto, la influencia de factores epigenéticos y genéticos, como el estado de la ApoE4, y aspectos evolucionistas de la cognición humana. Clinicamente, el análisis de la memoria ayuda a la definición de los subtipos de EA, a la clasificación de la enfermedad y a las predicciones pronósticas. A pesar de los nuevos criterios de EA que permiten un diagnóstico más precoz de la enfermedad mediante la incorporación de biomarcadores derivados del liquido céfalo raquideo o del análisis del volumen del hipocampo, las pruebas neuropsicológicas persisten en to nuclear del diagnóstico de EA.	Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. Working memory and long-term declarative memory are affected early during the course of the disease. The individual pattern of impaired memory functions correlates with parameters of structural or functional brain integrity. AD pathology interferes with the formation of memories from the molecular level to the framework of neural networks. The investigation of AD memory loss helps to identify the involved neural structures, such as the default mode network, the influence of epigenetic and genetic factors, such as ApoE4 status, and evolutionary aspects of human cognition. Clinically, the analysis of memory assists the definition of AD subtypes, disease grading, and prognostic predictions. Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis. 	
24444515	Human memory is imperfect; thus, periodic review is required for the long-term preservation of knowledge and skills. However, students at every educational level are challenged by an ever-growing amount of material to review and an ongoing imperative to master new material. We developed a method for efficient, systematic, personalized review that combines statistical techniques for inferring individual differences with a psychological theory of memory. The method was integrated into a semester-long middle-school foreign-language course via retrieval-practice software. Using a cumulative exam administered after the semester's end, we compared time-matched review strategies and found that personalized review yielded a 16.5% boost in course retention over current educational practice (massed study) and a 10.0% improvement over a one-size-fits-all strategy for spaced study. 
24436638	Over the first decade of life there are marked improvements in mnemonic abilities. An important question from both a theoretical and applied perspective is the extent of continuity in the nature of memory over this period. The present longitudinal investigation examined declarative memory during the transition from toddlerhood to school-age using both experimental and standardized assessments. Results indicate significant associations between immediate nonverbal recall at 20 months (measured by elicited imitation) and immediate verbal and nonverbal memory (measured by standardized and laboratory-based tasks) at 6 years in typically developing children. Regression models revealed this association was specific, as measures of language abilities and temperament were not predictive of later memory performance. These findings suggest both continuity and specificity within the declarative memory system over the first years of life. Theoretical and applied implications of these findings are discussed.
24426817	Numerous studies have demonstrated that sleep promotes memory consolidation, but there is little research on the effect of hypnotics on sleep-dependent memory consolidation. We compared bedtime administration of zolpidem-ER 12.5 mg (6- to 8-h duration of action), middle-of-the-night administration of zaleplon 10 mg (3- to 4-h duration of action), and placebo to examine the effect of different durations of hypnotic drug exposure on memory consolidation during sleep.Twenty-two participants with no sleep complaints underwent 3 conditions in a counterbalanced crossover study: (1) zolpidem-ER 12.5 mg (bedtime dosing), (2) zaleplon 10 mg (middle-of-the-night dosing), and (3) placebo. Memory testing was conducted before and after an 8-h sleep period, using a word pair association task (WPT; declarative memory) and a finger-tapping task (FTT; procedural memory).	ANOVA revealed a significant condition effect for the WPT (p = 0.025) and a trend for the FTT (p = 0.067), which was significant when sex was added to the model (p = 0.014). Improvement in memory performance following sleep was lower with bedtime dosing of zolpidem-ER compared to placebo and middle-of-the-night dosing of zaleplon. There were no differences between placebo and zaleplon.	The results suggest that in some circumstances hypnotics may have the potential to reduce the degree of sleep-dependent memory consolidation and that drug-free sleep early in the night may ameliorate this effect.	
24423786	Atypical antipsychotics fail to substantially improve cognitive impairment associated with schizophrenia (CIAS) and one strategy to improve it is to stimulate adult neurogenesis in hippocampus, because this structure is part of an altered circuitry that underlies aspects of CIAS. Deficits in hippocampal adult neurogenesis may disrupt cognitive processes that are dependent on newborn neurons, such as pattern separation (the formation of distinct representations of similar inputs). Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT(1A) receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus. We hypothesize that use of antipsychotics possessing 5-HT(1A) receptor agonist properties may protect against or attenuate CIAS by a dual mechanism: a favorable influence on adult neurogenesis that develops upon sustained drug treatment, and an increase in dopamine levels in the prefrontal cortex that starts upon acute treatment. This hypothesis is consistent with the beneficial properties of 5-HT(1A) activation reported from pilot clinical studies using 5-HT(1A) agonists as adjunct to antipsychotic treatments. Recent antipsychotics, including clozapine and aripiprazole, exhibit different levels of 5-HT(1A) receptor partial agonism and may, therefore, differentially elicit hippocampal adult neurogenesis and increases in prefrontal cortex dopamine. We suggest that comparative studies should elucidate correlations between effects of antipsychotics on adult neurogenesis and prefrontal cortex dopamine with effects on performance in translational cognitive tasks known to involve new born neurons, such as tasks involving pattern separation, and working memory tasks sensitive to prefrontal cortex dopamine levels.
24423358	TSH-suppressive doses of levothyroxine (L-T4) have adverse effects on bone and cardiac function, but it is unclear whether central nervous system function is also affected.The aim of the study was to determine whether women receiving TSH-suppressive L-T4 doses have decrements in health status, mood, or cognitive function.	A cross-sectional comparison was made among three groups of women in an academic medical center research clinic.	Twenty-four women receiving chronic TSH-suppressive L-T4 doses, 35 women receiving chronic replacement L-T4 doses, and 20 untreated control women participated in the study.	Subjects underwent testing at a single outpatient visit.	We measured health status (SF-36), mood (Profile of Mood States, Symptom Checklist 90-R, Affective Lability Scale), and cognitive function (declarative memory [Paragraph Recall], working memory [N-back, Subject Ordered Pointing], motor learning [Pursuit Rotor, Motor Sequence Learning Test], and executive function [Letter Cancellation Test, Trail Making Test, Iowa Gambling Test]).	Women receiving TSH-suppressive or replacement L-T4 doses had decrements in health status and mood compared to healthy controls. These decrements were more pronounced in women receiving replacement, rather than suppressive, L-T4 doses. Memory and executive function were not affected in either treated group, compared to healthy controls.	Women receiving TSH-suppressive doses of L-T4 do not have central nervous system dysfunction due to exogenous subclinical thyrotoxicosis, but TSH-suppressed and L-T4-replaced women have slight decrements in health status and mood that may be related to self-knowledge of the presence of a thyroid condition or other uncharacterized factors. These mood alterations do not impair cognitive function.	
24416219	In the past years many studies have demonstrated the role of sleep on memory consolidation. It is known that sleeping after learning a declarative or non-declarative task, is better than remaining awake. Furthermore, there are reports of a possible role for dreams in consolidation of declarative memories. Other studies have reported the effect of naps on memory consolidation. With similar protocols, another set of studies indicated that sleep has a role in creativity and problem-solving. Here we hypothesised that sleep can increase the likelihood of solving problems. After struggling to solve a video game problem, subjects who took a nap (n = 14) were almost twice as likely to solve it when compared to the wake control group (n = 15). It is interesting to note that, in the nap group 9 out 14 subjects engaged in slow-wave sleep (SWS) and all solved the problem. Surprisingly, we did not find a significant involvement of Rapid Eye Movement (REM) sleep in this task. Slow-wave sleep is believed to be crucial for the transfer of memory-related information to the neocortex and implement intentions. Sleep can benefit problem-solving through the generalisation of newly encoded information and abstraction of the gist. In conclusion, our results indicate that sleep, even a nap, can potentiate the solution of problems that involve logical reasoning. Thus, sleep's function seems to go beyond memory consolidation to include managing of everyday-life events. 
24406640	Stress has been associated with negative changes observed during the aging process. However, very little research has been carried out on the role of age in acute stress effects on memory. We aimed to explore the role of age and sex in the relationship between hypothalamus-pituitary-adrenal axis (HPA-axis) and sympathetic nervous system (SNS) reactivity to psychosocial stress and short-term declarative memory performance. To do so, sixty-seven participants divided into two age groups (each group with a similar number of men and women) were exposed to the Trier Social Stress Test (TSST) and a control condition in a crossover design. Memory performance was assessed by the Rey Auditory Verbal Learning Test (RAVLT). As expected, worse memory performance was associated with age; but more interestingly, the stressor impaired recall after interference only in the older group. In addition, this effect was negatively correlated with the alpha-amylase over cortisol ratio, which has recently been suggested as a good marker of stress system dysregulation. However, we failed to find sex differences in memory performance. These results show that age moderates stress-induced effects on declarative memory, and they point out the importance of studying both of the physiological systems involved in the stress response together. 
24406466	For a long time, the insular cortex (IC) has been related with taste physiology and taste memory processes in animal studies. Recently, the role of the IC has been highlighted by findings involving the IC in non-taste memory formation in both human and animal studies. Recognition memory is based on the ability to assess the familiarity of a previously encountered stimulus, and it is considered a form of declarative memory. In this work, I am proposing that the IC and its related circuitry are highly involved in the conversion of novel to familiar stimulus for both object and taste recognition memory. In addition, I will review some of the molecular mechanisms involved in the modification of novelty to familiarity memory processes, including the role of epigenetic mechanisms on the consolidation of recognition memory within the IC. In the second part of the paper, I will review some of the possible mechanisms to transform a novel taste into a familiar aversive taste by a functional interaction between the IC and the amygdala. In summary, the IC is an important area that will open a new avenue for the study of the mechanisms involved in the neurobiology of learning and memory in the near future. 
24402653	Previous studies have shown that acute psychosocial stress impairs recognition of declarative memory and that emotional material is especially sensitive to this effect. Animal studies suggest a central role of the amygdala which modulates memory processes in hippocampus, prefrontal cortex and other brain areas. We used functional magnetic resonance imaging (fMRI) to investigate neural correlates of stress-induced modulation of emotional recognition memory in humans. Twenty-seven healthy, right-handed, non-smoker male volunteers performed an emotional face recognition task. During encoding, participants were presented with 50 fearful and 50 neutral faces. One hour later, they underwent either a stress (Trier Social Stress Test) or a control procedure outside the scanner which was followed immediately by the recognition session inside the scanner, where participants had to discriminate between 100 old and 50 new faces. Stress increased salivary cortisol, blood pressure and pulse, and decreased the mood of participants but did not impact recognition memory. BOLD data during recognition revealed a stress condition by emotion interaction in the left inferior frontal gyrus and right hippocampus which was due to a stress-induced increase of neural activity to fearful and a decrease to neutral faces. Functional connectivity analyses revealed a stress-induced increase in coupling between the right amygdala and the right fusiform gyrus, when processing fearful as compared to neutral faces. Our results provide evidence that acute psychosocial stress affects medial temporal and frontal brain areas differentially for neutral and emotional items, with a stress-induced privileged processing of emotional stimuli. 
24397965	The reconsolidation hypothesis states that memories, when reactivated, enter a transient, labile state followed by a re-stabilization termed reconsolidation. By affecting the reconsolidation process, memory persistence can be influenced, leading to memory enhancement or decrement. This is a time-dependent process and the result of modulating reconsolidation is present only after the reconsolidation process is completed. Historically, reconsolidation research has been performed on non-human animals, since the methods originally used for reconsolidation disruption are not safe. However, there now exist several techniques safe for humans, and consequently, in recent years, papers on human reconsolidation have emerged. Here, the existing literature on human reconsolidation is reviewed and discussed, including studies on fear memories, appetitive memories, procedural memories, and declarative memories. Methods of memory reactivation are compared between studies, and the consistency and lack of consistency in results over reactivation methods and memory types are discussed. These results provide future challenges, both experimental and clinical, in defining the boundary conditions and mechanisms governing the reconsolidation phenomenon. This article is part of a Special Issue entitled 'Memory Enhancement'. 
24395522	Sleep benefits memory consolidation. Previous theoretical accounts have proposed a differential role of slow-wave sleep (SWS), rapid-eye-movement (REM) sleep, and stage N2 sleep for different types of memories. For example the dual process hypothesis proposes that SWS is beneficial for declarative memories, whereas REM sleep is important for consolidation of non-declarative, procedural and emotional memories. In fact, numerous recent studies do provide further support for the crucial role of SWS (or non-REM sleep) in declarative memory consolidation. However, recent evidence for the benefit of REM sleep for non-declarative memories is rather scarce. In contrast, several recent studies have related consolidation of procedural memories (and some also emotional memories) to SWS (or non-REM sleep)-dependent consolidation processes. We will review this recent evidence, and propose future research questions to advance our understanding of the role of different sleep stages for memory consolidation. 
24385962	It is widely accepted that human learning and memory is mediated by multiple memory systems that are each best suited to different requirements and demands. Within the domain of categorization, at least two systems are thought to facilitate learning: an explicit (declarative) system depending largely on the prefrontal cortex, and a procedural (non-declarative) system depending on the basal ganglia. Substantial evidence suggests that each system is optimally suited to learn particular categorization tasks. However, it remains unknown precisely how these systems interact to produce optimal learning and behavior. In order to investigate this issue, the present research evaluated the progression of learning through simulation of categorization tasks using COVIS, a well-known model of human category learning that includes both explicit and procedural learning systems. Specifically, the model's parameter space was thoroughly explored in procedurally learned categorization tasks across a variety of conditions and architectures to identify plausible interaction architectures. The simulation results support the hypothesis that one-way interaction between the systems occurs such that the explicit system "bootstraps" learning early on in the procedural system. Thus, the procedural system initially learns a suboptimal strategy employed by the explicit system and later refines its strategy. This bootstrapping could be from cortical-striatal projections that originate in premotor or motor regions of cortex, or possibly by the explicit system's control of motor responses through basal ganglia-mediated loops. 
24382711	Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder.To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia.	Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry.	All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples.	Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score.	These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia.	
28446859	Divergent thinking is the ability to produce a range of responses or solutions and is an element of creative processing. Divergent thinking requires disengagement, the ability to associate between words or ideas, and the production of responses. Lesion and imaging studies have shown frontal-lobe involvement for these activities, and frontal lobe function is highly dependent on white matter pathways. Normal aging often results in deficits in functions controlled by the frontal lobes as well as decrements in white matter connectivity. The objectives of this study were to compare non time-constrained tasks of verbal divergent processing in young adults (YAs) and older adults (OAs) and correlate performance with tasks of working memory, language ability, and disengagement/inhibition. Participants were 30 YAs and 30 OAs. Contrary to the a priori hypothesis, OAs produced significantly more unique responses than YAs, although total fluency was not significantly different. Correlational analyses examining the groups together and separately revealed a number of differences suggesting that the groups were utilizing different underlying cognitive abilities to complete these tasks. The authors propose that the primary factor resulting in higher uniqueness scores for the OAs was a greater wealth of experience as well as longer exposure to language use.
26527987	Responses to stress are mediated by a complex network of the nervous and endocrine systems. Glucocorticoids, which are among the most important "players" in stress resilience, may have important implications in the cognitive functions, particularly in the modulation of memory. Declarative memory, the memory for facts, events and word meaning is the most studied type of memory on which glucocorticoids exert an influence, both positively through consolidation and negatively through impairment. These effects depend on the receptor type, dose, time of exposure, memory component and the salience of stimuli, retrieval being generally affected and storage being facilitated, especially for emotionally relevant events. Glucocorticoids also induce hippocampal atrophy, which is a hallmark seen in various diseases accompanied by a chronic high level of cortisol, such as the Cushing syndrome, major depression, post-traumatic stress disorder. Also, chronic stress might be a risk factor for the development of Alzheimer's disease, especially when a genetic background and other environmental influences are present. 
24367093	Declarative memory for rapidly learned, novel associations is thought to depend on structures in the medial temporal lobe (MTL), whereas associations learned more gradually can sometimes be supported by nondeclarative memory and by structures outside the MTL. A recent study suggested that even rapidly learned associations can be supported by structures outside the MTL when an incidental encoding procedure termed "fast mapping" (FM) is used. We tested six memory-impaired patients with bilateral damage to hippocampus and one patient with large bilateral lesions of the MTL. Participants saw photographs and names of animals, plants, and foods that were previously unfamiliar (e.g., mangosteen). Instead of asking participants to study name-object pairings for a later memory test (as with traditional memory instructions), participants answered questions that allowed them to infer which object corresponded to a particular name. In a second condition, participants learned name-object associations of unfamiliar items by using standard, explicit encoding instructions (e.g., remember the mangosteen). In FM and explicit encoding conditions, patients were impaired (and performed no better than a group that was given the same tests but had not previously studied the material). The same results were obtained in a second experiment that used the same procedures with modifications to allow for more robust learning and more reliable measures of performance. Thus, our results with the FM procedure and memory-impaired patients yielded the same deficits in learning and memory that have been obtained by using other more traditional paradigms. 
24362071	Benign Epilepsy with centrotemporal spikes (BECTS) is considered a benign type of epilepsy; nevertheless a significant number of children present clear and heterogeneous cognitive deficits such as memory disturbances. Thus far, evidence about memory impairment has been less than conclusive. To clarify the quality of memory functioning in BECTS children, an analysis of existing findings has been conducted trying to identify the type of memory deficits and their underlying factors. Short- and long-term declarative memory are impaired in BECTS children, with both verbal and non-verbal material; co-occurrence of attentional, linguistic and behavioral disturbances is reported. In children with continuous spikes and waves during the slow-wave sleep pattern the normal downscaling of slow-wave activity is absent, disrupting plastic brain processes of sleep-related memory consolidation. In BECTS children, NREM sleep interictal epileptiform discharges (IED) may interfere in the dialogue between temporal and frontal cortex, causing declarative memory deficits: the role of NREM sleep IED acquires a special importance, leading to methodological guidance and suggesting aims for future researches in the field of childhood neuroscience. 
24349492	To determine if sleep talkers with REM sleep behavior disorder (RBD) would utter during REM sleep sentences learned before sleep, and to evaluate their verbal memory consolidation during sleep.Eighteen patients with RBD and 10 controls performed two verbal memory tasks (16 words from the Free and Cued Selective Reminding Test and a 220-263 word long modified Story Recall Test) in the evening, followed by nocturnal video-polysomnography and morning recall (night-time consolidation). In 9 patients with RBD, daytime consolidation (morning learning/recall, evening recall) was also evaluated with the modified Story Recall Test in a cross-over order. Two RBD patients with dementia were studied separately. Sleep talking was recorded using video-polysomnography, and the utterances were compared to the studied texts by two external judges.	Sleep-related verbal memory consolidation was maintained in patients with RBD (+24±36% words) as in controls (+9±18%, p=0.3). The two demented patients with RBD also exhibited excellent nighttime consolidation. The post-sleep performance was unrelated to the sleep measures (including continuity, stages, fragmentation and apnea-hypopnea index). Daytime consolidation (-9±19%) was worse than night-time consolidation (+29±45%, p=0.03) in the subgroup of 9 patients with RBD. Eleven patients with RBD spoke during REM sleep and pronounced a median of 20 words, which represented 0.0003% of sleep with spoken language. A single patient uttered a sentence that was judged to be semantically (but not literally) related to the text learned before sleep.	Verbal declarative memory normally consolidates during sleep in patients with RBD. The incorporation of learned material within REM sleep-associated sleep talking in one patient (unbeknownst to himself) at the semantic level suggests a replay at a highly cognitive creative level.	
24345269	Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.
24335605	The controversy over multiple category-learning systems is reminiscent of the controversy over multiple memory systems. Researchers continue to seek paradigms to sharply dissociate explicit category-learning processes (featuring category rules that can be verbalized) from implicit category-learning processes (featuring learned stimulus-response associations that lie outside declarative cognition). We contribute a new dissociative paradigm, adapting the technique of deferred-rearranged reinforcement from comparative psychology. Participants learned matched category tasks that had either a one-dimensional, rule-based solution or a multidimensional, information-integration solution. They received feedback either immediately or after each block of trials, with the feedback organized such that positive outcomes were grouped and negative outcomes were grouped (deferred-rearranged reinforcement). Deferred reinforcement qualitatively eliminated implicit, information-integration category learning. It left intact explicit, rule-based category learning. Moreover, implicit-category learners facing deferred-rearranged reinforcement turned by default and information-processing necessity to rule-based strategies that poorly suited their nominal category task. The results represent one of the strongest explicit-implicit dissociations yet seen in the categorization literature. 
24329689	Spatial navigation comprises a widely-studied complex of animal behaviors. Its study offers many methodological advantages over other approaches, enabling assessment of a variety of experimental questions and the possibility to compare the results across different species. Spatial navigation in laboratory animals is often considered a model of higher human cognitive functions including declarative memory. Almost fifteen years ago, a novel dry-arena task for rodents was designed in our laboratory, originally named the place avoidance task, and later a modification of this approach was established and called active place avoidance task. It employs a continuously rotating arena, upon which animals are trained to avoid a stable sector defined according to room-frame coordinates. This review describes the development of the place avoidance tasks, evaluates the cognitive processes associated with performance and explores the application of place avoidance in the testing of spatial learning after neuropharmacological, lesion and other experimental manipulations. 
24324743	There is growing evidence of the active involvement of sleep in memory consolidation. Besides hippocampal sharp wave-ripple complexes and sleep spindles, slow oscillations appear to play a key role in the process of sleep-associated memory consolidation. Furthermore, slow oscillation amplitude and spectral power increase during the night after learning declarative and procedural memory tasks. However, it is unresolved whether learning-induced changes specifically alter characteristics of individual slow oscillations, such as the slow oscillation up-state length and amplitude, which are believed to be important for neuronal replay. 24 subjects (12 men) aged between 20 and 30 years participated in a randomized, within-subject, multicenter study. Subjects slept on three occasions for a whole night in the sleep laboratory with full polysomnography. Whereas the first night only served for adaptation purposes, the two remaining nights were preceded by a declarative word-pair task or by a non-learning control task. Slow oscillations were detected in non-rapid eye movement sleep over electrode Fz. Results indicate positive correlations between the length of the up-state as well as the amplitude of both slow oscillation phases and changes in memory performance from pre to post sleep. We speculate that the prolonged slow oscillation up-state length might extend the timeframe for the transfer of initial hippocampal to long-term cortical memory representations, whereas the increase in slow oscillation amplitudes possibly reflects changes in the net synaptic strength of cortical networks. 
24317640	The relationship between emotional or neutral declarative memory consolidation and sleep architecture was investigated. Thirty university students (21 females) viewed negative, neutral, or positive pictures and rated their valence and arousal in the evening. Participants performed a recognition test 1 h later and then underwent overnight polysomnography. Their post-encoding sleep architecture was compared to a baseline night. Participants returned 6 days following encoding for a second recognition test. Results showed no group (Negative, Neutral, Positive) differences in recognition 1 h or 6 days following encoding. Stage 2 sleep spindle density decreased across all groups following encoding, and recognition after 6 days was positively correlated with Stage 2 sleep spindle density on both nights. There was no change in REM density in any of the groups. This is the first investigation into phasic sleep microarchitecture changes following emotional and neutral declarative learning. Future investigations may benefit from more salient emotional stimuli.
24315929	Stress and stress hormones are known to affect learning and memory processes. However, although effects of stress on hippocampus-dependent declarative learning and memory are well-documented, relatively little attention has been paid to the impact of stress on striatum-dependent stimulus-response (S-R) learning and memory. Recent evidence indicates that glucocorticoid stress hormones shortly after learning enhance S-R memory consolidation, whereas stress prior to retention testing impairs S-R memory retrieval. Whether stress affects also the acquisition of S-R memories in humans remains unclear. For this reason, we examined here the effects of acute stress on S-R memory formation and contrasted these stress effects with those on hippocampus-dependent spatial memory. Healthy men and women underwent a stressor (socially evaluated cold pressor test, SECPT) or a control manipulation before they completed an S-R task and two spatial learning tasks. Memory was assessed one week later. Our data showed that stress impaired S-R memory performance in men but not in women. Conversely, spatial memory was impaired by stress in women but not in men. These findings provide further evidence that stress may alter learning and memory processes beyond the hippocampus. Moreover, our data underline that participants' sex may play a critical role in the impact of stress on multiple memory systems. 
24315731	Meta-analysis and meta-regression were used to evaluate whether evidence to date demonstrates deficits in procedural memory in individuals with specific language impairment (SLI), and to examine reasons for inconsistencies of findings across studies. The Procedural Deficit Hypothesis (PDH) proposes that SLI is largely explained by abnormal functioning of the frontal-basal ganglia circuits that support procedural memory. It has also been suggested that declarative memory can compensate for at least some of the problems observed in individuals with SLI. A number of studies have used Serial Reaction Time (SRT) tasks to investigate procedural learning in SLI. In this report, results from eight studies that collectively examined 186 participants with SLI and 203 typically-developing peers were submitted to a meta-analysis. The average mean effect size was .328 (CI95: .071, .584) and was significant. This suggests SLI is associated with impairments of procedural learning as measured by the SRT task. Differences among individual study effect sizes, examined with meta-regression, indicated that smaller effect sizes were found in studies with older participants, and in studies that had a larger number of trials on the SRT task. The contributions of age and SRT task characteristics to learning are discussed with respect to impaired and compensatory neural mechanisms in SLI. 
24298162	Understanding the molecular and cellular changes that underlie memory, the engram, requires the identification, isolation and manipulation of the neurons involved. This presents a major difficulty for complex forms of memory, for example hippocampus-dependent declarative memory, where the participating neurons are likely to be sparse, anatomically distributed and unique to each individual brain and learning event. In this paper, I discuss several new approaches to this problem. In vivo calcium imaging techniques provide a means of assessing the activity patterns of large numbers of neurons over long periods of time with precise anatomical identification. This provides important insight into how the brain represents complex information and how this is altered with learning. The development of techniques for the genetic modification of neural ensembles based on their natural, sensory-evoked, activity along with optogenetics allows direct tests of the coding function of these ensembles. These approaches provide a new methodological framework in which to examine the mechanisms of complex forms of learning at the level of the neurons involved in a specific memory. 
24295206	We aimed to study the associations between peripheral artery disease (PAD) and ankle-brachial index (ABI) and performance in a range of cognitive domains in nondemented elderly persons.Data were collected within the Lothian Birth Cohort 1921 and 1936 studies. These are two narrow-age cohorts at age 87 (n = 170) and 73 (n = 748) years. ABI was analyzed as a dichotomous (PAD vs. no PAD) and a continuous measure. PAD was defined as having an ABI less than 0.90. Measures of nonverbal reasoning, verbal declarative memory, verbal fluency, working memory, and processing speed were administered. Both samples were screened for dementia.	We observed no significant differences in cognitive performance between persons with or without PAD. However, higher ABI was associated with better general cognition (β = .23, p = .02, R2 change = .05) and processing speed (β = .29, p < .01, R2 change = .08) in the older cohort and better processing speed (β = .12, p < .01, R2 change = .01) in the younger cohort. This was after controlling for age, sex, and childhood mental ability and excluding persons with abnormally high ABI (>1.40) and a history of cardiovascular or cerebrovascular disease.	Lower ABI is associated with worse cognitive performance in old age, especially in the oldest old (>85 years), possibly because of long-term exposure to atherosclerotic disease. Interventions targeting PAD in persons free of manifest cardiovascular and cerebrovascular disease may reduce the incidence of cognitive impairment and dementia.	
24293762	To test the hypothesis that rapid eye movement (REM) sleep contributes to the consolidation of new memories, whereas non-rapid eye movement (NREM) sleep contributes to the prevention of retroactive interference.Randomized, crossover study.	Two sessions of either a morning nap or wakefulness.	Twenty-five healthy young adults.	Declarative learning of word pairs followed by a nap or a wake interval, then learning of interfering word pairs and delayed recall of list A.	After a restricted night (24:00-06:00), participants learned a list of word pairs (list A). They were then required to either take a nap or stay awake during 45 min, after which they learned a second list of word pairs (list B) and then had to recall list A. Fifty percent of word pairs in list B shared the first word with list A, resulting in interference. Ten subjects exhibited REM sleep whereas 13 subjects exhibited NREM stage 3 (N3) sleep. An interference effect was observed in the nap but not in the wake condition. In post-learning naps, N3 sleep was associated with a reduced interference effect, which was not the case for REM sleep. Moreover, participants exhibiting N3 sleep in the post-learning nap condition also showed a reduced interference effect in the wake condition, suggesting a higher protection ability against interference.	Our results partly support the hypothesis that non-rapid eye movement sleep contributes in protecting novel memories against interference. However, rapid eye movement sleep-related consolidation is not evidenced.	
24275832	Neurobiological theories of memory posit that the neocortex is a storage site of declarative memories, a hallmark of which is the association of two arbitrary neutral stimuli. Early sensory cortices, once assumed uninvolved in memory storage, recently have been implicated in associations between neutral stimuli and reward or punishment. We asked whether links between neutral stimuli also could be formed in early visual or auditory cortices. Rats were presented with a tone paired with a light using a sensory preconditioning paradigm that enabled later evaluation of successful association. Subjects that acquired this association developed enhanced sound evoked potentials in their primary and secondary visual cortices. Laminar recordings localized this potential to cortical Layers 5 and 6. A similar pattern of activation was elicited by microstimulation of primary auditory cortex in the same subjects, consistent with a cortico-cortical substrate of association. Thus, early sensory cortex has the capability to form neutral stimulus associations. This plasticity may constitute a declarative memory trace between sensory cortices. 
24247674	Despite the U.S. Food and Drug Administration (FDA) warning regarding cognitive impairment, the relationship between statins and cognition remains unknown.To examine the effect of statins on cognition.	PubMed, Embase, and Cochrane Library from inception through October 2012; FDA databases from January 1986 through March 2012.	Randomized, controlled trials (RCTs) and cohort, case-control, and cross-sectional studies evaluating cognition in patients receiving statins.	Two reviewers extracted data, 1 reviewer assessed study risk of bias, and 1 reviewer checked all assessments.	Among statin users, low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance related to procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment or any change in cognitive performance related to global cognitive performance scores, executive function, declarative memory, processing speed, or visuoperception. Examination of the FDA postmarketing surveillance databases revealed a low reporting rate for cognitive-related adverse events with statins that was similar to the rates seen with other commonly prescribed cardiovascular medications.	The absence of many well-powered RCTs for most outcomes resulted in final strengths of evidence that were low or moderate. Imprecision, inconsistency, and risk of bias also limited the strength of findings.	Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition. Published data do not suggest an adverse effect of statins on cognition; however, the strength of available evidence is limited, particularly with regard to high-dose statins.	
24246058	The quintessential memory system in the human brain--the hippocampus and surrounding medial temporal lobe--is often treated as a module for the formation of conscious, or declarative, memories. However, growing evidence suggests that the hippocampus plays a broader role in memory and cognition and that theories organizing memory into strictly dedicated systems may need to be updated. We first consider the historical evidence for the specialized role of the hippocampus in declarative memory. Then, we describe the serendipitous encounter that motivated the special section in this issue, based on parallel research from our labs that suggested a more pervasive contribution of the hippocampus to cognition beyond declarative memory. Finally, we develop a theoretical framework that describes 2 general mechanisms for how the hippocampus interacts with other brain systems and cognitive processes: the memory modulation hypothesis, in which mnemonic representations in the hippocampus modulate the operation of other systems, and the adaptive function hypothesis, in which specialized computations in the hippocampus are recruited as a component of both mnemonic and nonmnemonic functions. This framework is consistent with an emerging view that the most fertile ground for discovery in cognitive psychology and neuroscience lies at the interface between parts of the mind and brain that have traditionally been studied in isolation.
24245769	Spindles and slow waves are hallmarks of non-rapid eye movement sleep. Both these oscillations are markers of neuronal plasticity, and play a role in memory and cognition. Normal ageing is associated with spindle and slow wave decline and cognitive changes. The present study aimed to assess whether spindle and slow wave characteristics during a baseline night predict cognitive performance in healthy older adults the next morning. Specifically, we examined performance on tasks measuring selective and sustained visual attention, declarative verbal memory, working memory and verbal fluency. Fifty-eight healthy middle-aged and older adults (aged 50-91 years) without sleep disorders underwent baseline polysomnographic sleep recording followed by neuropsychological assessment the next morning. Spindles and slow waves were detected automatically on artefact-free non-rapid eye movement sleep electroencephalogram. All-night stage N2 spindle density (no./min) and mean frequency (Hz) and all-night non-rapid eye movement sleep slow wave density (no./min) and mean slope (μV/s) were analysed. Pearson's correlations were performed between spindles, slow waves, polysomnography and cognitive performance. Higher spindle density predicted better performance on verbal learning, visual attention and verbal fluency, whereas spindle frequency and slow wave density or slope predicted fewer cognitive performance variables. In addition, rapid eye movement sleep duration was associated with better verbal learning potential. These results suggest that spindle density is a marker of cognitive functioning in older adults and may reflect neuroanatomic integrity. Rapid eye movement sleep may be a marker of age-related changes in acetylcholine transmission, which plays a role in new information encoding. 
24244264	It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved. 
24231200	Traumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms.Nineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors.	Early trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks.	These results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma.	
24218156	Declarative memory evaluation is an essential step in the clinical and neuropsychological assessment of a variety of neurological disorders. It typically addresses the issue of normality/abnormality of an individual's performance. Another clinical application of the neuropsychological assessment of declarative memory is the longitudinal evaluation of an individual's performance change. In fact, in a variety of neurological conditions repeated assessments are needed to evaluate the modifications of a memory disorder as a function of time or in response to a pharmacological or rehabilitation treatment. This study was aimed at collecting data for measuring and interpreting performance change on a memory test for verbal material. For this purpose, we administered to 100 healthy subjects (age range 20-80 years; years of formal education range 8-17 years) three parallel forms of a test requiring the immediate and delayed recall of a 15-word list. The subjects performed the recall test three times (each time with a different list) at least 1 week apart. The order of the lists was randomized across subjects. Results revealed that performance on the three lists was highly correlated and did not vary as a function of the order of presentation. However, accuracy of recall was slightly better on a list compared to the others. Based on a method devised by Payne and Jones (J Clin Psychol 13:115-121, 1957), we provide normative data for establishing whether a discrepancy in recall accuracy on two versions of the test exceeds the discrepancy expected based on the performance of normal controls.
24216081	This study aims at providing an insight into early handling procedures on learning and memory performance in adult female rats. Early handling procedures were started on post-natal day 2 until 21, and consisted in 15 min, daily separations of the dams from their litters. Assessment of declarative memory was carried out in the novel-object recognition task; spatial learning, reference- and working memory were evaluated in the Morris water maze (MWM). Our results indicate that early handling induced an enhancement in: (1) declarative memory, in the object recognition task, both at 1h and 24h intervals; (2) reference memory in the probe test and working memory and behavioral flexibility in the "single-trial and four-trial place learning paradigm" of the MWM. Short-term separation by increasing maternal care causes a dampening in HPA axis response in the pups. A modulated activation of the stress response may help to protect brain structures, involved in cognitive function. In conclusion, this study shows the long-term effects of a brief maternal separation in enhancing object recognition-, spatial reference- and working memory in female rats, remarking the impact of early environmental experiences and the consequent maternal care on the behavioral adaptive mechanisms in adulthood.
24191011	Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes that facilitate successful brain aging are considerable, including a lack of established phenotypes and difficulties in modeling the effects of aging per se, rather than genes that influence the underlying trait. In a large cohort of randomly selected pedigrees (n = 1,129 subjects), we documented profound aging effects from young adulthood to old age (18-83 y) on neurocognitive ability and diffusion-based white-matter measures. Despite significant phenotypic correlation between white-matter integrity and tests of processing speed, working memory, declarative memory, and intelligence, no evidence for pleiotropy between these classes of phenotypes was observed. Applying an advanced quantitative gene-by-environment interaction analysis where age is treated as an environmental factor, we demonstrate a heritable basis for neurocognitive deterioration as a function of age. Furthermore, by decomposing gene-by-aging (G × A) interactions, we infer that different genes influence some neurocognitive traits as a function of age, whereas other neurocognitive traits are influenced by the same genes, but to differential levels, from young adulthood to old age. In contrast, increasing white-matter incoherence with age appears to be nongenetic. These results clearly demonstrate that traits sensitive to the genetic influences on brain aging can be identified, a critical first step in delineating the biological mechanisms of successful aging. 
24188909	Pediatric neurologists and neonatologists often are asked to predict cognitive outcome after perinatal brain injury (including likely memory and learning outcomes). However, relatively few data exist on how accurate predictions can be made. Furthermore, although the consequences of brain injury on hippocampal volume and memory performance have been studied extensively in adults, little work has been done in children.We measured the volume of the hippocampus in 27 children with perinatal stroke and 19 controls, and measured their performance on standardized verbal and non-verbal memory tests.	We discovered the following: (1) As a group, children with perinatal stroke had smaller left and right hippocampi compared with control children. (2) Individually, children with perinatal stroke demonstrated 1 of 3 findings: no hippocampal loss, unilateral hippocampal loss, or bilateral hippocampal volume loss compared with control children. (3) Hippocampal volume inversely correlated with memory test performance in the perinatal stroke group, with smaller left and right hippocampal volumes related to poorer verbal and non-verbal memory test performance, respectively. (4) Seizures played a significant role in determining memory deficit and extent of hippocampal volume reduction in patients with perinatal stroke.	These findings support the view that, in the developing brain, the left and right hippocampi preferentially support verbal and nonverbal memory respectively, a consistent finding in the adult literature but a subject of debate in the pediatric literature. This is the first work to report that children with focal brain injury incurred from perinatal stroke have volume reduction in the hippocampus and impairments in certain aspects of declarative memory.	
24177990	Achieving our goals often requires guiding access to relevant information from memory. Such goal-directed retrieval requires interactions between systems supporting cognitive control, including ventrolateral prefrontal cortex (VLPFC), and those supporting declarative memory, such as the medial temporal lobes (MTL). However, the pathways by which VLPFC interacts with MTL during retrieval are underspecified. Prior neuroanatomical evidence suggests that a polysynaptic ventral fronto-temporal pathway may support VLPFC-MTL interactions. To test this hypothesis, human participants were scanned using fMRI during performance of a source-monitoring task. The strength of source information was varied via repetition during encoding. Single encoding events should produce a weaker memory trace, thus recovering source information about these items should demand greater cognitive control. Results demonstrated that cortical targets along the ventral path--anterior VLPFC, temporal pole, anterior parahippocampus, and hippocampus--exhibited increases in univariate BOLD response correlated with increases in controlled retrieval demand, independent of factors related to response selection. Further, a functional connectivity analysis indicated that these regions functionally couple and are distinguishable from a dorsal pathway related to response selection demands. These data support a ventral retrieval pathway linking PFC and MTL.
24166189	Many patients with acquired brain injury have acute impairments in declarative memory, the memory system responsible for learning facts and remembering events, whereas implicit memory for skills, habits, and emotional associations remains intact. The combination of impaired declarative memory and preserved implicit memory has implications for communicating with patients in inpatient rehabilitation, not only in therapy sessions but also in nontherapy interactions with rehabilitation staff. The aim of this study was to describe communication patterns among inpatients with declarative memory impairments and rehabilitation staff members during the early stage postinjury. Participants were five adults with acquired brain injury and declarative memory impairments. Each participant was observed for a full inpatient rehabilitation day. Results showed that staff and visitors frequently asked participants declarative questions to which answers were not verifiable (e.g., questions about preinjury events). Answers that could be verified often were incorrect but were accepted by staff as correct. Results suggest that acute rehabilitation staff may need training in communicating with patients with declarative memory impairments. We suggest strategies to create a more supportive communication environment for inpatients with memory impairment. 
24163702	In the 1980s and 1990s, there was a major theoretical debate in the memory domain regarding the multiple memory systems and processing modes frameworks. The components of processing framework argued for a middle ground: Instead of neatly divided memory systems or processing modes, this framework proposed the existence of numerous processing components that are recruited in different combinations by memory tasks and yield complex patterns of associations and dissociations. Because behavioral evidence was not sufficient to decide among these three frameworks, the debate was largely abandoned. However, functional neuroimaging evidence accumulated during the last two decades resolves the stalemate, because this evidence is more consistent with the components framework than with the other two frameworks. For example, functional neuroimaging evidence shows that brain regions attributed to one memory system can contribute to tasks associated with other memory systems and that brain regions attributed to the same processing mode (perceptual or conceptual) can be dissociated from each other. Functional neuroimaging evidence suggests that memory processes are supported by transient interactions between a few regions called process-specific alliances. These conceptual developments are an example of how functional neuroimaging can contribute to theoretical debates in cognitive psychology. 
24151486	In a companion paper (1), we used computer simulations to show that a strategy of activity-dependent, on-line net synaptic potentiation during wake, followed by off-line synaptic depression during sleep, can provide a parsimonious account for several memory benefits of sleep at the systems level, including the consolidation of procedural and declarative memories, gist extraction, and integration of new with old memories. In this paper, we consider the theoretical benefits of this two-step process at the single-neuron level and employ the theoretical notion of Matching between brain and environment to measure how this process increases the ability of the neuron to capture regularities in the environment and model them internally. We show that down-selection during sleep is beneficial for increasing or restoring Matching after learning, after integrating new with old memories, and after forgetting irrelevant material. By contrast, alternative schemes, such as additional potentiation in wake, potentiation in sleep, or synaptic renormalization in wake, decrease Matching. We also argue that, by selecting appropriate loops through the brain that tie feedforward synapses with feedback ones in the same dendritic domain, different subsets of neurons can learn to specialize for different contingencies and form sequences of nested perception-action loops. By potentiating such loops when interacting with the environment in wake, and depressing them when disconnected from the environment in sleep, neurons can learn to match the long-term statistical structure of the environment while avoiding spurious modes of functioning and catastrophic interference. Finally, such a two-step process has the additional benefit of desaturating the neuron's ability to learn and of maintaining cellular homeostasis. Thus, sleep-dependent synaptic renormalization offers a parsimonious account for both cellular and systems level effects of sleep on learning and memory. 
24144441	Smaller hippocampal volumes similar to those found in schizophrenia (SZ) are frequently observed to a lesser extent in non-psychotic first-degree relatives of patients with the illness, compared to control subjects. In this study, subdivisions of the hippocampal formation and their association with verbal and visual learning and memory were assessed in persons at familial high risk (FHR) for SZ.MRI scans were acquired using a 3T Siemens scanner of young adult (ages 19-32) FHR subjects (N=46) and controls with no family history of illness (i.e., at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. Subfields of the hippocampal formation were evaluated using the van Leemput method (Van Leemput et al., 2010). Learning and memory measures were collected by standardized neurocognitive tests.	Controlling intracranial volume, significantly reduced left (p<0.025), and right hippocampus (p<0.024) volumes were observed in FHR subjects. Among the subfields, the left (p<0.01) and right subicula (p<0.005) were significantly reduced in the FHR group. Immediate verbal recall of stories was significantly impaired and was significantly correlated with the left and right subicula within the FHR group.	Reduced subiculum volume and its association with verbal memory refines further the association with left and right hippocampus reported in previous FHR studies of schizophrenia. Further research is needed to determine the specific genetic and environmental risk factors that may be related to hippocampal subfield alterations.	
24137153	Sleep can favor the consolidation of both procedural and declarative memories, promote gist extraction, help the integration of new with old memories, and desaturate the ability to learn. It is often assumed that such beneficial effects are due to the reactivation of neural circuits in sleep to further strengthen the synapses modified during wake or transfer memories to different parts of the brain. A different possibility is that sleep may benefit memory not by further strengthening synapses, but rather by renormalizing synaptic strength to restore cellular homeostasis after net synaptic potentiation in wake. In this way, the sleep-dependent reactivation of neural circuits could result in the competitive down-selection of synapses that are activated infrequently and fit less well with the overall organization of memories. By using computer simulations, we show here that synaptic down-selection is in principle sufficient to explain the beneficial effects of sleep on the consolidation of procedural and declarative memories, on gist extraction, and on the integration of new with old memories, thereby addressing the plasticity-stability dilemma. 
24137151	The architecture of sleep and the functional neuroanatomical networks subtending memory consolidation processes are both modified with aging, possibly leading to accelerated forgetting in long-term memory. We investigated associative learning and declarative memory consolidation processes in 16 young (18-30 years) and 16 older (65-75 years) healthy adults. Performance was tested using a cued recall procedure at the end of learning (immediate recall), and 30 min and 7 days later. A delayed recognition test was also administered on day 7. Daily sleep diaries were completed during the entire experiment. Results revealed a similar percentage of correct responses at immediate and 30-min recall in young and older participants. However, recall was significantly decreased 7 days later, with an increased forgetting in older participants. Additionally, intra-sleep awakenings were more frequent in older participants than young adults during the seven nights, and were negatively correlated with delayed recall performance on day 7 in the older group. Altogether, our results suggest a decline in verbal declarative memory consolidation processes with aging, eventually leading to accelerated long-term forgetting indicating that increased sleep fragmentation due to more frequent intra-sleep awakenings in older participants contribute to the reported age-related decline in long-term memory retrieval. Our results highlight the sensitivity of long-term forgetting measures to evidence consolidation deficits in healthy aging. 
24135168	In contrast to our increasing knowledge of the role that oscillations in single brain regions play in cognition, very little is known about how coherence between oscillations in distant brain regions is related to information transmission. Here I present a cognitive modeling approach that can address that question. Specifically, I show how a model of the attentional blink implemented in the ACT-R cognitive architecture is related to the amplitude and coherence of EEG oscillations. The dynamics of the model's working memory resource is primarily associated with parietal 4-9 Hz theta oscillations, while the dynamics of the model's declarative memory, visual perception and procedural resources together are correlated with posterior theta oscillations. I further show that model predictions about inter-module communication during the processes of stimulus identification and target consolidation are associated with selective increases in coherence at the predicted points in time.
24126929	Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2(MAPK) signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GR(NesCre)). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2(MAPK) responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2(MAPK) signaling pathways as one of the core effectors of stress-related effects of GC.
24123555	Creativity requires the rapid combination and recombination of existing mental representations to create novel ideas and ways of thinking. The hippocampal system, through its interaction with neocortical storage sites, provides a relational database necessary for the creation, updating, maintenance, and juxtaposition of mental representations used in service of declarative memory. Given this functionality, we hypothesized that hippocampus would play a critical role in creative thinking. We examined creative thinking, as measured by verbal and figural forms of the torrance tests of creative thinking (TTCT), in a group of participants with hippocampal damage and severe declarative memory impairment as well as in a group of demographically matched healthy comparison participants. The patients with bilateral hippocampal damage performed significantly worse than comparison participants on both the verbal and figural portions of the TTCT. These findings suggest that hippocampus plays a role critical in creative thinking, adding to a growing body of work pointing to the diverse ways the hallmark processing features of hippocampus serve a variety of behaviors that require flexible cognition.
24123475	At a similar stage, patients with early onset Alzheimer's disease (EOAD) have greater neocortical but less medial temporal lobe dysfunction and atrophy than the late-onset form of the disease (LOAD). Whether the organization of neural networks also differs has never been investigated. This study aims at characterizing basal functional connectivity (FC) patterns of EOAD and LOAD in two groups of 14 patients matched for disease duration and severity, relative to age-matched controls. All subjects underwent an extensive neuropsychological assessment. Magnetic resonance imaging was used to quantify atrophy and resting-state FC focusing on : the default mode network (DMN), found impaired in earlier studies on AD, and the anterior temporal network (ATN) and dorso-lateral prefrontal network (DLPFN), respectively involved in declarative memory and executive functions. Patterns of atrophy and cognitive impairment in EOAD and LOAD were in accordance with previous reports. FC within the DMN was similarly decreased in both EOAD and LOAD relative to controls. However, a double-dissociated pattern of FC changes in ATN and DLPFN was found. EOAD exhibited decreased FC in the DLPFN and increased FC in the ATN relative to controls, while the reverse pattern was found in LOAD. In addition, ATN and DLPFN connectivity correlated respectively with memory and executive performances, suggesting that increased FC is here likely to reflect compensatory mechanisms. Thus, large-scale neural network changes in EOAD and LOAD endorse both common features and differences, probably related to a distinct distribution of pathological changes.
24119823	Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40 mg of MPH on memory performance were compared to 100mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30 min delay, but it improved 24 h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory.
24099265	The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.
24072504	Diminished synthesis of the neurotransmitter serotonin (5-HT) in the brain has been linked to disturbed memory processes. The present study investigated the effects of diminished central nervous 5-HT synthesis as achieved by an acute dietary tryptophan depletion (ATD) on verbal declarative episodic memory in young women while controlling for the effects of female sex hormones. Eighteen healthy females (aged 20-31 years) participated in a within-subject repeated measures study, with two separate days of assessment spaced at least one individual menstrual cycle apart. On one day, participants were subjected to ATD, thus lowering central nervous 5-HT synthesis. The other day participants received a tryptophan-balanced amino acid load (BAL = control condition). The study was randomized, counterbalanced and double blind in terms of ATD/BAL administration. Measurements took place in the early follicular phase of the participants' menstrual cycle. Estrogen, FSH and LH levels were assessed at baseline. Verbal declarative episodic memory was assessed using a structured word-learning task. Short-term memory, as indexed by immediate recall, was reduced after ATD intake, whereas delayed recall and recognition after a 25-min delay did not show any differences after intake of ATD or BAL. In young women, verbal short-term memory function was more vulnerable to ATD than consolidation processes. In light of the possible interplay between female sex hormones and 5-HT, further studies comparing different menstrual cycle phases are needed.
24069003	It has been shown that applying transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) influences declarative memory processes. This study investigates the efficacy of tDCS on emotional memory consolidation, especially experimental fear conditioning. We applied an auditory fear-conditioning paradigm, in which two differently colored squares (blue and yellow) were presented as conditioned stimuli (CS) and an auditory stimulus as unconditioned stimulus (UCS). Sixty-nine participants were randomly assigned into three groups: anodal, cathodal, and sham stimulation. The participants of the two active groups (i.e., anodal and cathodal) received tDCS over the left DLPFC for 12 min after fear conditioning. The effect of fear conditioning and consolidation (24 h later) was measured by assessing the skin conductance response (SCR) to the CS. The results provide evidence that cathodal stimulation of the left DLPFC leads to an inhibitory effect on fear memory consolidation compared to anodal and sham stimulation, as indicated by decreased SCRs to CS+ presentation during extinction training at day 2. In conclusion, current work suggests that cathodal stimulation interferes with processes of fear memory consolidation. 
24059444	This study describes a follow-up investigation of numerical abilities and visuospatial memory in a patient suffering from semantic dementia whose progressive decline of semantic memory variably affected different types of knowledge. Crucially, we investigated in detail her outstanding performance with Sudoku that has been only anecdotally reported in the previous literature.We tested spatial cognition and memory, body representation, number processing, calculation, and Sudoku tasks, and we compared the patient's performance with that of matched controls.	In agreement with the neuroanatomical data, showing substantial sparing of the parietal lobes in the face of severe atrophy of the temporal (and frontal) regions, we report full preservation of skills known to be supported by intact parietal-basal ganglia networks, and impaired knowledge related to long-term stored declarative information mediated by temporal regions. Performance in tasks sensitive to parietal dysfunction (such as right-left orientation, finger gnosis, writing, and visuospatial memory) was normal; within the numerical domain, preserved quantity-based number knowledge dissociated from increasing difficulties with nonquantitative number knowledge (such as knowledge of encyclopedic and personal number facts) and arithmetic facts knowledge.	This case confirms the relation between numbers and space, and, although indirectly, their anatomical correlates, underlining which abilities are preserved in the case of severe semantic loss. In addition, although Sudoku is not inherently numerical, the patient was able to solve even the most difficult pattern, provided that it required digits and not letters, showing that digits have, in any case, a specific status.	
24042851	According to the standard model of systems consolidation (SMC), neocortical circuits are reactivated during the retrieval of declarative memories. This process initially requires the hippocampus. However, with the passage of time, neocortical circuits become strengthened and can eventually retrieve memory without input from the hippocampus. Although consistent with lesion data, these assumptions have been difficult to confirm experimentally. In the current review, we discuss recent methodological advances in behavioral neuroscience that are making it possible to test the basic assumptions of SMC for the first time. For example, new transgenic mice can be used to monitor the activity of individual neurons across the entire brain while optogenetic approaches provide precise control over the activity of these cells using light stimulation. These tools can be used to examine the reactivation of neocortical neurons during recent and remote memory retrieval and determine if this process requires the hippocampus. 
24035099	Corticosteroids are known to modulate the consolidation of memories during sleep, specifically in the hippocampus-dependent declarative memory system. However, effects of the major human corticosteroid cortisol are conveyed via two different receptors, i.e., mineralocorticoid (MRs) and glucocorticoid receptors (GRs) whose specific contributions to memory consolidation are unclear. Whereas a shift in the balance between MR and GR activation toward predominant GR activation has been found to impair sleep-dependent consolidation of declarative memories, the effect of predominant MR activation is not well characterized. Here, we examined differential corticosteroid receptor contributions to memory consolidation during post-learning sleep in two placebo-controlled double-blind studies in humans, by comparing the effects of the selective MR agonist fludrocortisone (0.2 mg, orally, Study 1) and of hydrocortisone (22 mg, intravenously, Study 2) with strong binding affinity to both MR and GR. We hypothesized increased activation of MRs during sleep to enhance declarative memory consolidation, but the joint MR/GR activation to impair it. Participants (16 men in each study) learned a declarative (word pair associates) and a procedural task (mirror tracing) before a 7-h period of nocturnal retention sleep, with the substances administered before sleep (Study 1) and during sleep (Study 2), respectively. As hypothesized, retention of word pairs, but not of mirror tracing skill, was selectively enhanced by the MR agonist fludrocortisone. An impairing effect of hydrocortisone on word pair retention remained non-significant possibly reflecting that hydrocortisone administration failed to establish robust predominance of GR activation. Our results show that predominant MR activation benefits declarative memory consolidation presumably by enhancing the sleep-dependent reactivation of hippocampal memories and resultant synaptic plastic processes. The effect is counteracted by additional GR activation. Insufficient MR activation, like GR overactivation, might be a factor contributing to memory impairment in pathological conditions.
24023376	To determine whether word learning problems associated with developmental language impairment (LI) reflect deficits in encoding or subsequent remembering of forms and meanings.Sixty-nine 18- to 25-year-olds with LI or without (the normal development [ND] group) took tests to measure learning of 16 word forms and meanings immediately after training (encoding) and 12 hr, 24 hr, and 1 week later (remembering). Half of the participants trained in the morning, and half trained in the evening.	At immediate posttest, participants with LI performed more poorly on form and meaning than those with ND. Poor performance was more likely among those with more severe LI. The LI-ND gap for word form recall widened over 1 week. In contrast, the LI and ND groups demonstrated no difference in remembering word meanings over the week. In both groups, participants who trained in the evening, and therefore slept shortly after training, demonstrated greater gains in meaning recall than those who trained in the morning.	Some adults with LI have encoding deficits that limit the addition of word forms and meanings to the lexicon. Similarities and differences in patterns of remembering in the LI and ND groups motivate the hypothesis that consolidation of declarative memory is a strength for adults with LI.	
24018724	The common view of Alzheimer's disease (AD) is that of an age-related memory disorder, i.e. declarative memory deficits are the first signs of the disease and associated with progressive brain changes in the medial temporal lobes and the default mode network. However, two findings challenge this view. First, new model-based tools of attention research have revealed that impaired selective attention accompanies memory deficits from early pre-dementia AD stages on. Second, very early distributed lesions of lateral parietal networks may cause these attention deficits by disrupting brain mechanisms underlying attentional biased competition. We suggest that memory and attention impairments might indicate disturbances of a common underlying neurocognitive mechanism. We propose a unifying account of impaired neural interactions within and across brain networks involved in attention and memory inspired by the biased competition principle. We specify this account at two levels of analysis: at the computational level, the selective competition of representations during both perception and memory is biased by AD-induced lesions; at the large-scale brain level, integration within and across intrinsic brain networks, which overlap in parietal and temporal lobes, is disrupted. This account integrates a large amount of previously unrelated findings of changed behaviour and brain networks and favours a brain mechanism-centred view on AD. 
24010959	Although a beneficial role of post-training sleep for declarative memory has been consistently evidenced in children, as in adults, available data suggest that procedural memory consolidation does not benefit from sleep in children. However, besides the absence of performance gains in children, sleep-dependent plasticity processes involved in procedural memory consolidation might be expressed through differential interference effects on the learning of novel but related procedural material. To test this hypothesis, 32 10-12-year-old children were trained on a motor rotation adaptation task. After either a sleep or a wake period, they were first retested on the same rotation applied at learning, thus assessing offline sleep-dependent changes in performance, then on the opposite (unlearned) rotation to assess sleep-dependent modulations in proactive interference coming from the consolidated visuomotor memory trace. Results show that children gradually improve performance over the learning session, showing effective adaptation to the imposed rotation. In line with previous findings, no sleep-dependent changes in performance were observed for the learned rotation. However, presentation of the opposite, unlearned deviation elicited significantly higher interference effects after post-training sleep than wakefulness in children. Considering that a definite feature of procedural motor memory and skill acquisition is the implementation of highly automatized motor behaviour, thus lacking flexibility, our results suggest a better integration and/or automation or motor adaptation skills after post-training sleep, eventually resulting in higher proactive interference effects on untrained material. 
24009680	Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus) [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.
24005125	Deferred imitation studies are used to assess infants' declarative memory performance. These studies have found that deferred imitation performance improves with age, which is usually attributed to advancing memory capabilities. Imitation studies, however, are also used to assess infants' action understanding. In this second research program it has been observed that infants around the age of one year imitate selectively, i.e., they imitate certain kinds of target actions and omit others. In contrast to this, two-year-olds usually imitate the model's exact actions. 18-month-olds imitate more exactly than one-year-olds, but more selectively than two-year-olds, a fact which makes this age group especially interesting, since the processes underlying selective vs. exact imitation are largely debated. The question, for example, if selective attention to certain kinds of target actions accounts for preferential imitation of these actions in young infants is still open. Additionally, relations between memory capabilities and selective imitation processes, as well as their role in shaping 18-month-olds' neither completely selective, nor completely exact imitation have not been thoroughly investigated yet. The present study, therefore, assessed 18-month-olds' gaze toward two types of actions (functional vs. arbitrary target actions) and the model's face during target action demonstration, as well as infants' deferred imitation performance. Although infants' fixation times to functional target actions were not longer than to arbitrary target actions, they imitated the functional target actions more frequently than the arbitrary ones. This suggests that selective imitation does not rely on selective gaze toward functional target actions during the demonstration phase. In addition, a post hoc analysis of interindividual differences suggested that infants' attention to the model's social-communicative cues might play an important role in exact imitation, meaning the imitation of both functional and arbitrary target actions. 
23997832	Brain regions in medial temporal lobe have seen a shift in emphasis in their role in long-term declarative memory to an appreciation of their role in cognitive domains beyond declarative memory, such as implicit memory, working memory, and perception. Recent theoretical accounts emphasize the function of perirhinal cortex in terms of its role in the ventral visual stream. Here, we used functional magnetic resonance adaptation (fMRa) to show that brain structures in the visual processing stream can bind item features prior to the involvement of hippocampal binding mechanisms. Evidence for perceptual binding was assessed by comparing BOLD (blood-oxygen-level-dependent) responses between fused objects and variants of the same object as different, non-fused forms (e.g., physically separate objects). Adaptation of the neural response to fused, but not non-fused, objects was in left fusiform cortex and left perirhinal cortex, indicating the involvement of these regions in the perceptual binding of item representations.
23997364	Slow wave sleep (SWS) plays a pivotal role in consolidating memories. Tiagabine has been shown to increase SWS in favor of REM sleep without impacting subjective sleep. However, it is unknown whether this effect is paralleled by an improved sleep-dependent consolidation of memory.This double-blind within-subject crossover study tested sensitivity of overnight retention of declarative neutral and emotional materials (word pairs, pictures) as well as a procedural memory task (sequence finger tapping) to oral administration of placebo or 10 mg tiagabine (at 22:30).	Fourteen healthy young men aged 21.9 years (range 18-28 years).	Tiagabine significantly increased the time spent in SWS and decreased REM sleep compared to placebo. Tiagabine also enhanced slow wave activity (0.5-4.0 Hz) and density of < 1 Hz slow oscillations during NREM sleep. Fast (12-15 Hz) and slow (9-12 Hz) spindle activity, in particular that occurring phase-locked to the slow oscillation cycle, was decreased following tiagabine. Despite signs of deeper and more SWS, overnight retention of memory tested after sleep the next evening (19:30) was generally not improved after tiagabine, but on average even lower than after placebo, with this impairing effect reaching significance for procedural sequence finger tapping.	Our data show that increasing slow wave sleep with tiagabine does not improve memory consolidation. Possibly this is due to functional differences from normal slow wave sleep, i.e., the concurrent suppressive influence of tiagabine on phase-locked spindle activity.	
23978187	Recollecting past experiences and imagining future experiences activate a common set of brain regions that includes the hippocampus (Schacter, Addis, & Buckner, 2007), and both functions are impaired in people with compromised hippocampal function (Klein, Loftus, & Kihlstrom, 2002; Tulving, 1985). These findings indicate a role for the hippocampus that extends beyond declarative memory. However, a case study revealed that a person with extensive medial temporal lobe (MTL) damage and episodic amnesia was able to forgo smaller, immediate rewards for a larger future payoff to a degree similar to control participants (Kwan et al., 2012). This finding suggests that typical regard for the future does not depend on hippocampal integrity. To test this hypothesis, the current study examined the nature and limits of the role of the hippocampus in future thinking and decision making in amnesic individuals with hippocampal damage and associated impairments in episodic memory and future imagining. The amnesic individuals were administered a delay discounting task to assess valuation of future rewards, a probability discounting task to assess risk taking, and the Zimbardo Time Perspective Inventory to assess personal orientation toward the past, present, and future. Comparisons with demographically matched controls indicated that aspects of temporal thought and future-oriented decision making are preserved in individuals with hippocampal amnesia despite their inability to imagine themselves in detailed future events. Thus, even extensive MTL damage and the resulting episodic amnesia do not preclude prudent decision making, including consideration of future financial outcomes and personal identification with the past and future.
23973448	Addiction is a chronic disorder marked by long-lasting maladaptive changes in behavior and in reward system function. However, the factors that contribute to the behavioral and biological changes that occur with addiction are complex and go beyond reward. Addiction involves changes in cognitive control and the development of disruptive drug-stimuli associations that can drive behavior. A reason for the strong influence drugs of abuse can exert on cognition may be the striking overlap between the neurobiological substrates of addiction and of learning and memory, especially areas involved in declarative memory. Declarative memories are critically involved in the formation of autobiographical memories, and the ability of drugs of abuse to alter these memories could be particularly detrimental. A key structure in this memory system is the hippocampus, which is critically involved in binding multimodal stimuli together to form complex long-term memories. While all drugs of abuse can alter hippocampal function, this review focuses on nicotine. Addiction to tobacco products is insidious, with the majority of smokers wanting to quit; yet the majority of those that attempt to quit fail. Nicotine addiction is associated with the presence of drug-context and drug-cue associations that trigger drug seeking behavior and altered cognition during periods of abstinence, which contributes to relapse. This suggests that understanding the effects of nicotine on learning and memory will advance understanding and potentially facilitate treating nicotine addiction. The following sections examine: (1) how the effects of nicotine on hippocampus-dependent learning change as nicotine administration transitions from acute to chronic and then to withdrawal from chronic treatment and the potential impact of these changes on addiction, (2) how nicotine usurps the cellular mechanisms of synaptic plasticity, (3) the physiological changes in the hippocampus that may contribute to nicotine withdrawal deficits in learning, and (4) the role of genetics and developmental stage (i.e., adolescence) in these effects. 
23969995	Alzheimer's disease (AD) is characterized by retrograde memory deficits primarily caused by dysfunction of the hippocampal complex. Unresolved questions exist concerning the time course of hippocampal involvement in conscious recollection of declarative knowledge, as reports of temporal gradients of retrograde amnesia have been inconclusive. The aim of this study was to examine whether the extent and severity of retrograde amnesia is mediated by retrieval frequency or, in contrast, whether it depends on the age of the memory according to the assumptions of the main current theories of memory formation. We compared recall of past public events in patients with AD and healthy control (HC) individuals using the Historic Events Test (HET). The HET assesses knowledge about famous public events of the past 60 years divided into four time segments and consists of subjective memory rating, dating accuracy, and contextual memory tasks. Although memory for public events was impaired in AD patients, there was a strong effect of retrieval frequency across all time segments and both groups. As AD and HC groups derived similar benefits from greater retrieval frequency, cortical structures other than the hippocampal complex may mediate memory retrieval. These findings suggest that more frequently retrieved events and facts become more independent of the hippocampal complex and thus better protected against early damage of AD. This could explain why cognitive activity may delay the onset of memory decline in persons who develop AD. 
23962957	The complementary learning systems account of declarative memory suggests two distinct memory networks, a fast-mapping, episodic system involving the hippocampus, and a slower semantic memory system distributed across the neocortex in which new information is gradually integrated with existing representations. In this study, we investigated the extent to which these two networks are involved in the integration of novel words into the lexicon after extensive learning, and how the involvement of these networks changes after 24h. In particular, we explored whether having richer information at encoding influences the lexicalization trajectory. We trained participants with two sets of novel words, one where exposure was only to the words' phonological forms (the form-only condition), and one where pictures of unfamiliar objects were associated with the words' phonological forms (the picture-associated condition). A behavioral measure of lexical competition (indexing lexicalization) indicated stronger competition effects for the form-only words. Imaging (fMRI) results revealed greater involvement of phonological lexical processing areas immediately after training in the form-only condition, suggesting that tight connections were formed between novel words and existing lexical entries already at encoding. Retrieval of picture-associated novel words involved the episodic/hippocampal memory system more extensively. Although lexicalization was weaker in the picture-associated condition, overall memory strength was greater when tested after a 24hour delay, probably due to the availability of both episodic and lexical memory networks to aid retrieval. It appears that, during lexicalization of a novel word, the relative involvement of different memory networks differs according to the richness of the information about that word available at encoding. 
23948312	The experience of childhood maltreatment is related to an increased risk of developing a variety of psychiatric disorders, as well as a change in the structure of the brain. However, not much is known about the neurobiological basis of resilience to childhood maltreatment. This study aims to identify resting-state functional connectivity (RSFC) patterns specific for resilience to childhood maltreatment, focusing on the default mode and salience network and networks seeded from the amygdala and left dorsomedial prefrontal cortex. Resting-state functional MRI scans were obtained in 33 individuals. Seeds in the bilateral amygdala, the dorsal anterior cingulate cortex (dACC), the posterior cingulate cortex and the left dorsomedial prefrontal cortex were defined and used to examine whether resilient individuals differed from vulnerable individuals and healthy controls in RSFC with other brain regions. Within the salience network, the resilient group was associated with increased RSFC between the left dACC and a region containing the bilateral lingual gyrus and the occipital fusiform gyrus compared to both the vulnerable group and the healthy controls. In this study, we found RSFC patterns specific for resilient individuals. Regions that are implicated are related on a functional level to declarative memory and the processing of emotional stimuli. 
23948219	Pattern separation is a mechanism for encoding memories, whereby distinct memory representations are created for very similar stimuli and events. It has been proposed that depression negatively impacts pattern separation abilities. However, a link between depression and performance in memory tasks requiring pattern separation is still unclear even though it is well established that depression is associated with reduced declarative memory performance and decreased hippocampal volume. Accordingly, we designed a study to investigate the relationship between pattern separation performance and the severity of depression symptoms in an otherwise healthy population. Participants completed a pattern separation memory test and a set of questionnaires to gauge their level of depression. We found a negative relationship between depression scores and pattern separation scores. These results provide support for the idea that depression is negatively related to pattern separation performance. 
23937234	Visuospatial attention prioritizes regions of space for perceptual processing. Knowing how attended locations are represented is critical for understanding the architecture of attention. We examined the spatial reference frame of incidentally learned attention and asked how it is influenced by explicit, top-down knowledge. Participants performed a visual search task in which a target was more likely to appear in one, "rich," quadrant of the screen than in the others. The spatial relationship between the display and the viewer's perspective changed partway through the experiment. Because incidentally learned attention is persistent, the spatial bias that developed during training was present following the change in viewer perspective. Despite the presence of multiple environmental landmarks including a background scene, participants prioritized rich regions relative to their perspective, rather than relative to the environment. Remarkably, the egocentric attentional bias was unaffected by explicit knowledge of where the target was likely to appear. Although participants used this knowledge to prioritize the region of space they were told was likely to contain a target, a strong egocentric bias to a region that was unlikely to contain a target persisted. These data indicate that incidental attention differs fundamentally from attention driven by explicit knowledge. We propose that attention takes 2 forms. One is declarative, based on maps that explicitly prioritize some regions of space over others. The other is procedural, influenced by implicit knowledge that modulates how attention is moved through space.
23937178	A growing body of work suggests the hippocampus contributes to a variety of cognitive domains beyond its traditional role in memory. We propose that the hippocampus, in its capacity for relational binding, representational flexibility, and online maintenance and integration of multimodal relational representations, is a key contributor to language processing. Here we test the hypothesis that the online interpretation of pronouns is hippocampus-dependent. We combined eye tracking with neuropsychological methods, where participants (4 patients with bilateral hippocampal damage and severe declarative memory impairment, 4 patients with ventromedial prefrontal cortex [vmPFC] damage, and healthy comparison participants) viewed a scene while listening to short dialogues introducing 2 characters; for example, Melissa is playing violin for Debbie/Danny as the sun is shining overhead. She is wearing a blue/purple dress. Consistent with previous work, analysis of eye gaze showed that younger and older healthy comparison participants and the vmPFC patients rapidly identified the intended referent of the pronoun when gender uniquely identified the referent, and when it did not, they showed a preference to interpret the pronoun as referring to the first-mentioned character. By contrast, hippocampal patients, while exhibiting a similar gender effect, exhibited significant disruptions in their ability to use information about which character had been mentioned first to interpret the pronoun. This finding suggests that the hippocampus plays a role in maintaining and integrating information even over a very short discourse history. These observed disruptions in referential processing demonstrate how promiscuously the hallmark processing features of the hippocampus are used in service of a variety of cognitive domains including language.
23937177	Over 50 years of research has revealed a critical role for the hippocampus in the formation of long-term declarative memories. More recent evidence has specified the functions of the hippocampus as the binding and comparison of memory representations that may be used under shorter, as well as longer, delays (Olsen, Moses, Riggs, & Ryan, 2012). Hippocampal neural oscillations (e.g., theta rhythm) have been studied extensively in animals; however, the oscillations that underlie binding, comparison, and their relationship to memory performance remain to be fully explored in humans. Here magnetoencephalography was used to examine theta oscillations within the hippocampus and cortex to address this critical gap in the literature. The task consisted of (a) an encoding phase in which participants had to integrate the relative spatial positions among 3 sequentially presented objects, (b) a delay phase, and (c) a test phase in which all study objects were presented simultaneously in novel locations, and participants had to indicate whether the relative positions had changed. Theta power in the hippocampus and medial prefrontal cortex (PFC) increased across encoding and delay periods during which binding and maintenance processes dominate, while comparison of spatial relations at test was associated with greater theta power in right lateral PFC and intraparietal sulcus for manipulated versus intact trials. Critically, relational memory was positively related to hippocampal theta power increases across the encoding period. These findings provide novel evidence for the role of hippocampal theta in the incremental formation and retention of relations across space and time.
23936679	Environmental enrichment (EE) is known to enhance learning and memory. Declarative memories are thought to undergo a first rapid and local consolidation process, followed by a prolonged process of system consolidation, which consist in a time-dependent gradual reorganization of brain regions supporting remote memory storage and crucial for the formation of enduring memories. At present, it is not known whether EE can affect the process of declarative memory system consolidation. We characterized the time course of hippocampal and cortical activation following recall of progressively more remote spatial memories. Wild-type mice either exposed to EE for 40 days or left in standard environment were subjected to spatial learning in the Morris water maze and to the probe test 1, 10, 20, 30, and 50 days after learning. Following the probe test, regional expression of the inducible immediate early gene c-Fos was mapped by immunohistochemistry, as an indicator of neuronal activity. We found that activation of the medial prefrontal cortex (mPFC), suggested to have a privileged role in processing remote spatial memories, was evident at shorter time intervals after learning in EE mice; in addition, EE induced the progressive activation of a distributed cortical network not activated in non-EE mice. This suggests that EE not only accelerates the process of mPFC recruitment but also recruits additional cortical areas into the network supporting remote spatial memories. 
23929764	People experiencing early-life stress (ELS) exhibit increased incidence of behaviors that lead to addiction and obesity as adults. Many of these behaviors may be viewed as resulting from an overreliance on habits as opposed to goal-directed instrumental behavior. This increased habitization may result from alterations in the interactions between dorsolateral striatum-dependent and hippocampus-dependent learning systems. As an initial examination of this idea, we investigated the effect of ELS on instrumental learning and extinction. In Experiment 1, we examined the effect of ELS in two groups of people, one trained on a continuous reinforcement schedule and one trained on a partial reinforcement schedule. We found that people who experienced ELS had a diminished effect of the partial reinforcement schedule on extinction. In Experiment 2, we again manipulated reinforcement schedule and also challenged declarative memory by requiring subjects to perform a concurrent task. We found that the declarative challenge did not affect extinction responding in the non-ELS group. In a moderate-ELS group, we observed a diminished sensitivity to the reinforcement schedule during extinction only under divided attention. In the high-ELS group, we observed a reduced sensitivity to reinforcement schedule even in the absence of the declarative memory challenge, consistent with Experiment 1. Our results suggest that ELS reduces the tendency to use declarative, hippocampus-dependent memory in instrumental tasks in favor of habits. ELS may affect hippocampal development, thus altering the interaction between memory systems and potentially contributing to poor health outcomes.
23929594	While several models of memory consolidation have previously associated hippocampal activity with declarative memory, there is now increasing evidence that the hippocampus also plays a crucial role in procedural memory. Here, we review recent human functional neuroimaging studies demonstrating that the hippocampus is involved in the acquisition and sleep-related consolidation of procedural memories, and motor sequence-based skills in particular. More specifically, we present evidence that hippocampal activity and its functional interactions with other brain structures, particularly competition with the striatum, contribute to initial learning of sequential motor behavior. Interestingly, these early cerebral representations in the hippocampus and striatum, which may interact through the prefrontal cortex, can even predict subsequent sleep-related memory consolidation processes. We propose that sleep can reorganize the activity within, as well as the functional interactions between, these structures, ultimately favoring overnight performance enhancement. Finally, we conclude by offering insights into the respective roles of these structures in procedural memory consolidation processes. We argue that, in the context of motor sequence memory consolidation, the hippocampal system triggers subsequent sleep-dependent performance enhancement whereas the striatal system is involved in the maintenance of the motor behavior over time.
23911642	Procedural deficit hypothesis claims that language deficit in children with specific language impairment is affiliated to sequence learning problems. However, studies did not explore on aspects of grammar vulnerable to sequence learning deficits. The present study makes predictions for aspects of grammar that could be sensitive to procedural deficits based on core ideas of procedural deficit hypothesis. The hypothesis for the present study was that the grammatical operations that require greater sequencing abilities (such as inflectional operations) would be more affected in children with language impairment. Further, the influence of sequencing difficulties would be even greater in agglutinating inflectional languages. An adapted serial reaction time task for sequence learning measurements along with grammatical tasks on derivation, inflection, and sentence complexity were examined on typically developing and language impaired children. Results were in favor of procedural deficit hypothesis and its close relation to non-adjacent grammatical operations. The findings were discussed using procedural deficits, declarative compensatory mechanism, and statistical learning deficits. 
23899504	Amnesic mild cognitive impairment (aMCI) is a heterogeneous syndrome that could be subdivided into distinct neuropsychological variants. To investigate relationships between the neuropsychological profile of memory impairment at baseline and the neuroimaging pattern of grey matter (GM) loss over 18 months, we performed a prospective volumetric brain study on 31 aMCI patients and 29 matched controls. All subjects were tested at baseline using a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for the assessment of verbal declarative memory. Over 18 months, patients with impaired free recall but normal total recall (high index of cueing) on the FCSRT developed subcortical and frontal GM loss, while patients with impaired free and total recall (low index of cueing) developed GM atrophy within the left anterior and lateral temporal lobe. In summary, cued recall deficits are associated with a progression of atrophy that closely parallels the spatiotemporal distribution of neurofibrillary degeneration in early Alzheimer's disease (AD), indicating possible AD pathological changes.
23888131	Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder, in which morphological alterations of brain tissue develop many years before the first neuropsychological and clinical changes occur. Among the first and most prominent symptoms are deficiencies of declarative memory functions. This stage of precursory symptoms to AD has been described as amnestic mild cognitive impairment (aMCI) and is discussed as a potential AD prodrome. As therapy in the later stages of AD has been shown to be of limited impact, aMCI would be the key target for early intervention. For that purpose a comprehensive neuropsychological and anatomical characterization of this group is necessary. Previous neuropsychological investigations identified tests which are highly sensitive in diagnosing aMCI and very early AD. However, the sensitivity of those neuropsychological tests to the particular structural neuropathology in aMCI remains to be specified. To this end, we investigated 25 patients with single-domain aMCI. All participants underwent extensive neuropsychological testing and anatomical scanning with structural magnetic resonance imaging. Voxel-based morphometry (VBM) was performed to identify brain regions that show a significant correlation between regional brain volume and behavioral measures of memory and executive functioning. We found that performance in a variety of mnemonic tests was directly related to the integrity of the medial temporal lobe cortex (MTLC). Moreover, impairment of memory sub-functions in aMCI might be detected earlier than overt structural damage. By this, these findings contribute to the identification of cerebral structures associated with memory deficits in aMCI. 
23887151	Sleep has a pivotal role in the consolidation of declarative memory. The coordinated neuronal replay of information encoded before sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of longer-term neuronal representations. Here, we tested the effects of blocking and enhancing glutamatergic neurotransmission during sleep on declarative memory consolidation in humans. We conducted three placebo-controlled, crossover, double-blind studies in which participants learned a word-pair association task. Afterwards, they slept in a sleep laboratory and received glutamatergic modulators. Our first two studies aimed at impairing consolidation by administering the NMDA receptor blocker ketamine and the AMPA receptor blocker caroverine during retention sleep, which, paradoxically, remained unsuccessful, inasmuch as declarative memory performance was unaffected by the treatment. However, in the third study, administration of the NMDA receptor coagonist D-cycloserine (DCS) during retention sleep facilitated consolidation of declarative memory (word pairs) but not consolidation of a procedural control task (finger sequence tapping). Administration of DCS during a wake interval remained without effect on retention of word pairs but improved encoding of numbers. From the overall pattern, we conclude that the consolidation of hippocampus-dependent declarative memory during sleep relies on NMDA-related plastic processes that differ from those processes leading to wake encoding. We speculate that glutamatergic activation during sleep is not only involved in consolidation but also in forgetting of hippocampal memory with both processes being differentially sensitive to DCS and unselective blockade of NMDA and AMPA receptors. 
23881092	Autism spectrum disorders (ASDs) are neurodevelopmental conditions that severely affect social interaction, communication and several behavioural and cognitive functions, such as planning and monitoring motor actions. A renewed interest in intrapersonal cognition has recently emerged suggesting a putative dissociation between impaired declarative processes, such as autobiographical memory, and spared implicit processes, such as the sense of agency (SoA) in ASDs. However, so far only a few studies have investigated the integrity of SoA using tasks exclusively tapping reflective mechanisms. Since pre-reflective processes of SoA are based on the same predictive internal models that are involved in planning and monitoring actions, we hypothesized that pre-reflective aspects of SoA, as measured by the intentional binding effect, would be altered in adults with high functioning autism spectrum disorders, relative to volunteers with typical development. Here, in accordance with our hypothesis, we report reduced IB in participants with ASDs. 
23871473	Accumulating evidence suggests that stress may orchestrate the engagement of multiple memory systems in the brain. In particular, stress is thought to favor dorsal striatum-dependent procedural over hippocampus-dependent declarative memory. However, the neuroendocrine mechanisms underlying these modulatory effects of stress remain elusive, especially in humans. Here, we targeted the role of the mineralocorticoid receptor (MR) in the stress-induced modulation of dorsal striatal and hippocampal memory systems in the human brain using a combination of event-related functional magnetic resonance imaging and pharmacologic blockade of the MR.Eighty healthy participants received the MR antagonist spironolactone (300 mg) or a placebo and underwent a stressor or control manipulation before they performed, in the scanner, a classification task that can be supported by the hippocampus and the dorsal striatum.	Stress after placebo did not affect learning performance but reduced explicit task knowledge and led to a relative increase in the use of more procedural learning strategies. At the neural level, stress promoted striatum-based learning at the expense of hippocampus-based learning. Functional connectivity analyses showed that this shift was associated with altered coupling of the amygdala with the hippocampus and dorsal striatum. Mineralocorticoid receptor blockade before stress prevented the stress-induced shift toward dorsal striatal procedural learning, same as the stress-induced alterations of amygdala connectivity with hippocampus and dorsal striatum, but resulted in significantly impaired performance.	Our findings indicate that the stress-induced shift from hippocampal to dorsal striatal memory systems is mediated by the amygdala, required to preserve performance after stress, and dependent on the MR.	
23856944	A large number of questions in clinical and/or experimental neuropsychology require the multiple repetition of memory tests at relatively short intervals. Studies on the impact of the associated exercise and interference effects on the validity of the test results are rare. Moreover, hardly any neuropsychological instruments exist to date to record the memory performance with several parallel versions in which the emotional valence of the test material is also taken into consideration. The aim of the present study was to test whether a working memory test (WST, a digit-span task with neutral or negative distraction stimuli) devised by our workgroup can be used with repeated measurements. This question was also examined in parallel versions of a wordlist learning paradigm and an autobiographical memory test (AMT). Both tests contained stimuli with neutral, positive and negative valence. Twenty-four participants completed the memory testing including the working memory test and three versions of a wordlist and the AMT at intervals of a week apiece (measuring points 1. - 3.). The results reveal consistent performances across the three measuring points in the working and autobiographical memory test. The valence of the stimulus material did not influence the memory performance. In the delayed recall of the wordlist an improvement in memory performance over time was seen. The tests on working memory presented and the parallel versions for the declarative and autobiographical memory constitute informal economic instruments within the scope of the measurement repeatability designs. While the WST and AMT are appropriate for study designs with repeated measurements at relatively short intervals, longer intervals might seem more favourable for the use of wordlist learning paradigms. 
23856708	This study demonstrates for the first time deferred imitation of novel actions in dogs (Canis familiaris) with retention intervals of 1.5 min and memory of familiar actions with intervals ranging from 0.40 to 10 min. Eight dogs were trained using the 'Do as I do' method to match their own behaviour to actions displayed by a human demonstrator. They were then trained to wait for a short interval to elapse before they were allowed to show the previously demonstrated action. The dogs were then tested for memory of the demonstrated behaviour in various conditions, also with the so-called two-action procedure and in a control condition without demonstration. Dogs were typically able to reproduce familiar actions after intervals as long as 10 min, even if distracted by different activities during the retention interval and were able to match their behaviour to the demonstration of a novel action after a delay of 1 min. In the two-action procedure, dogs were typically able to imitate the novel demonstrated behaviour after retention intervals of 1.5 min. The ability to encode and recall an action after a delay implies that facilitative processes cannot exhaustively explain the observed behavioural similarity and that dogs' imitative abilities are rather based on an enduring mental representation of the demonstration. Furthermore, the ability to imitate a novel action after a delay without previous practice suggests presence of declarative memory in dogs. 
23852106	In this column, the authors first present a composite of several cases of psychiatrically healthy individuals who developed manic-depressive symptoms after receiving a course of prednisone to treat symptoms of inflammatory processes, such as Crohn's disease. The next section summarizes keys points from 50 years of clinical experience with such cases. The authors then present an overview of the effects of exogenous administration of glucocorticoids on cognitive performance and emotional processing via effects on medial temporal lobe and prefrontal structures, including the amygdala, hippocampus, and dorsolateral prefrontal cortex. These effects include glucocorticoid-induced deficits in declarative and autobiographical memory, altered activation of medial temporal lobe structures, and delayed habituation of hemodynamic responses to emotional faces. Finally, these findings are connected in a discussion of how glucocorticoid exposure can result in mood disturbances and what light that may shed on the neurobiology underlying spontaneous bipolar and unipolar affective illnesses.
23848557	A large amount of studies have investigated the association between sleep and memory systems. However, remarkably little is known of the effect of sleep disorders on declarative and nondeclarative memory for children. In the present study we examined the effects of sleep disorders on different aspects of memory functions by testing children with sleep-disordered breathing (SDB), which is characterized by disrupted sleep patterns. We used "The War of the Ghosts" test to measure declarative memory and the Alternating Serial Reaction Time (ASRT) task. This enabled us to measure two aspects of nondeclarative memory--general skill learning and sequence-specific learning--separately. Ten children with SDB and 10 healthy controls participated in this study. Our data showed dissociation between declarative and nondeclarative memory in children with SDB. They showed impaired declarative memory, while the sequence-specific and general skill learning was similar to that of healthy controls, in spite of sleep disruption. Our findings suggest that sleep-disordered breathing affects declarative and nondeclarative memory differently in children. Moreover, these findings imply that the disrupted sleep pattern influences the more attention-demanding and cortical structure-guided explicit processes, while the less attention-demanding implicit processes mediated by subcortical structures are preserved.
23835043	The val66met polymorphism of the brain-derived neurotrophic factor gene (BDNFMet) is associated with impaired learning/memory function, affective dysregulation and maladaptive personality traits. Here, we examine the potential relationship between the BDNFMet allele, introversion and declarative memory in middle-age adults.A total of 132 middle-aged healthy adults took part in this study that included taking a blood sample for genetic profiling, a short battery of neuropsychological tests and the NEO-Five Factor Inventory (NEO-FFI), widely used to assess the Big Five personality.	Controlling for age, level of education and sex, a multiple analysis of covariance (MANCOVA) computing the effect of BDNF polymorphism on extraversion and declarative memory revealed a significant association (D1,128=4.79; p=0.03; ηp(2)=0.053). Using the Sobel Goodman Mediation Test, it was found that 25.61% of the relationship between genotype and declarative memory performance was mediated by introversion. Subsequent correlational analyses yielded a strong and significant correlation (β=0.53; p<0.001) between introversion and declarative memory specific to BDNFMet individuals.	this study highlights the pertinence of further investigating gene×personality×environment interactions to account for the significant variability that is observed in cognitive function in late life.	
23810995	Cognitive impairments are often associated with abnormal sleep activity in developmental disorders and pathologies of childhood. Besides, accumulated evidence indicates that post-training sleep benefits to the consolidation of recently learned information in healthy adults and children. Although sleep-dependent consolidation effects in children are clearly established for declarative memories, they remain more debated in the procedural memory domain. Nowadays, recent experimental data suggest close interactions between the development of sleep-dependent plasticity markers, cortical maturation and cognition in children. In the present review, we propose that studying sleep and memory consolidation processes in developmental disorders and acquired childhood pathologies can provide novel, enlightening clues to understand the pathophysiological mechanisms subtending the disruption of long-term cerebral plasticity processes eventually leading to cognitive and learning deficits in children. 
23810208	Studies in young healthy volunteers provided evidence of a beneficial impact of an anodal time-varied transcranial direct current stimulation (tDCS) during early slow wave rich sleep on declarative memory but not on procedural memory.The present study investigated whether sleep-dependent memory consolidation can also be affected by slow oscillating tDCS in a population of elderly subjects.	26 subjects (69.1 years ± 7.7 years) received bi-frontal anodal stimulation (max. current density: 0.331 mA/cm(2)) during early NREM sleep in a double-blind placebo-controlled randomized crossover study. Stimulation effects on offline consolidation were tested by using a declarative and a procedural memory task. Furthermore, sleep stages were scored, EEG power was analyzed and spindle densities were assessed.	Independently from stimulation condition, performance in both memory tasks significantly decreased overnight. Stimulation revealed no significant effect on sleep-dependent memory consolidation. Verum tDCS was accompanied by significantly more time awake and significantly less NREM stage 3 sleep during five 1-min stimulation free intervals.	The results of the present study are in line with other studies showing that offline consolidation during sleep varies with age and is less pronounced in the elderly than in young or middle-aged subjects. Contrary to an almost identical positive study in young adults, slow oscillatory tDCS applied to the elderly failed to show a beneficial effect on memory consolidation in the present study.	
23807175	Gender differences in creativity have been widely studied in behavioral investigations, but this topic has rarely been the focus of neuroscientific research. The current paper presents follow-up analyses of a previous fMRI study (Abraham et al., Neuropsychologia 50(8):1906-1917, 2012b), in which behavioral and brain function during creative conceptual expansion as well as general divergent thinking were explored. Here, we focus on gender differences within the same sample. Conceptual expansion was assessed with the alternate uses task relative to the object location task, whereas divergent thinking was assessed in terms of responses across both the alternate uses and object location tasks relative to n-back working memory tasks. While men and women were indistinguishable in terms of behavioral performance across all tasks, the pattern of brain activity while engaged in the tasks in question was indicative of strategy differences between the genders. Brain areas related to semantic cognition, rule learning and decision making were preferentially engaged in men during conceptual expansion, whereas women displayed higher activity in regions related to speech processing and social perception. During divergent thinking, declarative memory related regions were strongly activated in men, while regions involved in theory of mind and self-referential processing were more engaged in women. The implications of gender differences in adopted strategies or cognitive style when faced with generative tasks are discussed. 
23806840	Memory systems research has typically described the different types of long-term memory in the brain as either declarative versus non-declarative or implicit versus explicit. These descriptions reflect the difference between declarative, conscious, and explicit memory that is dependent on the medial temporal lobe (MTL) memory system, and all other expressions of learning and memory. The other type of memory is generally defined by an absence: either the lack of dependence on the MTL memory system (nondeclarative) or the lack of conscious awareness of the information acquired (implicit). However, definition by absence is inherently underspecified and leaves open questions of how this type of memory operates, its neural basis, and how it differs from explicit, declarative memory. Drawing on a variety of studies of implicit learning that have attempted to identify the neural correlates of implicit learning using functional neuroimaging and neuropsychology, a theory of implicit memory is presented that describes it as a form of general plasticity within processing networks that adaptively improve function via experience. Under this model, implicit memory will not appear as a single, coherent, alternative memory system but will instead be manifested as a principle of improvement from experience based on widespread mechanisms of cortical plasticity. The implications of this characterization for understanding the role of implicit learning in complex cognitive processes and the effects of interactions between types of memory will be discussed for examples within and outside the psychology laboratory. 
23799058	Recent EEG studies have shown that implicit learning involving specific cortical circuits results in an enduring local trace manifested as local changes in spectral power. Here we used a well characterized visual sequence learning task and high density-(hd-)EEG recording to determine whether also declarative learning leaves a post-task, local change in the resting state oscillatory activity in the areas involved in the learning process. Thus, we recorded hd-EEG in normal subjects before, during and after the acquisition of the order of a fixed spatial target sequence (VSEQ) and during the presentation of targets in random order (VRAN). We first determined the temporal evolution of spectral changes during VSEQ and compared it to VRAN. We found significant differences in the alpha and theta bands in three main scalp regions, a right occipito-parietal (ROP), an anterior-frontal (AFr), and a right frontal (RFr) area. The changes in frontal theta power during VSEQ were positively correlated with the learning rate. Further, post-learning EEG recordings during resting state revealed a significant increase in alpha power in ROP relative to a pre-learning baseline. We conclude that declarative learning is associated with alpha and theta changes in frontal and posterior regions that occur during the task, and with an increase of alpha power in the occipito-parietal region after the task. These post-task changes may represent a trace of learning and a hallmark of use-dependent plasticity. 
23792693	Different roles have been attributed to mesio-temporal areas and frontal lobes in declarative memory functioning, and qualitative differences have been observed in the amnesic symptoms due to pathological damage of these two portions of the central nervous system.The aim of the present study was to look for memory profiles related to pathological involvement in the temporal and frontal structures in patients with different dementia syndromes on word-list and prose memory tasks.	20 patients with Alzheimer's disease (AD), 20 with frontal variant of FTD (fvFTD), 20 with subcortical ischemic vascular dementia (SIVD), and 20 with Lewy body dementia (LBD) and 34 healthy subjects (NCs) were submitted to word-list and prose memory tasks.	All groups performed similarly on both the immediate and delayed recall of the word-list. Conversely, AD patients performed worse than all the other dementia groups on the immediate prose recall. On delayed prose recall, AD patients performed worse than fvFTD and SIVD patients but similar to LBD patients. Differential scores between word-list and prose tests were minimal in the AD group and very pronounced in fvFTD and SIVD groups.	The combined use of the prose and word-list tasks evidenced a "mesio-temporal" memory profile in AD patients as opposed to a "frontal" one in fvFTD and SIVD patients and a mixed profile in the LBD patients. In particular, a differential score between the two tests can be useful in differentiating AD patients from patients with other forms of dementia.	
23789911	Glucose facilitation of cognitive function has been widely reported in previous studies (including our own). However, several studies have also failed to detect glucose facilitation. There is sparsity of research examining the factors that modify the effect of glucose on cognition. The aims of the present study were to (1) demonstrate the previously observed enhancement of cognition through glucose administration and (2) investigate some of the factors that may exert moderating roles on the behavioural response to glucose, including glucose regulation, body composition (BC) and hypothalamic–pituitary–adrenal axis response. A total of twenty-four participants took part in a double-blind, placebo-controlled, randomised, repeated-measures study, which examined the effect of 25 and 60 g glucose compared with placebo on cognitive function. At 1 week before the study commencement, all participants underwent an oral glucose tolerance test. Glucose facilitated performance on tasks of numeric and spatial working memory, verbal declarative memory and speed of recognition. Moderating variables were examined using several indices of glucoregulation and BC. Poorer glucoregulation predicted improved immediate word recall accuracy following the administration of 25 g glucose compared with placebo. Those with better glucoregulation showed performance decrements on word recall accuracy following the administration of 25 g glucose compared with placebo. These findings are in line with accumulating evidence that glucose load may preferentially enhance cognition in those with poorer glucoregulation. Furthermore, the finding that individuals with better glucoregulation may suffer impaired performance following a glucose load is novel and requires further substantiation.
23773160	Functional neuroimaging studies have increasingly noted hippocampal activation associated with a variety of cognitive functions--such as decision making, attention, perception, incidental learning, prediction, and working memory--that have little apparent relation to declarative memory. Such findings might be difficult to reconcile with classical hippocampal lesion studies that show remarkable sparing of cognitive functions outside the realm of declarative memory. Even the oft-reported hippocampal activations during confident episodic retrieval are not entirely congruent with evidence that hippocampal lesions reliably impair encoding but inconsistently affect retrieval. Here we explore the conditions under which the hippocampus responds during episodic recall and recognition. Our findings suggest that anterior hippocampal activity may be related to the imbalance of incidental encoding across tasks and conditions rather than due to retrieval per se. Incidental encoding and hippocampal activity may be reduced during conditions where retrieval requires greater attentional engagement. During retrieval, anterior hippocampal activity decreases with increasing search duration and retrieval effort, and this deactivation corresponds with a coincident impaired encoding of the external environment (Israel, Seibert, Black, & Brewer, 2010; Reas & Brewer, 2013; Reas, Gimbel, Hales, & Brewer, 2011). In light of this emerging evidence, we discuss the proposal that some hippocampal activity observed during memory retrieval, or other non-memory conditions, may in fact be attributable to concomitant encoding activity that is regulated by the attentional demands of the principal task.
23770411	Sleep is strongly conserved within species, yet marked and perplexing inter-individual differences in sleep physiology are observed. Combining EEG sleep recordings and high-resolution structural brain imaging, here we demonstrate that the morphology of the human brain offers one explanatory factor of such inter-individual variability. Gray matter volume in interoceptive and exteroceptive cortices correlated with the expression of slower NREM sleep spindle frequencies, supporting their proposed role in sleep protection against conscious perception. Conversely, and consistent with an involvement in declarative memory processing, gray matter volume in bilateral hippocampus was associated with faster NREM sleep spindle frequencies. In contrast to spindles, gray matter volume in the homeostatic sleep-regulating center of the basal forebrain/hypothalamus, together with the medial prefrontal cortex, accounted for individual differences in NREM slow wave oscillations. Together, such findings indicate that the qualitative and quantitative expression of human sleep physiology is significantly related to anatomically specific differences in macroscopic brain structure. 
23768770	The hippocampus is thought to automatically encode all experience, yet the vast majority of our experiences are not remembered later. Although psychological theories have postulated the existence of decay processes for declarative memory, the corresponding neurobiological mechanisms are unknown. Here we develop the hypothesis that ongoing hippocampal neurogenesis represents a decay process that continually clears memories from the hippocampus. As newborn granule cells integrate into established hippocampal circuits, they form new input and output connections over the course of several weeks. Because successful memory retrieval relies on reinvoking patterns of activity that occurred at the time of encoding (pattern completion), neurogenesis-induced remodeling of hippocampal circuits incrementally reduces the likelihood that a given retrieval cue will reinvoke a previously stored pattern. 
23767926	Sleep affects declarative memory for emotional stimuli differently than it affects declarative memory for nonemotional stimuli. However, the interaction between specific sleep characteristics and emotional memory is not well understood. Recent studies on how sleep affects emotional memory have focused on rapid eye movement sleep (REM) but have not addressed non-REM sleep, particularly sleep spindles. This is despite the fact that sleep spindles are implicated in declarative memory as well as neural models of memory consolidation (e.g., hippocampal neural replay). Additionally, many studies examine a limited range of emotional stimuli and fail to disentangle differences in memory performance because of variance in valence and arousal. Here, we experimentally increase non-REM sleep features, sleep spindle density, and SWS, with pharmacological interventions using zolpidem (Ambien) and sodium oxybate (Xyrem) during daytime naps. We use a full spread of emotional stimuli to test all levels of valence and arousal. We find that increasing sleep spindle density increases memory discrimination (da) for highly arousing and negative stimuli without altering measures of bias (ca). These results indicate a broader role for sleep in the processing of emotional stimuli with differing effects based on arousal and valence, and they raise the possibility that sleep spindles causally facilitate emotional memory consolidation. These findings are discussed in terms of the known use of hypnotics in individuals with emotional mood disorders. 
23761759	Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features.
23754372	We begin by describing an historical scientific debate in which the fundamental idea that species are related by evolutionary descent was challenged. The challenge was based on supposed neuroanatomical differences between humans and other primates with respect to a structure known then as the hippocampus minor. The debate took place in the early 1860 s, just after the publication of Darwin's famous book. We then recount the difficult road that was traveled to develop an animal model of human memory impairment, a matter that also turned on questions about similarities and differences between humans and other primates. We then describe how the insight that there are multiple memory systems helped to secure the animal model and how the animal model was ultimately used to identify the neuroanatomy of long-term declarative memory (sometimes termed explicit memory). Finally, we describe a challenge to the animal model and to cross-species comparisons by considering the case of the concurrent discrimination task, drawing on findings from humans and monkeys. We suggest that analysis of such cases, based on the understanding that there are multiple memory systems with different properties, has served to emphasize the similarities in memory function across mammalian species.
23751172	Recent neuroimaging studies suggest that prototype learning may be mediated by at least two dissociable memory systems depending on the mode of acquisition, with A/Not-A prototype learning dependent upon a perceptual representation system located within posterior visual cortex and A/B prototype learning dependent upon a declarative memory system associated with medial temporal and frontal regions. The degree to which patients with Alzheimer's disease (AD) can acquire new categorical information may therefore critically depend upon the mode of acquisition. The present study examined A/Not-A and A/B prototype learning in AD patients using procedures that allowed direct comparison of learning across tasks. Despite impaired explicit recall of category features in all tasks, patients showed differential patterns of category acquisition across tasks. First, AD patients demonstrated impaired prototype induction along with intact exemplar classification under incidental A/Not-A conditions, suggesting that the loss of functional connectivity within visual cortical areas disrupted the integration processes supporting prototype induction within the perceptual representation system. Second, AD patients demonstrated intact prototype induction but impaired exemplar classification during A/B learning under observational conditions, suggesting that this form of prototype learning is dependent on a declarative memory system that is disrupted in AD. Third, the surprisingly intact classification of both prototypes and exemplars during A/B learning under trial-and-error feedback conditions suggests that AD patients shifted control from their deficient declarative memory system to a feedback-dependent procedural memory system when training conditions allowed. Taken together, these findings serve to not only increase our understanding of category learning in AD, but to also provide new insights into the ways in which different memory systems interact to support the acquisition of categorical knowledge. 
23747650	Sleep-dependent consolidation has been demonstrated for declarative and procedural memory but few theories of consolidation distinguish between rote and generalized learning, suggesting similar consolidation should occur for both. However, studies using rote and generalized learning have suggested different patterns of consolidation may occur, although different tasks have been used across studies. Here we directly compared consolidation of rote and generalized learning using a single speech identification task. Training on a large set of novel stimuli resulted in substantial generalized learning, and sleep restored performance that had degraded after 12 waking hours. Training on a small set of repeated stimuli primarily resulted in rote learning and performance also degraded after 12 waking hours but was not restored by sleep. Moreover performance was significantly worse 24-h after rote training. Our results suggest a functional dissociation between the mechanisms of consolidation for rote and generalized learning which has broad implications for memory models. 
23745287	During emergencies maladaptive behavior can reduce survival. This study compared the effects of a basic firefighter training course on 21 volunteers (with no firefighting experience) with age and gender-matched controls.Stress reactivity (salivary cortisol and anxiety) were monitored across the course: day 1 (classroom), day 2 (physical equipment training), and day 3 (simulated fire emergency). Cognitive performance (visual attention, declarative and working memory) considered important in surviving a fire emergency were measured immediately post-training or after a 20-min delay.	Prior to threat subjects showed an anticipatory cortisol increase but no corresponding increase in self-reported anxiety. On day 3 cortisol was higher in firefighters tested immediately after (10.37 nmol x L(-1) and 20 min after training (7.20 nmol L(-1)) compared to controls (3.13 nmol x L(-1)). Differences in cognitive performance were observed post-threat, with impairments in visual declarative memory in the firefighting subjects tested immediately, and working memory impairments observed in those tested after a 20-min delay.	Cognitive impairments were found following a simulated emergency and could explain maladaptive responses observed during real fires. Moreover, the results suggest the type of cognitive impairments observed may be time dependent, with different cognitive difficulties becoming evident at different times following an emergency.	
23741438	As research into the neurobiology of language has focused primarily on the systems level, fewer studies have examined the link between molecular genetics and normal variations in language functions. Because the ability to learn a language varies in adults and our genetic codes also vary, research linking the two provides a unique window into the molecular neurobiology of language. We consider a candidate association between the dopamine receptor D2 gene (DRD2) and linguistic grammar learning. DRD2-TAQ-IA polymorphism (rs1800497) is associated with dopamine receptor D2 distribution and dopamine impact in the human striatum, such that A1 allele carriers show reduction in D2 receptor binding relative to carriers who are homozygous for the A2 allele. The individual differences in grammatical rule learning that are particularly prevalent in adulthood are also associated with striatal function and its role in domain-general procedural memory. Therefore, we reasoned that procedurally-based grammar learning could be associated with DRD2-TAQ-IA polymorphism. Here, English-speaking adults learned artificial concatenative and analogical grammars, which have been respectively associated with procedural and declarative memory. Language learning capabilities were tested while learners' neural hemodynamic responses were simultaneously measured by fMRI. Behavioral learning and brain activation data were subsequently compared with the learners' DRD2 (rs1800497) genotype. Learners who were homozygous for the A2 allele were better at concatenative (but not analogical) grammar learning and had higher striatal responses relative to those who have at least one A1 allele. These results provide preliminary evidence for the neurogenetic basis of normal variations in linguistic grammar learning and its link to domain-general functions.
23734106	The majority of adult people in western societies regularly consume psychoactive drugs. While this consumption is integrated in everyday life activities and controlled in most consumers, it may escalate and result in drug addiction. Non-addicted drug use requires the systematic establishment of highly organized behaviors, such as drug-seeking and -taking. While a significant role for classical and instrumental learning processes is well established in drug use and abuse, declarative drug memories have largely been neglected in research. Episodic memories are an important part of the declarative memories. Here a role of episodic drug memories in the establishment of non-addicted drug use and its transition to addiction is suggested. In relation to psychoactive drug consumption, episodic drug memories are formed when a person prepares for consumption, when the drug is consumed and, most important, when acute effects, withdrawal, craving, and relapse are experienced. Episodic drug memories are one-trial memories with emotional components that can be much stronger than "normal" episodic memories. Their establishment coincides with drug-induced neuronal activation and plasticity. These memories may be highly extinction resistant and influence psychoactive drug consumption, in particular during initial establishment and at the transition to "drug instrumentalization." In that, understanding how addictive drugs interact with episodic memory circuits in the brain may provide crucial information for how drug use and addiction are established.
25379240	Memory impairment is a consistent feature of the schizophrenic syndrome. Hippocampal dysfunction has also been consistently demonstrated. This review will discuss neurophysiological and neuroanatomical aspects of memory formation and how they relate to memory impairment in schizophrenia. An understanding of the cellular physiology and connectivity of the hippocampus with other regions can also aid in understanding the relationship between schizophrenic declarative or relational memory deficits, working memory deficits and the clinical symptoms of the syndrome. 
23717524	Developmental dyslexia (DD) has previously been associated with a number of cognitive deficits. Little attention has been directed to cognitive functions that remain intact in the disorder, though the investigation and identification of such strengths might be useful for developing new, and improving current, therapeutical interventions. In this study, an old/new recognition memory paradigm was used to examine previously untested aspects of declarative memory in children with DD and typically developing control children. The DD group was not only not impaired at the task, but actually showed superior recognition memory, as compared to the control children. These findings complement previous reports of enhanced cognition in other domains (e.g., visuo-spatial processing) in DD. Possible underlying mechanisms for the observed DD advantage in declarative memory, and the possibility of compensation by this system for reading deficits in dyslexia, are discussed.
23703315	Dependent cocaine users consistently display cognitive deficits but cognitive performance of recreational cocaine users has rarely been investigated.To examine whether cognitive performance is impaired in relatively pure recreational and dependent cocaine users.	The cognitive performance of recreational (n = 68) and dependent cocaine users (n = 30) was compared with the performance of stimulant-naive controls (n = 68) employing an extensive neuropsychological test battery. Moreover, the impact of attention-deficit hyperactivity disorder (ADHD) symptoms, craving and early age at onset was analysed.	Dependent cocaine users display broad cognitive impairments in the domains of attention, working memory, declarative memory and executive functions. The performance of recreational cocaine users in all four domains was intermediate between that of controls and dependent users and they displayed significant deficits foremost in the domains of attention and working memory. In addition, ADHD symptoms, craving and age at onset were important modulators of cognitive function in cocaine users.	Cognitive deficits occur at a recreational and non-dependent level of cocaine use. Cocaine use and ADHD seem to have mutually aggravating effects on cognitive impairment.	
23690586	During the past decade, a large body of research has shown that memory traces can become labile upon retrieval and must be restabilized. Critically, interrupting this reconsolidation process can abolish a previously stable memory. Although a large number of studies have demonstrated this reconsolidation associated amnesia in nonhuman animals, the evidence for its occurrence in humans is far less compelling, especially with regard to declarative memory. In fact, reactivating a declarative memory often makes it more robust and less susceptible to subsequent disruptions. Here we show that existing declarative memories can be selectively impaired by using a noninvasive retrieval-relearning technique. In six experiments, we show that this reconsolidation-associated amnesia can be achieved 48 h after formation of the original memory, but only if relearning occurred soon after retrieval. Furthermore, the amnesic effect persists for at least 24 h, cannot be attributed solely to source confusion and is attainable only when relearning targets specific existing memories for impairment. These results demonstrate that human declarative memory can be selectively rewritten during reconsolidation.
23660456	Serotonergic neurotoxicity following MDMA is well-established in laboratory animals, and neuroimaging studies have found lower serotonin transporter (SERT) binding in abstinent Ecstasy/MDMA users. Serotonin is a modulator for many different psychobiological functions, and this review will summarize the evidence for equivalent functional deficits in recreational users. Declarative memory, prospective memory, and higher cognitive skills are often impaired. Neurocognitive deficits are associated with reduced SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localised reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. The children of mothers who take Ecstasy/MDMA during pregnancy have developmental problems. These psychobiological deficits are wide-ranging, and occur in functions known to be modulated by serotonin. They are often related to lifetime dosage, with light users showing slight changes, and heavy users displaying more pronounced problems. In summary, abstinent Ecstasy/MDMA users can show deficits in a wide range of biobehavioral functions with a serotonergic component. 
23658614	Several reports have shown that after specific reminders are presented, consolidated memories pass from a stable state to one in which the memory is reactivated. This reactivation implies that memories are labile and susceptible to amnesic agents. This susceptibility decreases over time and leads to a re-stabilization phase usually known as reconsolidation. With respect to the biological role of reconsolidation, two functions have been proposed. First, the reconsolidation process allows new information to be integrated into the background of the original memory; second, it strengthens the original memory. We have previously demonstrated that both of these functions occur in the reconsolidation of human declarative memories. Our paradigm consisted of learning verbal material (lists of five pairs of nonsense syllables) acquired by a training process (L1-training) on Day 1 of our experiment. After this declarative memory is consolidated, it can be made labile by presenting a specific reminder. After this, the memory passes through a subsequent stabilization process. Strengthening creates a new scenario for the reconsolidation process; this function represents a new factor that may transform the dynamic of memories. First, we analyzed whether the repeated labilization-reconsolidation processes maintained the memory for longer periods of time. We showed that at least one labilization-reconsolidation process strengthens a memory via evaluation 5 days after its re-stabilization. We also demonstrated that this effect is not triggered by retrieval only. We then analyzed the way strengthening modified the effect of an amnesic agent that was presented immediately after repeated labilizations. The repeated labilization-reconsolidation processes made the memory more resistant to interference during re-stabilization. Finally, we evaluated whether the effect of strengthening may depend on the age of the memory. We found that the effect of strengthening did depend on the age of the memory. Forgetting may represent a process that weakens the effect of strengthening.
23646101	Arousal Biased Competition theory suggests that arousal enhances competitive attentional processes, but makes no strong claims about valence effects. Research suggests that the scope of enhanced attention depends on valence with negative arousal narrowing and positive arousal broadening attention. Attentional scope likely affects declarative-memory-mediated and perceptual-representation-mediated learning systems differently, with declarative-memory-mediated learning depending on narrow attention to develop targeted verbalizable rules, and perceptual-representation-mediated learning depending on broad attention to develop a perceptual representation. We hypothesize that negative arousal accentuates declarative-memory-mediated learning and attenuates perceptual-representation-mediated learning, while positive arousal reverses this pattern. Prototype learning provides an ideal test bed as dissociable declarative-memory and perceptual-representation systems mediate two-prototype (AB) and one-prototype (AN) prototype learning, respectively, and computational models are available that provide powerful insights on cognitive processing. As predicted, we found that negative arousal narrows attentional focus facilitating AB learning and impairing AN learning, while positive arousal broadens attentional focus facilitating AN learning and impairing AB learning.
26304203	Stress can affect cognition in many ways, with the outcome (i.e., facilitating or impairing) depending on a combination of factors related to both stress and the cognitive function under study. Among the factors identified as particularly relevant to define the cognitive effects of stress are the intensity or magnitude of stress, its origin (i.e., whether triggered by the task or externally), and its duration (i.e., whether acute or chronically delivered). At the cognitive end, the specific cognitive operation (e.g., implicit or explicit memory, long-term or working memory, goal-directed or habit learning) and information processing phases (e.g., learning, consolidation, and retrieval) are essential as well to define stress effects. The emerging view is that mild stress tends to facilitate cognitive function, particularly in implicit memory or simple declarative tasks or when the cognitive load is not excessive. Exposure to high or very high stress acutely (whether elicited by the cognitive task or experienced before being trained or tested in the task) or chronically impairs the formation of explicit memories and, more generally, of those that require complex, flexible reasoning (as typically observed for hippocampus- and prefrontal cortex-related functions) while improving performance of implicit memory and well-rehearsed tasks (as reported for amygdala-dependent conditioning tasks and for striatum-related processes). In addition to these general principles, there are important individual differences in the cognitive impact of stress, with gender and age being particularly influencing factors. WIREs Cogn Sci 2013, 4:245-261. doi: 10.1002/wcs.1222 For further resources related to this article, please visit the WIREs website. 
23624059	When a consolidated memory is reactivated, it can become labile and prone to enhancement or disruption, a process known as reconsolidation. The reconsolidation hypothesis has challenged the traditional view that memories after consolidation are fixed and unchangeable. Recent studies suggest that the mechanisms mediating memory retrieval and the mechanisms that underlie the behavioral expression of memory can be dissociated, offering a new promise for the understanding of human memory persistence. Although reconsolidation studies typically use amnesic agents, it has also been shown that memory can be enhanced by pharmacological agents and real-life events during reconsolidation. Recently, we demonstrated that a mild stressor, cold pressor stress (CPS), can enhance human declarative memory during reconsolidation in a cued-recall test. Here we evaluate whether the recollection of 7- or 20-day-old long-term memories can be improved by exposure to two different neuromodulators: a mild stressor and glucose during reconsolidation. As expected, poor and very poor memory performance was found at the time of memory reactivation (days 6 and 20 after training). CPS during reconsolidation improved the long-term expression of a declarative memory 6 -but not 20-days after training. However, the administration of an oral source of glucose (juice), but not a diet juice, can enhance memory during reconsolidation even 20 days after training. Interestingly, when a recognition test was applied instead of a cued-recall test, memory performance was still robust at both 1 and 3 weeks after training. Here we show that the period in which this memory can be reactivated and become labile largely exceeds the period in which that memory is recalled, proving evidence that conscious access is not needed for reconsolidation. Present results are consistent with dissociation between the mechanisms mediating memory labilization and the mechanisms that underlie the behavioral expression of memory.
23620781	Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45-60 days after treatment cessation. Untreated Ts65Dn mice had a hypotrophyc mossy fiber bundle, fewer synaptic contacts, fewer glutamatergic contacts, and fewer dendritic spines in the stratum lucidum of CA3, the terminal field of the granule cell projections. Electrophysiological recordings from CA3 pyramidal neurons showed that in Ts65Dn mice the frequency of both mEPSCs and mIPSCs was reduced, indicating an overall impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons. In treated Ts65Dn mice all these aberrant features were fully normalized, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions.
23613463	Surgical resection of the temporal lobe is an effective treatment for medically intractable temporal lobe epilepsy, but can cause memory impairment. Deep brain stimulation in epilepsy has targeted gray matter structures using high frequencies, but achieved limited success. We tested the hypothesis that low-frequency stimulation of the fornix reduces interictal epileptiform discharges and seizures in patients with intractable mesial temporal lobe epilepsy, without affecting memory.We implanted depth electrodes in 11 patients for surgical evaluation of intractable epilepsy. Low-frequency stimulation of the fornix occurred in 4-hour sessions in the video-electroencephalography unit. Mental status assessment was performed at baseline and during stimulation. We studied the effect of stimulation on hippocampal spikes and seizures.	There were no complications, and the patients were unaware of the stimulation. Fornix stimulation elicited evoked responses in the hippocampus and the posterior cingulate gyrus. Hourly Mini-Mental Status Examination (MMSE) scores showed an increase during stimulation when compared to prestimulation MMSE, largely due to improvement in recall, possibly representing a practice effect. Hippocampal spikes were significantly reduced during and outlasting each stimulation session. Seizure odds (n = 7) were reduced by 92% in the 2 days that followed stimulation.	Low-frequency stimulation of the fornix activates the hippocampus and other areas of the declarative memory circuit. The results of this preliminary study suggest that low-frequency stimulation is tolerable and reduces epileptiform discharges and seizures in patients with intractable mesial temporal lobe epilepsy. A controlled clinical trial may be warranted.	
23609914	Animal models agree that the perirhinal cortex plays a critical role in object recognition memory, but qualitative aspects of this mnemonic function are still debated. A recent model claims that the perirhinal cortex is required to recognize the novelty of confusable distractor stimuli, and that damage here results in an increased propensity to judge confusable novel objects as familiar (i.e., false positives). We tested this model in healthy participants and patients with varying degrees of perirhinal cortex damage, i.e., amnestic mild cognitive impairment and very early Alzheimer's disease (AD), with a recognition memory task with confusable and less confusable realistic object pictures, and from whom we acquired high-resolution anatomic MRI scans. Logistic mixed-model behavioral analyses revealed that both patient groups committed more false positives with confusable than less confusable distractors, whereas healthy participants performed comparably in both conditions. A voxel-based morphometry analysis demonstrated that this effect was associated with atrophy of the anteromedial temporal lobe, including the perirhinal cortex. These findings suggest that also the human perirhinal cortex recognizes the novelty of confusable objects, consistent with its border position between the hierarchical visual object processing and medial temporal lobe memory systems, and explains why AD patients exhibit a heightened propensity to commit false positive responses with inherently confusable stimuli.
23606881	NBM-T-L-BMX-OS01 (BMX) was derived from the semisynthesis of osthole, isolated from Cnidium monnieri (L.) Cuss., and was identified to be a potent inhibitor of HDAC8. This study shows that HDAC8 is highly expressed in the pancreas and the brain. The function of HDAC8 in the brain has not been adequately studied. Because BMX enhances neurite outgrowth and cAMP response element-binding protein (CREB) activation, the effect of BMX on neural plasticity such as learning and memory is examined. To examine declarative and nondeclarative memory, a water maze, a passive one-way avoidance task, and a novel object recognition task were performed. Results from the water maze revealed that BMX and suberoylanilide-hydroxamic-acid-(SAHA-) treated rats showed shorter escape latency in finding the hidden platform. The BMX-treated animals spent more time in the target quadrant in the probe trial performance. An analysis of the passive one-way avoidance results showed that the BMX-treated animals stayed longer in the illuminated chamber by 1 day and 7 days after footshock. The novel object recognition task revealed that the BMX-treated animals showed a marked increase in the time spent exploring novel objects. Furthermore, BMX ameliorates scopolamine-(Sco-) induced learning and memory impairment in animals, indicating a novel role of BMX in learning and memory.
23587533	This study explores the influence of pre-learning stress on performance on declarative memory tasks in healthy young adults in relation to sex and menstrual cycle phase. The sample was composed of 119 students (32 men and 87 women) from 18 to 25 years of age. The women were tested in different hormonal stages (30 in follicular phase, 34 in luteal phase, and 23 using oral contraceptives). The participants were exposed to the Trier Social Stress Test (TSST) or a control condition. Afterwards, their memory performance was measured using a standardized memory test (Rey's Auditory Verbal Learning Test). In the control condition, all groups of women recalled more words than men, but these differences disappeared in the group exposed to TSST because men's performance on the memory test improved, but only to the level of women. In addition, our data suggest that in women the relationship between cortisol and memory can be modulated by sex hormone levels, since in luteal women a negative relationship was found between memory performance and peak cortisol level. These results confirm that sex differences need to be considered in the relationship between pre-learning stress and memory performance.
23585882	3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational club drug with supposed neurotoxic effects selectively on the serotonin system. MDMA users consistently exhibit memory dysfunction but there is an ongoing debate if these deficits are induced mainly by alterations in the prefrontal or mediotemporal cortex, especially the hippocampus. Thus, we investigated the relation of verbal memory deficits with alterations of regional cerebral brain glucose metabolism (rMRGlu) in recreational MDMA users.Brain glucose metabolism in rest was assessed using 2-deoxy-2-((18)F)fluoro-D-glucose positron emission tomography ((18)FDG PET) in 19 male recreational users of MDMA and 19 male drug-naïve controls. (18)FDG PET data were correlated with memory performance assessed with a German version of the Rey Auditory Verbal Learning Test.	As previously shown, MDMA users showed significant impairment in verbal declarative memory performance. PET scans revealed significantly decreased rMRGlu in the bilateral dorsolateral prefrontal and inferior parietal cortex, bilateral thalamus, right hippocampus, right precuneus, right cerebellum, and pons (at the level of raphe nuclei) of MDMA users. Among MDMA users, learning and recall were positively correlated with rMRGlu predominantly in bilateral frontal and parietal brain regions, while recognition was additionally related to rMRGlu in the right mediotemporal and bihemispheric lateral temporal cortex. Moreover, cumulative lifetime dose of MDMA was negatively correlated with rMRGlu in the left dorsolateral and bilateral orbital and medial PFC, left inferior parietal and right lateral temporal cortex.	Verbal learning and recall deficits of recreational MDMA users are correlated with glucose hypometabolism in prefrontal and parietal cortex, while word recognition was additionally correlated with mediotemporal hypometabolism. We conclude that memory deficits of MDMA users arise from combined fronto-parieto-mediotemporal dysfunction.	
23585178	An important assumption concerning the physiology of consciousness is that all varieties of conscious experience are closely related to each other and, hence, are subserved by the same neural mechanism. There are several considerations that lead us to implicate the hippocampus in the generation of conscious perception and, ultimately, of conscious experiences of all kinds. Firstly, conscious perception of external events is intricately linked with the formation of episodic (declarative) memories, a key function attributed to the hippocampus. Secondly, conscious experience is allocentric and contextualized. Consciousness creates or simulates an image of the world that appears to surround us and to be independent of our observation of it. What is characteristic of wakeful consciousness and dreaming alike is that objects or events are experienced as being embedded in an external, that is, allocentric, frame of space and time. The hippocampus has been implicated in the rapid formation and memorization of allocentric representations that embed objects or events in a world context. Thirdly, the hippocampus is ideally positioned to bind information processed in different sensory association cortices. It is argued that rapidly forming patterns of neuronal ensemble firing in the hippocampus, particularly in region CA3, which encode arbitrary associations between objects and their spatiotemporal and emotional context, that is, associations between information derived from different neocortical processing streams, define the informational content of consciousness. Evidence suggestive of an important contribution of the hippocampus to conscious observation, mental imagery, dreaming, conscious anticipation of outcomes, and hallucinations will be reviewed.
23583623	Brain rhythms regulate information processing in different states to enable learning and memory formation. The <1 Hz sleep slow oscillation hallmarks slow-wave sleep and is critical to memory consolidation. Here we show in sleeping humans that auditory stimulation in phase with the ongoing rhythmic occurrence of slow oscillation up states profoundly enhances the slow oscillation rhythm, phase-coupled spindle activity, and, consequently, the consolidation of declarative memory. Stimulation out of phase with the ongoing slow oscillation rhythm remained ineffective. Closed-loop in-phase stimulation provides a straight-forward tool to enhance sleep rhythms and their functional efficacy.
23583499	Previous studies have shown that acute psychosocial stress impairs retrieval of declarative memory with emotional material being especially sensitive to this effect. A functional deletion variant of the ADRA2B gene encoding the α2B-adrenergic receptor has been shown to increase emotional memory and neural activity in the amygdala. We investigated the effects of acute psychosocial stress and the ADRA2B allele on recognition memory for emotional and neutral faces. Fourty-two healthy, non-smoker male volunteers (30 deletion carriers, 12 noncarriers) were tested with a face recognition paradigm. During encoding they were presented with emotional and neutral faces. One hour later, participants underwent either a stress ("Trier Social Stress Test (TSST)") or a control procedure which was followed immediately by the retrieval session where subjects had to indicate whether the presented face was old or new. Stress increased salivary cortisol concentrations, blood pressure and pulse and impaired recognition memory for faces independent of emotional valence and genotype. Participants showed generally slower reaction times to emotional faces. Carriers of the ADRA2B functional deletion variant showed an impaired recognition and slower retrieval of neutral faces under stress. Further, they were significantly slower in retrieving fearful faces in the control condition. The findings indicate that a genetic variation of the noradrenergic system may preserve emotional faces from stress-induced memory impairments seen for neutral faces and heighten reactivity to emotional stimuli under control conditions.
23580110	The relationship between cannabis and cognitive performance is controversial. While both acute administration and long-term cannabis use impair cognitive performance in healthy subjects, several studies have shown improved cognitive outcomes in patients with schizophrenia spectrum disorders who use cannabis. The aim of this study was to determine the relationship between lifetime cannabis use, as assessed longitudinally over 10 years of follow-up in a sample of 42 patients and 35 of their unaffected siblings, and current cognitive performance. Forty-two healthy control subjects were assessed at follow-up with the same instruments. Stepwise linear regression revealed a negative effect of longitudinal cannabis use on performance in a social cognition task in the patient group. In the sibling group, lifetime cannabis use had a negative effect on processing speed and declarative memory performance. In the control group, cannabis use per se did not predict cognitive performance; however, when adding lifetime tobacco use to the model, we found a negative association between lifetime cannabis and tobacco use and processing speed and social cognition performance. Moreover, a lower IQ associated with current cannabis use predicted worse attentional performance in the control group. The differential pattern of associations between cannabis use and cognitive performance in patients compared with siblings and controls can be explained by the negative impact of illness on cognition.
23576763	Declarative memory is thought to rely on two processes: recollection and familiarity. Recollection involves remembering specific details about the episode in which an item was encountered, and familiarity involves simply knowing that an item was presented even when no information can be recalled about the episode itself. There has been debate whether the hippocampus supports only recollection or whether it supports both processes. We approached this issue in a relatively theory-neutral way by fitting two prominent models that have been used to describe recognition memory: dual process signal detection and unequal variance signal detection. Both models yield two parameters of interest when fit to recognition memory data. The dual process signal detection model yields estimates of recollection (r) and familiarity (d'). The unequal variance signal detection model yields estimates of the ratio of the variance of target and foil memory strength distributions (σtarget/σfoil) and the difference in the means of the two distributions (d). We asked how the two parameters of each model were affected by hippocampal damage. We tested five patients with well-characterized bilateral lesions thought to be limited to the hippocampus and age-matched controls. The patients exhibited a broad memory deficit that markedly reduced the value of both parameters in both models. In addition, the pattern of results exhibited by the patients was recapitulated in healthy controls as the delay between learning and testing was extended. Thus, hippocampal damage impairs both component processes of recognition memory.
23569380	This study investigated the effects of sleep deprivation on total and partial (early and late) declarative memory and activation in the areas of the brain involved in these activities. The study included two experiments. Experiment 1 included 40 male residents of an orphanage aged 16-19 years, who were divided into four groups (n = 10 each) and subjected to total sleep deprivation, normal sleep, early-night sleep deprivation, or late-night sleep deprivation. Experiment 2 included eight students from the same institution who were divided into the same four groups (n = 2) as in experiment 1. Declarative memory was tested using lists of associated word pairs in both experiments, and activation of the relevant brain regions was measured before and after retrieval by single-photon emission computed tomography for subjects in experiment 2 only.Students subjected to normal sleep had significantly higher scores for declarative memory retrieval than those subjected to total sleep deprivation (P = 0.002), early-night sleep deprivation (P = 0.005), or late-night sleep deprivation (P = 0.02). The left temporal lobe showed the highest rate of activity during memory retrieval after normal sleep, whereas the frontal, parietal, and right temporal lobes were more active after sleep deprivation.	Both slow wave sleep and rapid eye movement sleep play an active role in consolidation of declarative memory, which in turn allows memory traces to be actively reprocessed and strengthened during sleep, leading to improved performance in memory recall.	
23536062	Intense debate surrounds the role of medial temporal lobe (MTL) structures in recognition memory. Using high-resolution fMRI and analyses of pattern similarity in humans, we examined the encoding computations subserved by MTL subregions. Specifically, we tested the theory that MTL cortex supports memory by encoding overlapping representations, whereas hippocampus supports memory by encoding pattern-separated representations. Consistent with this view, the relationship between encoding pattern similarity and subsequent memory dissociated MTL cortex and hippocampus: later memory was predicted by greater across-item pattern similarity in perirhinal cortex and in parahippocampal cortex, but greater pattern distinctiveness in hippocampus. Additionally, by comparing neural patterns elicited by individual stimuli regardless of subsequent memory, we found that perirhinal cortex and parahippocampal cortex exhibited differential content sensitivity for multiple stimulus categories, whereas hippocampus failed to demonstrate content sensitivity. These data provide novel evidence that complementary MTL encoding computations subserve declarative memory.
23529005	Learning how to obtain rewards requires learning about their contexts and likely causes. How do long-term memory mechanisms balance the need to represent potential determinants of reward outcomes with the computational burden of an over-inclusive memory? One solution would be to enhance memory for salient events that occur during reward anticipation, because all such events are potential determinants of reward. We tested whether reward motivation enhances encoding of salient events like expectancy violations. During functional magnetic resonance imaging, participants performed a reaction-time task in which goal-irrelevant expectancy violations were encountered during states of high- or low-reward motivation. Motivation amplified hippocampal activation to and declarative memory for expectancy violations. Connectivity of the ventral tegmental area (VTA) with medial prefrontal, ventrolateral prefrontal, and visual cortices preceded and predicted this increase in hippocampal sensitivity. These findings elucidate a novel mechanism whereby reward motivation can enhance hippocampus-dependent memory: anticipatory VTA-cortical-hippocampal interactions. Further, the findings integrate literatures on dopaminergic neuromodulation of prefrontal function and hippocampus-dependent memory. We conclude that during reward motivation, VTA modulation induces distributed neural changes that amplify hippocampal signals and records of expectancy violations to improve predictions-a potentially unique contribution of the hippocampus to reward learning.
23526601	Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. The scientific investigation of empathy has focused on characterizing its cognitive and neural substrates, and has pointed to the importance of a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate). While the hippocampus has rarely been the focus of empathy research, the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity) make it well-suited to meet some of the crucial demands of empathy, and a careful investigation of this possibility could make a significant contribution to the neuroscientific understanding of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female) with focal, bilateral hippocampal (HC) damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. Unlike healthy comparison participants, in response to the empathy inductions hippocampal patients reported no increase in empathy ratings or prosocial behavior. The results provide preliminary evidence for a role for hippocampal declarative memory in empathy.
23521365	Many studies have shown that memory is enhanced when study sessions are spaced apart rather than massed. This spacing effect has been shown to have a lasting benefit to long-term memory when the study phase session follows the encoding session by 24 hours. Using a spacing paradigm we examined the impact of sleep and spacing gaps on long-term declarative memory for Swahili-English word pairs by including four spacing delay gaps (massed, 12 hours same-day, 12 hours overnight, and 24 hours). Results showed that a 12-hour spacing gap that includes sleep promotes long-term memory retention similar to the 24-hour gap. The findings support the importance of sleep to the long-term benefit of the spacing effect. 
23521165	Ethanol and 3, 4-Methylenedioxymethamphetamine (MDMA) are popular recreational drugs widely abused by adolescents that may induce neurotoxic processes associated with behavioural alterations. Adolescent CD1 mice were subjected to ethanol intake using the drinking in the dark (DID) procedure, acute MDMA or a combination. Considering that both drugs of abuse cause oxidative stress in the brain, protein oxidative damage in different brain areas was analysed 72 h after treatment using a proteomic approach. Damage to specific proteins in treated animals was significant in the hippocampus but not in the prefrontal cortex. The damaged hippocampus proteins were then identified by mass spectrometry, revealing their involvement in energy metabolism, structural function, axonal outgrowth and stability, and neurotransmitter release. Mice treated with MDMA displayed higher oxidative damage than ethanol-treated mice. To determine whether this oxidative damage was affecting hippocampus activity, declarative memory was evaluated at 72 h after treatment using the object recognition assay and the radial arm maze. Although acquisition in the radial arm maze was not impaired by ethanol intake, MDMA treatment impaired long-term memory in both tests. Therefore, oxidative damage to specific proteins observed under MDMA treatment affects important cellular function on the hippocampus that may contribute to declarative memory deficits.
23515168	Postoperative cognitive decline (POCD) is a frequent complication after cardiac surgeries. It remains unclear how relevant this decline in psychometric results is for daily life. The aim of the study was to assess cognitive failures, as seen by patients and close relatives, on a quantitative level.In addition to an extensive neuropsychological test battery, we interviewed 82 patients with a modified version of the self-assessment cognitive failure questionnaire (s-CFQ) and 62 close relatives (mostly spouses) with the CFQ-for-others version (f-CFQ) before and 3 months after aortic valve replacement. The questionnaires evaluate the frequency of failures in daily living related to memory, attention, action and perception.	POCD occurred in all tests that had been applied to assess declarative memory functions; the mean performance dropped from baseline in these tests (P-values ranging from 0.033 and <0.001). The s-CFQ did not differ between baseline and postoperative assessment [baseline: mean 37.60, standard deviation (SD) 14.38; post: mean 36.22, SD 12.29] (t(0.05, 76) = 1.17; P = 0.246). However, the assessment by others was worse in the f-CFQ after surgery (baseline: mean 8.02, SD 4.51; post: mean 9.58, SD 6.11) (t(0.05, 61) = 2.61; P = 0.012). All changes were observed in questions related to memory and attention failures only. Higher (worse) rates in f-CFQ change scores correlated with neuropsychological change scores, namely in pictorial memory (mistakes) (r = 0.35; P = 0.003) and word fluency (correct answers) (r = -0.29; P = 0.014). Additionally, those patients with worse f-CFQ change scores (>1 SD) from baseline had clearly worse outcomes in word fluency (t(0.05, 60) = 2.53; P = 0.007) and non-verbal learning (t(0.05, 60) = 2.66; P = 0.005). The effects remained significant when controlled for depression/anxiety scores.	The result demonstrates that cognitive side-effects could have a perceivable impact on daily living functions. However, slight deficits are more realized by others than by the patients themselves. Correlations between ratings by others and psychometric cognitive measures indicate that assessment by others is more reliable than self-assessment.	
23511251	The human serial reaction time task (SRTT) has widely been used to study the neural basis of implicit learning. It is well documented, in both human and animal studies, that striatal dopaminergic processes play a major role in this task. However, findings on the role of the hippocampus - which is mainly associated with declarative memory - in implicit learning and performance are less univocal. We used a SRTT to evaluate implicit learning and performance in rats with perforant pathway stimulation-induced hippocampal neuron loss; a clinically-relevant animal model of mesial temporal lobe epilepsy (MTLS-HS). As has been previously reported for the Sprague-Dawley strain, 8h of continuous stimulation in male Wistar rats reliably induced widespread neuron loss in areas CA3 and CA1 with a characteristic sparing of CA2 and the granule cells. Histological analysis revealed that hippocampal volume was reduced by an average of 44%. Despite this severe hippocampal injury, rats showed superior performance in our instrumental SRTT, namely shorter reaction times, and without a loss in accuracy, especially during the second half of our 16-days testing period. These results demonstrate that a hippocampal lesion can improve performance in a rat SRTT, which is probably due to enhanced instrumental performance. In line with our previous findings based on ibotenic-acid induced hippocampal lesion, these data support the hypothesis that loss or impairment of hippocampal function can enhance specific task performance, especially when it is dependent on procedural (striatum-dependent) mechanisms with minimal spatial requirements. As the animal model used here exhibits the defining characteristics of MTLE-HS, these findings may have implications for the study and management of patients with MTLE.
23477462	We investigated mental functions expected to remain impaired or not ain adulthood following childhood-onset brain lesions.Thirty unilaterally lesioned young adults were tested a decade after lesion onset with an effort-demanding complex executive function (EF) task as well as a task of incidental declarative retrospective episodic recognition memory (IRM). Thirty neurotypical participants were also tested.	The EF task was significantly impaired in the lesion group and significantly more so than the IRM task. Regarding the lesioned cases, performance on EF, but not IRM, was significantly positively correlated with long-term educational persistence (EP). Both EF and EP but not IRM were significantly positively correlated with the age of onset of the lesion. Severity of neurological impairment was unrelated to any variable.	Mental abilities acquired through early schooling remain impaired into adulthood when early schooling is disturbed, not everyday memory which does not depend on schooling.	
23460411	The classic view holds that the medial temporal lobes (MTL) are dedicated to declarative memory functioning. Recent evidence, however, suggests that perirhinal cortex (PrC), a structure within the anterior MTL, may also play a role in perceptual discriminations when representations of complex conjunctions of features, or of gestalt-characteristics of objects must be generated. Interestingly, neuroimaging and electrophysiological recordings in nonhuman primates have also revealed a face patch in the anterior collateral sulcus with preferential responses to face stimuli in various task contexts. In the present fMRI study, we investigated the representational demands that influence PrC involvement in different types of judgments on human faces. Holding stimulus complexity constant, we independently manipulated the nature of the task and the orientation of the stimuli presented (through face inversion). Aspects of right PrC showed increased responses in a forced-choice recognition-memory and a perceptual-oddity task, as compared to a feature-search task that was included to probe visual detection of an isolated face feature. Effects of stimulus orientation in right PrC were observed when the recognition-memory condition for upright faces was compared with all other experimental conditions, including recognition-memory for inverted faces-a result that can be related to past work on the role of PrC in object unitization. Notably, both effects in right PrC paralleled activity patterns in broader networks of regions that also included the right fusiform gyrus and the amygdala, regions frequently implicated in face processing in prior research. As such, the current findings do not support the view that reference to a prior study episode clearly distinguishes the role of PrC from that of more posterior ventral visual pathway regions. They add to a growing body of evidence suggesting that the functional role of specific MTL structures may be best understood in terms of the representations that are required by the task and the stimuli at hand.
23453674	Corticosteroid excess is associated with declarative memory impairment and hippocampal atrophy. These findings are clinically important because approximately 1% of the population receives prescription corticosteroids at any time, and major depressive disorder is associated with elevated cortisol levels and hippocampal atrophy. In animals, hippocampal changes with corticosteroids are blocked by phenytoin. The objective of the current study was to extend these preclinical findings to humans. We examined whether phenytoin attenuated the effects of hydrocortisone on declarative memory. Functional magnetic resonance imaging (fMRI) assessed task-related hippocampal activation.A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in 17 healthy adult volunteers. Participants received hydrocortisone (2.5 days), phenytoin (3.5 days), both medications together, or placebo, with 21-day washouts between conditions. Differences between treatments were estimated using a mixed-effects repeated measures analysis.	Fifteen participants had data from at least two treatment conditions and were used in the analysis. Basal cortisol levels negatively correlated with fMRI BOLD activation in the para-hippocampus with a similar trend observed in the hippocampus. Decrease in declarative memory with hydrocortisone was blocked with concomitant phenytoin administration. Relative to the placebo condition, a significant decrease in hippocampal BOLD activation was observed with hydrocortisone and phenytoin alone, and the two medications in combination. Declarative memory did not show significant correlations with hippocampal activation.	The modest sample size, which limited our statistical power, was a limitation.	Findings from this pilot study suggest phenytoin attenuated effects of corticosteroids memory in humans, but potentiated the reduction in hippocampal activation.	
23451218	Sleep has been shown to stabilize memory traces and to protect against competing interference in both the procedural and declarative memory domain. Here, we focused on an interference learning paradigm by testing patients with primary insomnia (N = 27) and healthy control subjects (N = 21). In two separate experimental nights with full polysomnography it was revealed that after morning interference procedural memory performance (using a finger tapping task) was not impaired in insomnia patients while declarative memory (word pair association) was decreased following interference. More specifically, we demonstrate robust associations of central sleep spindles (in N3) with motor memory susceptibility to interference as well as (cortically more widespread) fast spindle associations with declarative memory susceptibility. In general the results suggest that insufficient sleep quality does not necessarily show up in worse overnight consolidation in insomnia but may only become evident (in the declarative memory domain) when interference is imposed.
25379224	Over the last half century, neuropsychologists, cognitive psychologists and cognitive neuroscientists interested in human memory have accumulated evidence showing that there is not one general memory function but a variety of memory systems deserving distinct (but for an organism, complementary) functional entities. The first attempts to organize memory systems within a taxonomic construct are often traced back to the French philosopher Maine de Biran (1766-1824), who, in his book first published in 1803, distinguished mechanical memory, sensitive memory and representative memory, without, however, providing any experimental evidence in support of his view. It turns out, however, that what might be regarded as the first elaborated taxonomic proposal is 14 centuries older and is due to Augustine of Hippo (354-430), also named St Augustine, who, in Book 10 of his Confessions, by means of an introspective process that did not aim at organizing memory systems, nevertheless distinguished and commented on sensible memory, intellectual memory, memory of memories, memory of feelings and passion, and memory of forgetting. These memories were envisaged as different and complementary instances. In the current study, after a short biographical synopsis of St Augustine, we provide an outline of the philosopher's contribution, both in terms of questions and answers, and focus on how this contribution almost perfectly fits with several viewpoints of modern psychology and neuroscience of memory about human memory functions, including the notion that episodic autobiographical memory stores events of our personal history in their what, where and when dimensions, and from there enables our mental time travel. It is not at all meant that St Augustine's elaboration was the basis for the modern taxonomy, but just that the similarity is striking, and that the architecture of our current viewpoints about memory systems might have preexisted as an outstanding intuition in the philosopher's mind. 
23436341	Damage to anterior thalamic nuclei (ATN) is a well-known cause of diencephalic pathology that produces a range of cognitive deficits reminiscent of a hippocampal syndrome. Anatomical connections of the ATN also extend to cerebral areas that support affective cognition. Enriched environments promote recovery of declarative/relational memory after ATN lesions and are known to downregulate emotional behaviors. Hence, the performance of standard-housed and enriched ATN rats in a range of behavioral tasks engaging affective cognition was compared. ATN rats exhibited reduced anxiety responses in the elevated plus maze, increased activity and reduced corticosterone responses when exploring an open field, and delayed acquisition of a conditioned contextual fear response. ATN rats also exhibited reduced c-Fos and phosphorylated cAMP response element-binding protein (pCREB) immunoreactivity in the hippocampal formation and the amygdala after completion of the contextual fear test. Marked c-Fos hypoactivity and reduced pCREB levels were also evident in the granular retrosplenial cortex and, to a lesser extent, in the anterior cingulate cortex. Unlike standard-housed ATN rats, enriched ATN rats expressed virtually no fear of the conditioned context. These results show that the ATN regulate affective cognition and that damage to this region may produce markedly different behavioral effects as a function of environmental housing conditions.
23425593	This study tested the predictions of the procedural deficit hypothesis by investigating the relationship between sequential statistical learning and two aspects of lexical ability, lexical-phonological and lexical-semantic, in children with and without specific language impairment (SLI). Participants included forty children (ages 8;5-12;3), twenty children with SLI and twenty with typical development. Children completed Saffran's statistical word segmentation task, a lexical-phonological access task (gating task), and a word definition task. Poor statistical learners were also poor at managing lexical-phonological competition during the gating task. However, statistical learning was not a significant predictor of semantic richness in word definitions. The ability to track statistical sequential regularities may be important for learning the inherently sequential structure of lexical-phonological, but not as important for learning lexical-semantic knowledge. Consistent with the procedural/declarative memory distinction, the brain networks associated with the two types of lexical learning are likely to have different learning properties.
23421514	Accounts of task-set control generally assume that the current task's stimulus-response (S-R) rules must be elevated to a privileged state of activation. How are they represented in this state? In 3 task-cuing experiments, we tested the hypothesis that phonological working memory is used to represent S-R rules for task-set control by getting participants to switch between 2 sets of arbitrary S-R rules and manipulating the articulatory duration (Experiment 1) or phonological similarity (Experiments 2 and 3) of the names of the stimulus terms. The task cue specified which of 2 objects (Experiment 1) or consonants (Experiment 2) in a display to identify with a key press. In Experiment 3, participants switched between identifying an object/consonant and its color/visual texture. After practice, neither the duration nor the similarity of the stimulus terms had detectable effects on overall performance, task-switch cost, or its reduction with preparation. Only in the initial single-task training blocks was phonological similarity a significant handicap. Hence, beyond a very transient role, there is no evidence that (declarative) phonological working memory makes a functional contribution to representing S-R rules for task-set control, arguably because once learned, they are represented in nonlinguistic procedural working memory.
23418985	Animal experiments and studies in adults have shown that the neurotransmitter serotonin (5-HT) plays an important role in learning and memory processes. However, data on this relationship in young persons are scarce, and neurodietary research in this age group is limited compared with the extensive literature on adults. Here, we aimed to explore the effects of a diminished central nervous 5-HT synthesis, which is achieved by acute tryptophan depletion (ATD) Moja-De , on memory function in young males with attention deficit hyperactivity disorder (ADHD).Twenty-two male patients with ADHD (ages 9-15 years, mean 10.95 ± 1.17 years) received ATD, thus diminishing central nervous 5-HT synthesis, and a tryptophan-balanced amino acid load (BAL) in a randomized, double-blind, within-subject, crossover design study. Approximately 1.7 h after administration of ATD/BAL, verbal declarative memory was assessed using the 'Auditory Verbal-Learning-Test' (AVLT).	There were no significant effects of ATD administration on verbal declarative memory function.	In this study, changes in 5-HT neurotransmission were not associated with specific aspects of verbal declarative memory in young persons with ADHD. Future studies with healthy control groups that address effects of covarying attentional processes are warranted.	
23417137	Poor sleep is a common feature in autism even though patients themselves do not necessarily complain. The impact of poor sleep on daytime cognitive functioning in autism is not well-known and we therefore investigated whether sleep in autism correlates with daytime cognitive performance. A battery of non-verbal tasks was administered, in the morning after a second night of sleep in the laboratory, to 17 young adults with autism and normal intelligence, and 14 typically developed individuals matched for age and IQ; none of the participants complained about sleep problems. Two dimensions of attention (sustained and selective) and 4 types of memory (working, declarative, sensory-motor and cognitive procedural) were tested. Individuals with autism showed clear signs of poor sleep. Their performance differed from the controls in response speed but not in accuracy. Signs of poor sleep in the autism group were significantly correlated with either normal performance (selective attention and declarative memory) or performance inferior to that of the controls (sensory-motor and cognitive procedural memories). Both groups presented a significant negative correlation between slow-wave sleep (SWS) and learning a sensory-motor procedural memory task. Only control participants showed a positive association between SWS duration and number of figures recalled on the declarative memory task. Correlation patterns differed between groups when sleep spindles were considered: they were negatively associated with number of trials needed to learn the sensory-motor procedural memory task in autism and with reaction time and number of errors on selective attention in the controls. Correlation between rapid eye movements (REMs) in REM sleep and cognitive procedural memory was not significant. We conclude that some signs reflecting the presence of poor sleep in adults with high-functioning autism correlate with various aspects of motor output on non-verbal performance tasks. The question is raised whether poor sleep in non-complaining persons with autism should be treated.
23398120	Studies suggest that the consolidation of newly acquired memories and underlying long-term synaptic plasticity might represent a major function of sleep. In a combined repeated-measures and parallel-group sleep laboratory study (active waking versus sleep, passive waking versus sleep), we provide evidence that brief periods of daytime sleep (42.1 ± 8.9 min of non-rapid eye movement sleep) in healthy adolescents (16 years old, all female), compared with equal periods of waking, promote the consolidation of declarative memory (word-pairs) in participants with high power in the electroencephalographic sleep spindle (sigma) frequency range. This observation supports the notion that sleep-specific brain activity when reaching a critical dose, beyond a mere reduction of interference, promotes synaptic plasticity in a hippocampal-neocortical network that underlies the consolidation of declarative memory. 
23397036	Declarative memories of personal experiences are a key factor in defining oneself as an individual, which becomes particularly evident when this capability is impaired. Assessing the physiological mechanisms of human declarative memory is typically restricted to patients with specific lesions and requires invasive brain access or functional imaging. We investigated whether the pupil, an accessible physiological measure, can be utilized to probe memories for complex natural visual scenes. During memory encoding, scenes that were later remembered elicited a stronger pupil constriction compared to scenes that were later forgotten. Thus, pupil size predicts success or failure of memory formation. In contrast, novel scenes elicited stronger pupil constriction than familiar scenes during retrieval. When viewing previously memorized scenes, those that were forgotten (misjudged as novel) still elicited stronger pupil constrictions than those correctly judged as familiar. Furthermore, pupil constriction was influenced more strongly if images were judged with high confidence. Thus, we propose that pupil constriction can serve as a marker of novelty. Since stimulus novelty modulates the efficacy of memory formation, our pupil measurements during learning indicate that the later forgotten images were perceived as less novel than the later remembered pictures. Taken together, our data provide evidence that pupil constriction is a physiological correlate of a neural novelty signal during formation and retrieval of declarative memories for complex, natural scenes.
23376311	The functional relevance of septo-hippocampal cholinergic (SHC) degeneration to the degradation of hippocampus-dependent declarative memory (DM) in aging and Alzheimer's disease (AD) remains ill-defined. Specifically, selective SHC lesions often fail to induce overt memory impairments in animal models. In spite of apparent normal performance, however, neuronal activity within relevant brain structures might be altered by SHC disruption. We hypothesized that partial SHC degeneration may contribute to functional alterations within memory circuits occurring in aging before DM decline. In young adult mice, we studied the effects of behaviorally ineffective (saporin-induced) SHC lesions - similar in extent to that seen in aged animals - on activity patterns and functional connectivity between three main neural memory systems: the septo-hippocampal system, the striatum and the amygdala that sustain declarative, procedural and emotional memory, respectively. Animals were trained in a radial maze procedure dissociating the human equivalents of relational/DM and non-R/DM expressions in animals. Test-induced Fos activation pattern revealed that the partial SHC lesion significantly altered the brain's functional activities and connectivity (co-activation pattern) despite the absence of overt behavioral deficit. Specifically, hippocampal CA3 hyperactivity and abnormal septo-hippocampo-amygdalar inter-connectivity resemble those observed in aging and prodromal AD. Hence, SHC neurons critically coordinate hippocampal function in concert with extra-hippocampal structures in accordance with specific mnemonic demand. Although partial SHC degeneration is not sufficient to impact DM performance by itself, the connectivity change might predispose the emergence of subsequent DM loss when, due to additional age-related insults, the brain can no longer compensate the holistic imbalance caused by cholinergic loss.
23374327	Stress and cortisol are generally considered to impair declarative memory retrieval, although opposite results have also been reported. Dose-dependent effects and differences between genomic and non-genomic cortisol effects are possible reasons for these discrepancies. The aim of the current experiment was to assess the non-genomic effects of escalating doses of intravenous cortisol on cued recall of socially relevant information in humans. 40 participants (age range 20-30 years; 20 females) learned associations between male faces with a neutral facial expression and descriptions of either positive or negative social behaviors and were tested one week later in a cued recall paradigm. Escalating doses of cortisol (0, 3, 6, 12, 24 mg) were administered 8 min before testing according to a between-subjects design. An inverted U-shaped dose-response relationship between salivary cortisol levels and recall performance was observed, with moderate elevation of salivary cortisol resulting in the best recall performance. This is the first study in humans demonstrating that cortisol rapidly modulates declarative memory retrieval via a dose-dependent, non-genomic mechanism that follows an inverted U-shaped curve. Our result further emphasizes the importance of fast cortisol effects for human cognition.
25620901	Premutation carriers of the fragile X mental retardation gene (especially men) older than 50 may develop a neurodegenerative disease, the fragile X-associated tremor/ataxia syndrome (FXTAS). Carriers may present with varied cognitive impairments. Attention, working memory, declarative and procedural learning, information processing speed, and recall are among the cognitive domains affected. Executive dysfunction is a prominent deficit, which has been demonstrated mostly in men with FXTAS. In more advanced stages of FXTAS, both men and women may develop a mixed cortical-subcortical dementia, manifested by psychomotor slowing and deficits in attention, retrieval, recall, visuospatial skills, occasional apraxia, as well as overt personality changes. Studies have shown dementia rates as high as 37-42% in older men with FXTAS, although more research is needed to understand the prevalence and risk factors of dementia in women with FXTAS. Neuropsychiatric symptoms are common and reflect the dysfunction of underlying frontal-subcortical neural circuits, along with components of the cerebellar cognitive affective syndrome. These include labile or depressed mood, anxiety, disinhibition, impulsivity, and (rarely) psychotic symptoms. In this paper we review the information available to date regarding the prevalence and clinical picture of FXTAS dementia. Differential diagnosis may be difficult, given overlapping motor and non-motor signs with several other neurodegenerative diseases. Anecdotal response to cholinesterase inhibitors and memantine has been reported, while symptomatic treatments can address the neuropsychiatric manifestations of FXTAS dementia.
23359616	Dementia is a frequent and devastating complication in Parkinson's disease (PD). There is an intensive search for biomarkers that may predict the progression from normal cognition (PD-NC) to dementia (PDD) in PD. Mild cognitive impairment in PD (PD-MCI) seems to represent a transitional state between PD-NC and PDD. Few studies have explored the structural changes that differentiate PD-NC from PD-MCI and PDD patients.We aimed to analyze changes in cortical thickness on 3.0T Magnetic Resonance Imaging (MRI) across stages of cognitive decline in a prospective sample of PD-NC (n = 26), PD-MCI (n = 26) and PDD (n = 20) patients, compared to a group of healthy subjects (HC) (n = 18). Cortical thickness measurements were made using the automatic software Freesurfer.	In a sample of 72 PD patients, a pattern of linear and progressive cortical thinning was observed between cognitive groups in cortical areas functionally specialized in declarative memory (entorhinal cortex, anterior temporal pole), semantic knowledge (parahippocampus, fusiform gyrus), and visuoperceptive integration (banks of the superior temporal sulcus, lingual gyrus, cuneus and precuneus). Positive correlation was observed between confrontation naming and thinning in the fusiform gyrus, parahippocampal gyrus and anterior temporal pole; clock copy with thinning of the precuneus, parahippocampal and lingual gyrus; and delayed memory with thinning of the bilateral anteromedial temporal cortex.	The pattern of regional decreased cortical thickness that relates to cognitive deterioration is present in PD-MCI patients, involving areas that play a central role in the storage of prior experiences, integration of external perceptions, and semantic processing.	
23356248	The after-action review (AAR; also known as the after-event review or debriefing) is an approach to training based on a review of trainees' performance on recently completed tasks or performance events. Used by the military for decades, nonmilitary organizations' use of AARs has increased dramatically in recent years. Despite the prevalence of AARs, empirical research investigating their effectiveness has been limited. This study sought to investigate the comparative effectiveness of objective AARs (reviews based on an objective recording and playback of trainees' recent performance) and subjective AARs (reviews based on a subjective, memory-based recall of trainees' recent performance). One hundred eighty-eight individuals, participating in 47 4-person teams, were assigned to 1 of 3 AAR conditions and practiced and tested on a cognitively complex performance task. Although there were no significant differences between objective and subjective AAR teams across the 5 training outcomes, AAR teams had higher levels of team performance, team efficacy, openness of communication, and cohesion than did non-AAR teams but no differences in their levels of team declarative knowledge. Our results suggest that AARs are effective at enhancing training outcomes. Furthermore, AARs may not be dependent on objective reviews and therefore may be a viable training intervention when objective reviews are not feasible or possible.
23332680	Glucocorticoids (GCs) have repeatedly been shown to impair hippocampus-mediated, declarative memory retrieval and prefrontal cortex-based working memory in healthy subjects. However, recent experimental studies indicated that patients with major depressive disorder (MDD) lack these impairing effects. These missing effects have been suggested to result from dysfunctional brain GC receptors. The purpose of the present study was to investigate whether response inhibition, an executive function relying on the integrity of the prefrontal cortex, would be impaired after cortisol administration in patients with MDD. In a placebo-controlled, double blind crossover study, 50 inpatients with MDD and 54 healthy control participants conducted an emotional go/no-go task consisting of human face stimuli (fearful, happy, and neutral) after receiving a dose of 10 mg hydrocortisone and after placebo. GC administration had an enhancing effect on inhibitory performance in healthy control participants, indicated by faster responses, while no GC effect was revealed for the patients group. Moreover, patients showed an overall worse performance than healthy participants. In conclusion, this study further supports the hypothesis of impaired central glucocorticoid receptor function in MDD patients. Regarding the importance of inhibitory functioning for daily living, further studies are needed to examine the impact of glucocorticoids on response inhibition.
23320882	Deferred imitation (DI) is an established procedure for behavioral measurement of early declarative-like memories in infancy and previous work has indicated a link between this type of memory and brain potentials in infants. The present study compared infants' memory performance in this paradigm with electrophysiological indices of associative learning. Thirty children (M = 14.5 months) participated, of which 15 (8 boys) had acceptable event-related potentials (ERP) recordings that could be included in the final analysis. Deferred imitation was measured with an observation-only procedure using three actions and a 30 min delay. ERP was recorded with a high-density electrode net (128 electrodes) during associative learning. Change scores based on Nc, a middle latency component associated with attentional processes, predicted deferred imitation performance. Thus, associative learning measured with ERP predicts deferred imitation using a strict observation only design in 14 to 15 month old children.
23319628	In this study, we used model-based functional MRI (fMRI) to locate two functions of the fronto-parietal network: declarative memory retrievals and updating of working memory. Because regions in the fronto-parietal network are by definition coherently active, locating functions within this network is difficult. To overcome this problem, we applied model-based fMRI, an analysis method that uses predictions of a computational model to inform the analysis. We applied model-based fMRI to five previously published datasets with associated computational cognitive models, and subsequently integrated the results in a meta-analysis. The meta-analysis showed that declarative memory retrievals correlated with activity in the inferior frontal gyrus and the anterior cingulate, whereas updating of working memory corresponded to activation in the inferior parietal lobule, as well as to activation around the inferior frontal gyrus and the anterior cingulate.
23317523	Stress effects on memory are well-known. Most studies, however, focused on the impact of stress on hippocampus-dependent 'declarative' memory processes. Less is known about whether stress influences also striatum-based memory processes, such as stimulus-response (S-R) memory. First evidence from rodent experiments shows that glucocorticoid stress hormones may enhance the consolidation of S-R memories. Whether stress affects also S-R memory retrieval remains largely elusive. Therefore, we tested in the present experiment in humans the effect of stress on the retrieval of S-R memories. Healthy men and women were trained to locate three objects in an S-R version of a virtual eight-arm radial maze. One week later, participants underwent a stressor or a control condition before their memory of the S-R task was tested. Our results showed that participants (n=43) who were exposed to the stressor before retention testing made significantly more errors in this test trial, suggesting that stress impaired S-R memory retrieval. Moreover, high cortisol concentrations were associated with reduced S-R memory. These findings indicate that stress may affect memory retrieval processes in humans beyond hippocampal 'declarative' memory.
23301831	As well as consolidating memory, sleep has been proposed to serve a second important function for memory, i.e. to free capacities for the learning of new information during succeeding wakefulness. The slow wave activity (SWA) that is a hallmark of slow wave sleep could be involved in both functions. Here, we aimed to demonstrate a causative role for SWA in enhancing the capacity for encoding of information during subsequent wakefulness, using transcranial slow oscillation stimulation (tSOS) oscillating at 0.75 Hz to induce SWA in healthy humans during an afternoon nap. Encoding following the nap was tested for hippocampus-dependent declarative materials (pictures, word pairs, and word lists) and procedural skills (finger sequence tapping). As compared with a sham stimulation control condition, tSOS during the nap enhanced SWA and significantly improved subsequent encoding on all three declarative tasks (picture recognition, cued recall of word pairs, and free recall of word lists), whereas procedural finger sequence tapping skill was not affected. Our results indicate that sleep SWA enhances the capacity for encoding of declarative materials, possibly by down-scaling hippocampal synaptic networks that were potentiated towards saturation during the preceding period of wakefulness.
23290458	Consistent evidence nowadays indicates that sleep protects declarative memory from lexical interference. However, little is known about its effect against emotional interference. In a within-subject counterbalanced design, participants learned a list of word pairs after a mood induction procedure (MIP), then slept or stayed awake during the post-learning night. After two recovery nights, half of the list was recalled after a similar mood induction than at the encoding session (no interference condition) and the other half after a different mood induction (interference condition). Amongst participants for whom the MIP was effective, an emotional interference effect appeared only in the sleep-deprived condition, with a lower recall of word pairs subjected to contextual interference than of the other pairs. These findings support the hypothesis of a decoupling between memories and their "affective blanket" during post-learning sleep, protecting recent memories against emotional contextual interference. 
23276689	The article investigates the mechanisms of selecting and updating representations in declarative and procedural working memory (WM). Declarative WM holds the objects of thought available, whereas procedural WM holds representations of what to do with these objects. Both systems consist of three embedded components: activated long-term memory, a central capacity-limited component for building structures through temporary bindings, and a single-element focus of attention. Five experiments test the hypothesis of analogous mechanisms in declarative and procedural WM, investigating repetition effects across trials for individual representations (objects and responses) and for sets (memory sets and task sets), as well as set-congruency effects. Evidence for analogous processes was obtained from three phenomena: (1) Costs of task switching and of list switching are reduced with longer preparation interval. (2) The effects of task congruency and of list congruency are undiminished with longer preparation interval. (3) Response repetition interacts with task repetition in procedural WM; here we show an analogous interaction of list repetition with item repetition in declarative WM. All three patterns were reproduced by a connectionist model implementing the assumed selection and updating mechanisms. The model consists of two modules, an item-selection module selecting individual items from a memory set, or responses from a task set, and a set-selection module for selecting memory sets or task sets. The model codes the matrix of binding weights in the item-selection module as a pattern of activation in the set-selection module, thereby providing a mechanism for building chunks in LTM, and for unpacking them as structures into working memory.
25484909	Environmental cues often remind us of earlier experiences by triggering the reactivation of memories of events past. Recent evidence suggests that memory reactivation can be observed using functional MRI and that distributed pattern analyses can even provide evidence of reactivation on individual trials. The ability to measure memory reactivation offers unique and powerful leverage on theoretical issues of long-standing interest in cognitive psychology, providing a means to address questions that have proven difficult to answer with behavioral data alone. In this article, we consider three instances. First, reactivation measures can indicate whether memory-based inferences (i.e., generalization) arise through the encoding of integrated cross-event representations or through the flexible expression of separable event memories. Second, online measures of memory reactivation may inform theories of forgetting by providing information about when competing memories are reactivated during competitive retrieval situations. Finally, neural reactivation may provide a window onto the role of replay in memory consolidation. The ability to track memory reactivation, including at the individual trial level, provides unique leverage that is not afforded by behavioral measures and thus promises to shed light on such varied topics as generalization, integration, forgetting, and consolidation. 
25346870	The hallmark of Alzheimer's disease (AD) is declarative memory loss, but deficits in semantic fluency are also observed. We assessed how semantic fluency relates to cortical atrophy to identify specific regions that play a role in the loss of access to semantic information. Whole-brain structural magnetic resonance imaging (MRI) data were analyzed from 9 Normal Control (NC)(M=76.7, SD=5.6), 40 Mild Cognitive Impairment (MCI) (M=74.4, SD=8.6), and 10 probable AD (M=72.4, SD=8.0) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). They all were administered the Category Fluency (CF) animals and vegetables tests. Poorer semantic fluency was associated with bilateral cortical atrophy of the inferior parietal lobule (Brodman areas (BA) 39 and 40) and BA 6, 8, and 9 in the frontal lobe, as well as BA 22 in the temporal lobe. More diffuse frontal associations were seen in the left hemisphere involving BA 9, 10, 32, 44, 45, and 46. Additional cortical atrophy was seen in the temporoparietal (BA 37) and the right parastriate (BA 19, 18) cortices. Associations were more diffuse for performance on vegetable fluency than animal fluency. The permutation-corrected map-wise significance for CF animals was pcorrected=0.01 for the left hemisphere, and pcorrected=0.06 for the right hemisphere. The permutation-corrected map-wise significance for CF vegetables was pcorrected=0.009 for the left hemisphere, and pcorrected=0.03 for the right hemisphere. These results demonstrate the profound effect of cortical atrophy on semantic fluency. Specifically, tapping into semantic knowledge involves the frontal lobe in addition to the language cortices of the temporoparietal region.
24600607	A wealth of recent studies support a function of sleep on memory and cognitive processing. At a physiological level, sleep supports memory in a number of ways including neural replay and enhanced plasticity in the context of reduced ongoing input. This paper presents behavioral evidence for sleep's role in selective remembering and forgetting of declarative memories, in generalization of these memories, and in motor skill consolidation. Recent physiological data reviewed suggests how these behavioral changes might be supported by sleep. Importantly, in reviewing these findings, an integrated view of how distinct sleep stages uniquely contribute to memory processing emerges. This model will be useful in developing future behavioral and physiological studies to test predictions that emerge.
23269366	The importance of the hippocampus for declarative memory processes is firmly established. Nevertheless, the issue of a correlation between declarative memory performance and hippocampal volume in healthy subjects still remains controversial. The aim of the present study was to investigate this relationship in more detail. For this purpose, 50 healthy young male participants performed the California Verbal Learning Test. Hippocampal volume was assessed by manual segmentation of high-resolution 3D magnetic resonance images. We found a significant positive correlation between putatively hippocampus-dependent memory measures like short-delay retention, long-delay retention and discriminability and percent hippocampal volume. No significant correlation with measures related to executive processes was found. In addition, percent amygdala volume was not related to any of these measures. Our data advance previous findings reported in studies of brain-damaged individuals in a large and homogeneous young healthy sample and are important for theories on the neural basis of episodic memory. 
23263887	When memory is tested after a delay, performance is typically better if the retention interval includes sleep. However, it is unclear what accounts for this well-established effect. It is possible that sleep enhances the retrieval of information, but it is also possible that sleep protects against memory loss that normally occurs during waking activity. We developed a new research approach to investigate these possibilities. Participants learned a list of paired-associate items and were tested on the items after a 12-h interval that included waking or sleep. We analyzed the number of items gained versus the number of items lost across time. The sleep condition showed more items gained and fewer items lost than did the wake condition. Furthermore, the difference between the conditions (favoring sleep) in lost items was greater than the difference in gain, suggesting that loss prevention may primarily account for the effect of sleep on declarative memory consolidation. This finding may serve as an empirical constraint on theories of memory consolidation.
23253895	Stress and associated alterations in hypothalamic-pituitary-adrenal (HPA) function have deleterious influence on the development of multiple mental and physical health problems. Prior research has aimed to identify individuals most at risk for the development of these stress-related maladies by examining factors that may contribute to inter-individual differences in HPA responses to acute stress. The objectives of this study were to investigate, in adolescents, (1) whether differences in neurocognitive abilities influenced cortisol reactivity to an acute stressor, (2) whether internalizing psychiatric disorders influenced this relationship, and (3) whether acute cognitive stress-appraisal mechanisms mediated an association between neurocognitive function and cortisol reactivity. Subjects were 70 adolescents from a community sample who underwent standardized neurocognitive assessments of IQ, achievement, and declarative memory measures at mean age 14 and whose physiological and behavioral responses to a standardized psychosocial stress paradigm (Trier Social Stress Test, TSST) were assessed at mean age 18. Results showed that, among all adolescents, lower nonverbal memory performance predicted lower cortisol reactivity. In addition, internalizing disorders interacted with verbal memory such that the association with cortisol reactivity was strongest for adolescents with internalizing disorders. Finally, lower secondary cognitive appraisal of coping in anticipation of the TSST independently predicted lower cortisol reactivity but did not mediate the neurocognitive-cortisol relationship. Findings suggest that declarative memory may contribute to inter-individual differences in acute cortisol reactivity in adolescents, internalizing disorders may influence this relationship, and cognitive stress appraisal also predicts cortisol reactivity. Developmental, research, and clinical implications are discussed.
23248614	The human electroencephalogram (EEG) during non-rapid eye movement sleep (NREM) is characterized mainly by high-amplitude (>75 μV), slow-frequency (<4 Hz) waves (slow waves), and sleep spindles (∼11-15 Hz; >0.25 s). These NREM oscillations play a crucial role in brain plasticity, and importantly, NREM sleep oscillations change considerably with aging. This review discusses the association between NREM sleep oscillations and cerebral plasticity as well as the functional impact of age-related changes on NREM sleep oscillations. We propose that age-related reduction in sleep-dependent memory consolidation may be due in part to changes in NREM sleep oscillations.
23246326	While the consolidation of declarative memory is supported by slow wave sleep (SWS) in healthy subjects, it has been shown to be associated with rapid eye movement (REM) sleep in patients with insomnia. Sleep during a subject's first night in an unfamiliar environment is often disturbed, and this so-called first-night effect (FNE) has often been used as a model of transient insomnia. Additionally, sleeping for the first time in an unfamiliar environment can lead to increased cortisol secretion, and declarative memory consolidation likely depends on low cortisol levels, especially during the early part of the night. Accounting for intersubject variability in the FNE, we examined the relationship between sleep stages, cortisol secretion and declarative memory performance in 27 healthy young men. Declarative memory performance improved significantly after sleep. Whereas memory performance during the learning session and retrieval testing was strongly associated with cortisol secretion, the overnight gain was not. Post hoc analyses indicated that the overnight gain appears to be modulated by the extent of the FNE: a significant overnight improvement in memory performance was found only in subjects with a weak FNE (n=12). In these subjects, no association was found between any sleep stage and the improvement observed in their memory performance. In subjects with a strong FNE (n=12), however, the overnight change in memory performance was associated with the proportion of REM sleep and the total number of REMs. Disturbed sleep in an unfamiliar environment therefore appears to affect the memory consolidation process.
23233411	It has been suggested that complex visual discrimination deficits in patients with medial temporal lobe (MTL) damage may be explained by damage or dysfunction beyond the MTL. We examined the resting functional networks and white matter connectivity of two amnesic patients who have consistently demonstrated discrimination impairments for complex object and/or spatial stimuli across a number of studies. Although exploratory analyses revealed some significant differences in comparison with neurologically healthy controls (more specifically in the patient with a larger MTL lesion), there were no obvious findings involving posterior occipital or posterior temporal regions, which can account entirely for their discrimination deficits. These findings converge with previous work to support the suggestion that the MTL does not subserve long-term declarative memory exclusively.
23226554	Sleep facilitates off-line consolidation of memories, as shown for learning of motor skills in the absence of concomitant distractors. We often perform complex tasks focusing our attention mostly on one single part of them. However, we are equally able to skillfully perform other concurrent tasks. One may even improve performance on disregarded parts of complex tasks, which were learned implicitly. In the present study we investigated the role of sleep in the off-line consolidation of procedural skills when attention is diverted from the procedural task because of interference from a concurrent task.We used a dual-task paradigm containing (i) procedural serial reaction time task (SRTT), which was labeled as subordinate and unimportant and (ii) declarative word-pair association task (WPAT), performed concomitantly. The WPAT served as a masked distractor to SRTT and was strongly reinforced by the instructions. One experimental and three control groups were tested. The experimental group was re-tested after two nights of sleep (sleep group, SG). The first control group had sleep deprivation on the first post-learning night (nighttime-awake group, NA), the second control group was tested in the morning and then re-tested after 12-hours (daytime-awake group, DA); the third one had the same assignments as DA but with a subsequent, instead of a concomitant, WPAT (daytime-awake-subsequent-WPAT group, DAs). We found SRTT performance gains in SG but not in NA and DA groups. Furthermore, SG reached similar learning gains in SRTT as the DAs group, which gained in SRTT performance because of post-training interference from the declarative task.	The results demonstrate that sleep allows off-line consolidation, which is resistant to deteriorating effects of a reinforced distractor on the implicit procedural learning and allowing for gains which are consistent with those produced when inhibited declarative memories of SRTT do not compete with procedural ones.	
23219882	Hypoxia-ischemia (HI) is the main cause of mortality in the perinatal period and morbidity, in survivors, which is characterized by neurological disabilities. The immature brain is highly susceptible to hypoxic-ischemic insult and is responsive to environmental stimuli, such as environmental enrichment (EE). Previous results indicate that EE recovered memory deficits in adult rats without reversing hippocampal atrophy related to HI. The aim of this study was to investigate behavioral performance in the open field and rota-rod apparatuses, in object recognition and inhibitory avoidance tasks, as well as dendritic spine density in the hippocampus, in rats undergoing HI and exposed to EE. Seven-day old male rats were submitted to the HI procedure and divided into 4 groups: control maintained in standard environment (CTSE), controls submitted to EE (CTEE), HI in standard environment (HISE) and HI in EE (HIEE). Behavioral and morphological parameters were evaluated 9 weeks after the environmental stimulation. Results indicate impairment in the object recognition task after HI that was recovered by enrichment; however the aversive memory impairment in the inhibitory avoidance task shown by hypoxic-ischemic rats was independent of the environment condition. Hypoxic-ischemic groups showed more crossing responses during the first minute in the open field, when compared to controls, but no differences were found between experimental groups in the rota-rod test. Dendritic spine density in the CA1 subfield of the right hippocampus (ipsilateral to the artery occlusion) was decreased after the HI insult, and increased in enriched controls; interestingly enriched HI rats did not differ from CTSE. In conclusion, EE was effective in recovering declarative memory impairment in object recognition and preserved hippocampal dendritic spine density loss after neonatal HI injury.
26572272	Some studies have suggested that potentiated remembrance of negative events on people with depressive disorders seems to be an important factor in the etiology, course and maintenance of depression.Evaluate the emotional memory in people with and without depressive symptomatology by means of an audio-visual test.	73 university students were evaluated, male and female, between 18 and 40 years old, distributed in two groups: with depressive symptomatology (32) and without depressive symptomatology (40), using the Scale from the Center of Epidemiologic Studies for Depression (CES-D, English Abbreviation) and a cutting point of 20.	There were not meaningful differences between free and voluntary recalls, with and without depressive symptomatology, in spite of the fact that both groups had granted a higher emotional value to the audio-visual test and that they had associated it with emotional sadness.	People with depressive symptomatology did not exhibit the effect of mnemonic potentiation generally associated to the content of the emotional version of the test; therefore, the hypothesis of emotional consistency was not validated.	
23185361	EEG sleep spindle activity (SpA) during non-rapid eye movement (NREM) sleep has been reported to be associated with measures of intelligence and overnight performance improvements. The reticular nucleus of the thalamus is generating sleep spindles in interaction with thalamocortical connections. The same system enables efficient encoding and processing during wakefulness. Thus, we examined if the triangular relationship between SpA, measures of intelligence and declarative learning reflect the efficiency of the thalamocortical system. As expected, SpA was associated with general cognitive ability, e.g. information processing speed. SpA was also associated with learning efficiency, however, not with overnight performance improvement in a declarative memory task. SpA might therefore reflect the efficiency of the thalamocortical network and can be seen as a marker for learning during encoding in wakefulness, i.e. learning efficiency.
23183712	Dopamine (DA) plays an essential role in the enablement of cognition. It adds color to experience-dependent information storage, conferring salience to the memories that result. At the synaptic level, experience-dependent information storage is enabled by synaptic plasticity, and given its importance for memory formation, it is not surprising that DA comprises a key neuromodulator in the enablement of synaptic plasticity, and particularly of plasticity that persists for longer periods of time: Analogous to long-term memory. The hippocampus, that is a critical structure for the synaptic processing of semantic, episodic, spatial, and declarative memories, is specifically affected by DA, with the D1/D5 receptor proving crucial for hippocampus-dependent memory. Furthermore, D1/D5 receptors are pivotal in conferring the properties of novelty and reward to information being processed by the hippocampus. They also facilitate the expression of persistent forms of synaptic plasticity, and given reports that both long-term potentiation and long-term depression encode different aspects of spatial representations, this suggests that D1/D5 receptors can drive the nature and qualitative content of stored information in the hippocampus. In light of these observations, we propose that D1/D5 receptors gate hippocampal long-term plasticity and memory and are pivotal in conferring the properties of novelty and reward to information being processed by the hippocampus. 
23171911	Stress and cortisol administration are known to have impairing effects on memory retrieval in healthy humans. These effects are reported to be altered in patients with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) but they have not yet been investigated in borderline personality disorder (BPD).In a placebo-controlled cross-over study, 71 women with BPD and 40 healthy controls received either placebo or 10 mg of hydrocortisone orally before undertaking a declarative memory retrieval task (word list learning) and an autobiographical memory test (AMT). A working memory test was also applied.	Overall, opposing effects of cortisol on memory were observed when comparing patients with controls. In controls, cortisol had impairing effects on memory retrieval whereas in BPD patients cortisol had enhancing effects on memory retrieval of words, autobiographical memory and working memory. These effects were most pronounced for specificity of autobiographical memory retrieval. Patients with BPD alone and those with co-morbid PTSD showed this effect. We also found that co-morbid MDD influenced the cortisol effects: in this subgroup (BPD + MDD) the effects of cortisol on memory were absent.	The present results demonstrate beneficial effects of acute cortisol elevations on hippocampal-mediated memory processes in BPD. The absence of these effects in patients with co-morbid MDD suggests that these patients differ from other BPD patients in terms of their sensitivity to glucocorticoids (GCs).	
23149036	Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.
23145159	Sleep benefits veridical memories, resulting in superior recall relative to off-line intervals spent awake. Sleep also increases false memory recall in the Deese-Roediger-McDermott (DRM) paradigm. Given the suggestion that emotional veridical memories are prioritized for consolidation over sleep, here we examined whether emotion modulates sleep's effect on false memory formation. Participants listened to semantically related word lists lacking a critical lure representing each list's "gist." Free recall was tested after 12 hours containing sleep or wake. The Sleep group recalled more studied words than the Wake group but only for emotionally neutral lists. False memories of both negative and neutral critical lures were greater following sleep relative to wake. Morning and Evening control groups (20-minute delay) did not differ ruling out circadian accounts for these differences. These results support the adaptive function of sleep in both promoting the consolidation of veridical declarative memories and in extracting unifying aspects from memory details.
23142253	In laboratory rodents, procedural and declarative-like memory processes are often considered operating in dual, sometimes even competing with each other. There is evidence that the initial approach of a repetitive task first engages a hippocampus-dependent declarative-like memory system acquiring knowledge. Over repetition, there is a gradual shift towards a striatum-dependent response memory system. In the current experiment, Long-Evans male rats with bilateral, fiber-sparing ibotenic acid-induced lesions of the dorsolateral striatum or the dorsal hippocampus were trained in an olfactory associative task requiring the acquisition of both a procedural and a declarative-like memory. Rats with dorsolateral striatum lesions, and thus an intact hippocampus, were impaired on both sub-categories of memory performance. Rats with dorsal hippocampal lesions exhibited a substantial deficit in learning the declarative-like cue-reward associations, while the acquisition of the procedural memory component of the task was not affected. These data suggest that the dorsolateral striatum is required to acquire the task rule while the dorsal hippocampus is required to acquire the association between a given stimulus and its associated outcome. The finding is that the dorsolateral striatum and the dorsal hippocampus most probably contribute to successful learning of cue-reward associations in a sequential (from procedural to declarative-like memory) order using this olfactory associative learning task.
23137702	A new and weak memory trace undergoes consolidation to gain resistance against interfering stimuli. When an encoded memory is recalled, it becomes labile and another round of consolidation, or reconsolidation, is required to restore its stability. Transcranial direct current stimulation (tDCS) is a non-invasive method of altering cortical excitability. The aim of this study was to examine the effects of tDCS on the reconsolidation of long-term verbal memory. Participants (n = 15) memorized words in the encoding session, then reactivated the memory of the words 3 h later using an old-new recognition task under anodal, cathodal and sham stimulation to the left dorsolateral prefrontal cortex (DLPFC). Finally, after another 5 h, they performed another round of the old-new recognition task and rated their confidence. Anodal tDCS during the second session resulted in significantly more words recognized in the third session as compared to cathodal and sham stimulation. Cathodal tDCS did not affect the recognition performance compared to sham stimulation. These results cannot be attributed to differences in response times and confidence ratings, as they were comparable in all conditions. In order to study whether the activation of a memory was crucial for the enhancing effects of anodal tDCS, a group of controls (n = 15) did not perform the recognition task in the second session but still underwent stimulation. Contrary to the main group, anodal stimulation did not enhance the memory performance for the control group. This result suggests that anodal tDCS over the left DLPFC can enhance the reconsolidation of long-term memory only when the memory has been reactivated. 
23137697	In Huntington's disease (HD) cognitive deficits co-exist with motor impairments, both contributing to the overall disease symptomology. Despite short-term and working memory impairments, learning and other non-motoric behavioral deficits arising from the damage to frontostriatal loop being common in HD patients, most of the experimental work with transgenic animals focuses on motor symptoms. The transgenic rat model (tgHD) recapitulates many hallmark HD-like symptoms, such as huntingtin aggregates, cellular loss and dysfunction, and motor, and some cognitive deficits. In the current study we tested tgHD rats in two different cognitive, water maze competition paradigms to learn more about the impact of the transgene on learning and memory processing using hippocampal- and striatal-based memory systems. The tgHD rats had early and robust cognitive deficits in learning and memory function in both paradigms. Specifically, the transgenic animals were impaired in task acquisition and committed more procedural errors with the strongest phenotype amongst the homozygote tgHD. Although the transgenic animals were capable of using both procedural and declarative memory, their response patterns were distinct from wild-type animals. Wide spread huntingtin aggregates were observed at 13 months, but neither PET nor autoradiography indicated neuronal loss or dysfunction in striatal dopamine receptor population. In summary, the homozygote tgHD showed a robust learning and memory impairment prior to any clear motor deficits, or striatal dysfunction. However, the data were not conclusive regarding how the memory systems were compromised and the precise nature and underlying mechanism of the cognitive deficit in the tgHD model requires further investigation.
23133638	Several experiments have demonstrated an intimate relationship between hippocampal theta rhythm (4-12 Hz) and memory. Lesioning the medial septum or fimbria-fornix, a fiber track connecting the hippocampus and the medial septum, abolishes the theta rhythm and results in a severe impairment in declarative memory. To assess whether there is a causal relationship between hippocampal theta and memory formation we investigated whether restoration of hippocampal theta by electrical stimulation during the encoding phase also restores fimbria-fornix lesion induced memory deficit in rats in the fear conditioning paradigm. Male Wistar rats underwent sham or fimbria-fornix lesion operation. Stimulation electrodes were implanted in the ventral hippocampal commissure and recording electrodes in the septal hippocampus. Artificial theta stimulation of 8 Hz was delivered during 3-min free exploration of the test cage in half of the rats before aversive conditioning with three foot shocks during 2 min. Memory was assessed by total freezing time in the same environment 24 h and 28 h after fear conditioning, and in an intervening test session in a different context. As expected, fimbria-fornix lesion impaired fear memory and dramatically attenuated hippocampal theta power. Artificial theta stimulation produced continuous theta oscillations that were almost similar to endogenous theta rhythm in amplitude and frequency. However, contrary to our predictions, artificial theta stimulation impaired conditioned fear response in both sham and fimbria-fornix lesioned animals. These data suggest that restoration of theta oscillation per se is not sufficient to support memory encoding after fimbria-fornix lesion and that universal theta oscillation in the hippocampus with a fixed frequency may actually impair memory.
23103616	Retroactive interference from a declarative memory can prevent the consolidation of motor skill memories over wakefulness, but not over a night of sleep. Recently, motor imagery (MI) learning has been showed to allow for a stronger resistance against procedural interference rather than physical practice, but whether declarative interference might impact sleep-dependent consolidation process of an explicit finger tapping task learned with MI remains unknown. To address this issue, 57 subjects mentally rehearsed an explicit finger tapping sequence, and half of them were then requested to practice an interferential declarative task. All participants were re-tested on the initial procedural task either after a night of sleep or a similar daytime interval. The main findings provided evidence that declarative interference affected MI consolidation both over the night- and wakefulness intervals. These results extend our previous findings by underlying that declarative interference might impact more strongly explicit MI practice than physical practice, hence suggesting that MI might rely on declarative memory rather than exclusively on procedural memory system. The relationship between declarative and procedural memories during MI practice, as well as during off-line consolidation, is discussed.
23088427	Previous studies have demonstrated that stress or glucocorticoids impair the retrieval of spatial memory in rodents and declarative memory in humans. However, the effects on memory retrieval of stress introduced a long time after learning have not been well studied. We investigated whether a mild, extrinsic stressor (1-s 0.1 or 0.3 mA foot shock) would reactivate low baseline retrieval of an aversive memory [the plus-maze discriminative avoidance task (PM-DAT)] and if it would be modulated by glucocorticoids. In Experiment 1, male Swiss mice received pre-test foot shock (n = 10 mice/group) 7 days after training and just before testing. A time-retrieval curve for low baseline retrieval for the subsequent experiments was also determined (Experiment 2, n = 10 mice/group). We investigated if pre-test foot shock could modify corticosterone release (Experiment 3, n = 8-9 mice/group) and reinstate retrieval in the PM-DAT (Experiment 4, n = 15 mice/group). The effects of metyrapone (100 mg/kg) on retrieval reinstatement (Experiment 5, n = 15 mice/group) and serum corticosterone enhancement (Experiments 6, n = 7-9 mice/group) induced by foot shock were analyzed. Finally, the effects of foot shock itself on PM-DAT exploration were verified (Experiment 7, n = 10 mice/group). We demonstrated here that foot shock reinstated the retrieval of a low baseline, discriminative avoidance task 30 (but not 7) days after training. This facilitative effect was not dependent on corticosterone secretion because metyrapone abolished the enhancement of corticosterone concentration but did not reverse the stress-induced reinstatement of retrieval.
23078276	This study examined the contribution of verbal and visual memory to performance on the Family Pictures subtest of the Children's Memory Scale. This subtest purports to assess declarative memory functioning in the visual/nonverbal domain. A total of 115 nine-year-old children participated in this study. Fifty-eight had specific language impairment (SLI), whilst the remaining 57 were typically developing (TD), with no history of language difficulties. Results showed that the children with SLI, who had intact declarative memory for visual but not verbal information, obtained significantly lower scores on the Family Pictures subtest when compared to the TD group. Regression analyses revealed that across the entire sample, individual differences on the Family Pictures subtest was best predicted by a measure of verbal working memory. These results question whether the Family Pictures subtest can be considered a measure of visual memory in pediatric populations. These results have implications for the interpretation of scores on this subtest regarding the nature of the types of neurocognitive difficulties children may exhibit. 
23073721	Offline verbalization about a new motor experience is often assumed to positively influence subsequent performance. Here, we evaluated this presumed positive influence and whether it originates from declarative or from procedural knowledge using the explicit/implicit motor-learning paradigm. To this end, 80 nongolfers learned to perform a golf-putting task with high error rates (i.e., explicit motor learning), and thus relied on declarative knowledge, or low error rates (i.e., implicit motor learning), and thus relied on procedural knowledge. Afterward, they either put their memories of the previous motor experience into words or completed an irrelevant verbal task. Finally, they performed the putting task again. Verbalization did not improve novice motor performance: Putting was impaired, overall, and especially so for high-error learners. We conclude that declarative knowledge is altered by verbalization, whereas procedural knowledge is not.
23072834	Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment. To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects.
23066083	Every day people make new choices between alternatives that they have never directly experienced. Yet, such decisions are often made rapidly and confidently. Here, we show that the hippocampus, traditionally known for its role in building long-term declarative memories, enables the spread of value across memories, thereby guiding decisions between new choice options. Using functional brain imaging in humans, we discovered that giving people monetary rewards led to activation of a preestablished network of memories, spreading the positive value of reward to nonrewarded items stored in memory. Later, people were biased to choose these nonrewarded items. This decision bias was predicted by activity in the hippocampus, reactivation of associated memories, and connectivity between memory and reward regions in the brain. These findings explain how choices among new alternatives emerge automatically from the associative mechanisms by which the brain builds memories. Further, our findings demonstrate a previously unknown role for the hippocampus in value-based decisions.
23040159	Declarative memory is usually described as consisting of two systems: semantic and episodic memory. Between these two poles, however, may lie a third entity: personal semantics (PS). PS concerns knowledge of one's past. Although typically assumed to be an aspect of semantic memory, it is essentially absent from existing models of knowledge. Furthermore, like episodic memory (EM), PS is idiosyncratically personal (i.e., not culturally-shared). We show that, depending on how it is operationalized, the neural correlates of PS can look more similar to semantic memory, more similar to EM, or dissimilar to both. We consider three different perspectives to better integrate PS into existing models of declarative memory and suggest experimental strategies for disentangling PS from semantic and episodic memory.
23036073	The ability to play a musical instrument represents a unique procedural skill that can be remarkably resilient to disruptions in declarative memory. For example, musicians with severe anterograde amnesia have demonstrated preserved ability to play musical instruments. However, the question of whether amnesic musicians can learn how to play new musical material despite severe memory impairment has not been thoroughly investigated. We capitalized on a rare opportunity to address this question. Patient S.Z., an amateur musician (tenor saxophone), has extensive bilateral damage to his medial temporal lobes following herpes simplex encephalitis, resulting in a severe anterograde amnesia. We tested S.Z.'s capacity to learn new unfamiliar songs by sight-reading following three months of biweekly practices. Performances were recorded and were then evaluated by a professional saxophonist. S.Z. demonstrated significant improvement in his ability to read and play new music, despite his inability to recognize any of the songs at a declarative level. The results suggest that it is possible to learn certain aspects of new music without the assistance of declarative memory.
23034551	Dementia causes semantic and episodic memory impairments that limit patients' activities of daily living (ADL) and increase caregiver burden. Spaced retrieval training uses repetitive retrieval to strengthen cognitive and motor skills intuitively in mild / moderate dementia patients who retain preserved implicit / non-declarative memory. This article describes and discusses the operative mechanism, influencing variables, and practical applications of spaced retrieval training. We hope this article increases professional understanding and application of this training approach to improve dementia patient ADL and improve quality of life for both caregivers and patients.
23018127	Development of dopamine (DA) D(1) receptor agonists is a priority to improve cognitive impairment in schizophrenia (CIS). This study examined the dose-response relationship of the selective D(1) agonist, SKF38393 (0.5-40 mg/kg), to reverse the deficit in novel object recognition (NOR), an analog of declarative memory in man, produced by subchronic phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor non-competitive antagonist, and the ability of the D(1) antagonists, SCH23390 (0.05 mg/kg) and SKF83566 (0.15 mg/kg), to impair NOR in normal Long-Evans female rats. We also examined the ability of tandospirone, a serotonin (5-HT)(1A) receptor partial agonist, and LY341495, a mGluR2/3 receptor antagonist, to potentiate or block the effects of SKF38393 on NOR, respectively. SKF38393 reversed the persistent NOR deficit produced by subchronic PCP; the dose-response curve for SKF38393 was an inverted U-shape, with the peak effect at 6 mg/kg. SKF83566 and SCH23390 impaired NOR in normal rats. Co-administration of sub-effective doses of SKF38393 (0.25 mg/kg) and tandospirone (0.2 mg/kg) improved the PCP-induced NOR deficit, while LY341495 (1 mg/kg) blocked the ameliorating effect of SKF38393 (6 mg/kg), respectively. These data provide the first evidence that the reversal of the PCP-induced NOR deficit by D(1) agonism has an inverted U-shaped dose-response curve and that 5-HT(1A) and mGluR2/3 receptor signalling facilitates the efficacy of D(1) agonism to improve these deficits. These data suggest that although D(1) agonists may be useful to improve CIS, these agents, particularly higher doses, may also worsen cognitive function in some patients, because of an inverted U-shaped dose response curve.
23016766	Although the role of the hippocampus in spatial cognition is well accepted, it is unclear whether its involvement is restricted to the mnemonic domain or also extends to perception. We used fMRI to scan neurologically healthy participants during a scene oddity judgment task that placed no explicit demand on long-term memory. Crucially, a surprise recognition test was administered after scanning so that each trial could be categorized not only according to oddity accuracy but also according to subsequent memory. Univariate analyses showed significant hippocampal activity in association with correct oddity judgment, whereas greater parahippocampal place area (PPA) activity was observed during incorrect oddity trials, both irrespective of subsequent recognition performance. Consistent with this, multivariate pattern analyses revealed that a linear support vector machine was able to distinguish correct from incorrect oddity trials on the basis of activity in voxels within the hippocampus or PPA. Although no significant regions of activity were identified by univariate analyses in association with memory performance, a classifier was able to predict subsequent memory using voxels in either the hippocampus or PPA. Our findings are consistent with the idea that the hippocampus is important for processes beyond long-term declarative memory and that this structure may also play a role in complex spatial perception.
22998954	Post-Traumatic Stress Disorder (PTSD) is a common psychiatric disorder that is often associated with intrusive memories and deficits in declarative memory function. The neurobiology of this effect is complex. The report focus is to provide an overview of systems activated during stress and consequences of the activation as well as modulation of those effects. Two systems predominate in stress and related memory processing and encoding. They are the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal axis (HPA) axis. ANS has significant effect on enhancing encoding of emotional memories, sensitization, and fear conditioning with the main neurotransmitter being norepinephrine (NE). HPA system is involved in memory regulation where cortisol (CORT), by itself and with NE, regulates memories of emotional events. Therapeutic interference with stress-related memory dysfunction has been a focus of research for some time. New focus of this research may be the HPA axis and ANS. Recent evidence demonstrates significant efficacy in prevention of PTSD by administration of CORT, as well as treatment of PTSD by utilization of Stellate Ganglion Block (SGB), which reduces NE. Both therapeutic approaches may act by a common pathway involving Nerve Growth Factor (NGF). This factor may be the "missing link" between memory consolidation and PTSD. Suppression of NGF can reduce memory effect directly or by effect on NE, leading to prevention or effective treatment of PTSD.
22998599	Neurocognitive dysfunction is a central feature of schizophrenia and is observed during all phases of the illness. Because schizophrenia is known to run in families, studying neurocognitive function in first-degree, nonpsychotic relatives has been a widely utilised strategy for almost 50 years for understanding presumed "genetic risk". Studying nonpsychotic relatives ("familial high-risk", or FHR) allows for identification of cognitive vulnerability markers independent of confounds associated with psychosis.Prior meta-analyses have elucidated the level and pattern of cognitive deficits in the premorbid, prodromal, and postonset periods of psychosis, and in relatives regardless of age. However, no prior quantitative analyses have specifically focused on studies of young first-degree relatives of individuals with schizophrenia who have not passed through the peak age illness risk (<age 30). The English language literature of neuropsychological studies of first-degree relatives for schizophrenia was identified up to 15 May 2011.	From 33 studies, 28 studies met our criteria for quantitative review, utilising >70 individual tests and 250 variables.	In general, young FHR individuals demonstrated deficits with a moderate level of severity compared with healthy controls. The largest average effect sizes (ESs), based on tests given in at least three independent studies, were on estimates of Full Scale IQ (d= -0.777), followed by Vocabulary (d= -0.749) and single word reading tests (d= -0.698) (often used as estimates of IQ). Measures of declarative memory, sustained attention, working memory and others had more modest ESs. Deficits were milder than in established schizophrenia, but often as severe as in clinical high-risk or putatively prodromal participants and in older relatives examined in prior meta-analyses. Additionally, while assessed from a more limited literature, youth at FHR for schizophrenia tended to show worse neurocognitive functioning than those at FHR for affective psychosis. This suggests that genetic risk for schizophrenia as reflected in a positive FHR carries an especially heavy impact on cognitive ability.	
22990662	This review will concentrate on the consequences of sleep deprivation in adult humans. These findings form a paradigm that serves to demonstrate many of the critical functions of the sleep states.The drive to obtain food, water, and sleep constitutes important vegetative appetites throughout the animal kingdom. Unlike nutrition and hydration, the reasons for sleep have largely remained speculative. When adult humans are nonspecifically sleep-deprived, systemic effects may include defects in cognition, vigilance, emotional stability, risk-taking, and, possibly, moral reasoning. Appetite (for foodstuffs) increases and glucose intolerance may ensue. Procedural, declarative, and emotional memory are affected. Widespread alterations of immune function and inflammatory regulators can be observed, and functional MRI reveals profound changes in regional cerebral activity related to attention and memory. Selective deprivation of rapid eye movement (REM) sleep, on the contrary, appears to be more activating and to have lesser effects on immunity and inflammation.	The findings support a critical need for sleep due to the widespread effects on the adult human that result from nonselective sleep deprivation. The effects of selective REM deprivation appear to be different and possibly less profound, and the functions of this sleep state remain enigmatic.	
22967731	A fundamental principle in memory research is that memory is a function of the similarity between encoding and retrieval operations. Consistent with this principle, many neurobiological models of declarative memory assume that memory traces are stored in cortical regions, and the hippocampus facilitates the reactivation of these traces during retrieval. The present investigation tested the novel prediction that encoding-retrieval similarity can be observed and related to memory at the level of individual items. Multivariate representational similarity analysis was applied to functional magnetic resonance imaging data collected during encoding and retrieval of emotional and neutral scenes. Memory success tracked fluctuations in encoding-retrieval similarity across frontal and posterior cortices. Importantly, memory effects in posterior regions reflected increased similarity between item-specific representations during successful recognition. Mediation analyses revealed that the hippocampus mediated the link between cortical similarity and memory success, providing crucial evidence for hippocampal-cortical interactions during retrieval. Finally, because emotional arousal is known to modulate both perceptual and memory processes, similarity effects were compared for emotional and neutral scenes. Emotional arousal was associated with enhanced similarity between encoding and retrieval patterns. These findings speak to the promise of pattern similarity measures for evaluating memory representations and hippocampal-cortical interactions. 
22965328	Unstructured categories are those in which the stimuli are assigned to each contrasting category randomly, and thus there is no rule- or similarity-based strategy for determining category membership. Intuition suggests that unstructured categories are likely to be learned via explicit memorization that is under the control of declarative memory. In contrast to this prediction, neuroimaging studies of unstructured-category learning have reported task-related activation in the striatum, but typically not in the hippocampus--results that seem more consistent with procedural learning than with a declarative-memory strategy. This article reports the first known behavioral test of whether unstructured-category learning is mediated by explicit strategies or by procedural learning. Our results suggest that the feedback-based learning of unstructured categories is mediated by procedural memory.
22951626	Fear is maladaptive when it persists long after circumstances have become safe. It is therefore crucial to develop an approach that persistently prevents the return of fear. Pavlovian fear-conditioning paradigms are commonly employed to create a controlled, novel fear association in the laboratory. After pairing an innocuous stimulus (conditioned stimulus, CS) with an aversive outcome (unconditioned stimulus, US) we can elicit a fear response (conditioned response, or CR) by presenting just the stimulus alone. Once fear is acquired, it can be diminished using extinction training, whereby the conditioned stimulus is repeatedly presented without the aversive outcome until fear is no longer expressed. This inhibitory learning creates a new, safe representation for the CS, which competes for expression with the original fear memory. Although extinction is effective at inhibiting fear, it is not permanent. Fear can spontaneously recover with the passage of time. Exposure to stress or returning to the context of initial learning can also cause fear to resurface. Our protocol addresses the transient nature of extinction by targeting the reconsolidation window to modify emotional memory in a more permanent manner. Ample evidence suggests that reactivating a consolidated memory returns it to a labile state, during which the memory is again susceptible to interference. This window of opportunity appears to open shortly after reactivation and close approximately 6 hrs later, although this may vary depending on the strength and age of the memory. By allowing new information to incorporate into the original memory trace, this memory may be updated as it reconsolidates. Studies involving non-human animals have successfully blocked the expression of fear memory by introducing pharmacological manipulations within the reconsolidation window, however, most agents used are either toxic to humans or show equivocal effects when used in human studies. Our protocol addresses these challenges by offering an effective, yet non-invasive, behavioral manipulation that is safe for humans. By prompting fear memory retrieval prior to extinction, we essentially trigger the reconsolidation process, allowing new safety information (i.e., extinction) to be incorporated while the fear memory is still susceptible to interference. A recent study employing this behavioral manipulation in rats has successfully blocked fear memory using these temporal parameters. Additional studies in humans have demonstrated that introducing new information after the retrieval of previously consolidated motor, episodic, or declarative memories leads to interference with the original memory trace. We outline below a novel protocol used to block fear recovery in humans.
22937055	The role of the hippocampus in declarative memory consolidation is a matter of intense debate. We investigated the neural substrates of memory retrieval for recent and remote information using functional magnetic resonance imaging (fMRI). 18 young, healthy participants learned a series of pictures. Then, during two fMRI recognition sessions, 3 days and 3 months later, they had to determine whether they recognized or not each picture using the "Remember/Know" procedure. Presentation of the same learned images at both delays allowed us to track the evolution of memories and distinguish consistently episodic memories from those that were initially episodic and then became familiar or semantic over time and were retrieved without any contextual detail. Hippocampal activation decreased over time for initially episodic, later semantic memories, but remained stable for consistently episodic ones, at least in its posterior part. For both types of memories, neocortical activations were observed at both delays, notably in the ventromedial prefrontal and anterior cingulate cortices. These activations may reflect a gradual reorganization of memory traces within neural networks. Our data indicate maintenance and strengthening of hippocampal and cortico-cortical connections in the consolidation and retrieval of episodic memories over time, in line with the Multiple Trace theory (Nadel and Moscovitch, 1997). At variance, memories becoming semantic over time consolidate through strengthening of cortico-cortical connections and progressive disengagement of the hippocampus.
22925515	Although the acquisition of a novel word is apparently rapid, adult research suggests that integration of novel and existing knowledge (measured by engagement in lexical competition) requires sleep-associated consolidation. We present the first investigation of whether a similar time-course dissociation characterizes word learning across development. Consistent with previous research but counter to adults, 7-12-year-olds showed sleep-associated consolidation effects in declarative but not procedural memory. Nevertheless, the relationship between sleep and word learning in children was remarkably similar to the pattern for adults. Following exposure to nonword competitors (e.g. biscal) in the a.m. or p.m., children's ability to recognize and recall the nonwords improved only after sleep (after approximately 12-hrs for the p.m. group and 24-hrs for the a.m. group), with performance stable 1 week later. Novel nonwords only induced lexical competition effects after sleep. These findings suggest that children utilize a dual memory system when acquiring and integrating new vocabulary and highlight sleep as integral to this process. A video abstract of this article can be viewed at http://www.youtube.com/watch?feature=youtube_gdata&v=2UNuKCAakOk&gl=GB.
22910716	Reconsolidation refers to the destabilization/re-stabilization memory process upon its activation. However, the conditions needed to undergo reconsolidation, as well as its functional significance is quite unclear and a matter of intense investigation. Even so, memory retrieval is held as requisite to initiate reconsolidation. Therefore, in the present work we examined whether transient pharmacological disruption of memory retrieval impedes reconsolidation of stored memory in the widely used associative conditioning task, taste aversion. We found that AMPA receptors inhibition in the amygdala impaired retrieval of taste aversion memory. Furthermore, AMPA receptors blockade impeded retrieval regardless of memory strength. However, inhibition of retrieval did not affect anisomycin-mediated disruption of reconsolidation. These results indicate that retrieval is a dispensable condition to undergo reconsolidation and provide evidence of molecular dissociation between retrieval and activation of memory in the non-declarative memory model taste aversion.
22905817	Studies on H.M. generated five main findings: that memory is a distinct psychological function, that amnesia spares short-term and working memory, that amnesia is an impairment of declarative and episodic memory, that the hippocampus is a core brain structure supporting memory, and that the hippocampus supports the permanent consolidation of memories. Each of these basic findings has recently been challenged, but a consideration of these studies suggests the new observations serve to support the original findings on H.M. and improve our understanding of the memory functions of the hippocampal system.
22904373	In the late 19th Century, Sigmund Freud described the phenomenon in which people are unable to recall events from early childhood as infantile amnesia. Although universally observed, infantile amnesia is a paradox; adults have surprisingly few memories of early childhood despite the seemingly exuberant learning capacity of young children. How can these findings be reconciled? The mechanisms underlying this form of amnesia are the subject of much debate. Psychological/cognitive theories assert that the ability to maintain detailed, declarative-like memories in the long term correlates with the development of language, theory of mind, and/or sense of "self." However, the finding that experimental animals also show infantile amnesia suggests that this phenomenon cannot be explained fully in purely human terms. Biological explanations of infantile amnesia suggest that protracted postnatal development of key brain regions important for memory interferes with stable long-term memory storage, yet they do not clearly specify which particular aspects of brain maturation are causally related to infantile amnesia. Here, we propose a hypothesis of infantile amnesia that focuses on one specific aspect of postnatal brain development--the continued addition of new neurons to the hippocampus. Infants (humans, nonhuman primates, and rodents) exhibit high levels of hippocampal neurogenesis and an inability to form lasting memories. Interestingly, the decline of postnatal neurogenesis levels corresponds to the emergence of the ability to form stable long-term memory. We propose that high neurogenesis levels negatively regulate the ability to form enduring memories, most likely by replacing synaptic connections in preexisting hippocampal memory circuits.
22900536	The aim of this paper is twofold. First, it explores delayed effects of high endogenously evoked cortisol concentrations on visuo-spatial declarative memory. Subsequently, it applies multiple mediation (MM) analyses to reveal path processes between stress and cognitive performance in a sample of 24 male Special Forces (SF) candidates (mean age = 27.0 years, SD = 4.1). The SF candidates were randomly assigned to a control (n = 12) or an intense stress group (n = 12), and cortisol secretion for the intense stress condition was triggered by a brusque 60 min prisoner of war exercise. Stress exposure provoked robust increases in cortisol concentrations and a significant decline in immediate recall performance, measured with the Rey-Osterrieth Complex Figure (ROCF). The relative retrieval differences in regard to the ROCF persisted even after a recovery period of 24 h, as both groups showed similar levels of memory decline over 24 h. Next, the study applied a MM design that involved distribution-independent asymptotic and resampling strategies to extend traditional bivariate analyses. MM results showed that ROCF performance was mediated by increases in cortisol concentrations. Considering the studied variables, the current analysis was the first to provide statistical support for the generally accepted thesis that cortisol secretion in itself, rather than subjective strain or the experimental treatment, affects cognitive performance. The revelation of such path processes is important because it establishes process identification and may refine existing paradigms.

22884322	Declarative memory is known to depend on the medial temporal lobe memory system. Recently, there has been renewed focus on the relationship between the basal ganglia and declarative memory, including the involvement of striatum. However, the contribution of striatum to declarative memory retrieval remains unknown. Here, we review neuroimaging and neuropsychological evidence for the involvement of the striatum in declarative memory retrieval. From this review, we propose that, along with the prefrontal cortex (PFC), the striatum primarily supports cognitive control of memory retrieval. We conclude by proposing three hypotheses for the specific role of striatum in retrieval: (1) striatum modulates the re-encoding of retrieved items in accord with their expected utility (adaptive encoding), (2) striatum selectively admits information into working memory that is expected to increase the likelihood of successful retrieval (adaptive gating), and (3) striatum enacts adjustments in cognitive control based on the outcome of retrieval (reinforcement learning).
22879917	Sleep plays an important role in the consolidation of memory. This has been most clearly shown in adults for procedural memory (i.e. skills and procedures) and declarative memory (e.g. recall of facts). The effects of sleep and memory are relatively unstudied in adolescents. Declarative memory is important in school performance and consequent social functioning in adolescents. This is the first study to specifically examine the effects of normal sleep on auditory declarative memory in an early adolescent sample. Given that the majority of adolescents do not obtain the recommended amount of sleep, it is critical to study the cognitive effects of normal sleep. Forty male and female normal, healthy adolescents between the ages of ten and fourteen years old were randomly assigned to sleep and no sleep conditions. Subjects were trained on a paired-associate declarative memory task and a control working memory task at 9 am, and tested at night (12 hours later) without sleep. The same number of subjects was trained at 9 pm and tested 9 am following sleep. An increase of 20.6% in declarative memory, as measured by the number correct in a paired-associate test, following sleep was observed compared to the group which was tested at the same time interval without sleep (p<0.03). The performance on the control working memory task that involved encoding and memoranda manipulation was not affected by time of day or relationship to sleep. Declarative memory is significantly improved by sleep in a sample of normal adolescents.
22875937	Learning and memory are supported by anatomically and functionally distinct systems. Recent research suggests that stress may alter the contributions of multiple memory systems to learning, yet the underlying mechanism in the human brain remains completely unknown. Using event-related functional magnetic resonance imaging, we asked in the present experiment whether stress may modulate the engagement of hippocampus-based "declarative" and striatum-based "procedural" memory systems during classification learning in humans and what brain mechanisms are involved in this effect. We found that stress reduced declarative knowledge about the learning task and changed the used learning strategy from a single-cue-based declarative strategy to a multicue-based procedural strategy, whereas learning performance per se remained unaffected by stress. Neuroimaging revealed that hippocampal activity correlated positively with task performance in the control condition, whereas striatal activity correlated with performance in the stress condition. After stress, hippocampal activity was reduced and even negatively correlated with learning performance. These findings show for the first time that stress alters the engagement of multiple memory systems in the human brain. Stress impaired the hippocampus-dependent system and allowed the striatum to control behavior. The shift toward "procedural" learning after stress appears to rescue task performance, whereas attempts to engage the "declarative" system disrupt performance.
22865461	• Cognitive impairment is a common consequence of traumatic brain injury (TBI) and a substantial source of disability. Across all levels of TBI severity, attention, processing speed, episodic memory, and executive function are most commonly affected.• The differential diagnosis for post-traumatic cognitive impairments is broad, and includes emotional, behavioral, and physical problems as well as substance use disorders, medical conditions, prescribed and self-administered medications, and symptom elaboration. Thorough neuropsychiatric assessment for such problems is a prerequisite to treatments specifically targeting cognitive impairments.• First-line treatments for post-traumatic cognitive impairments are nonpharmacologic, including education, realistic expectation setting, environmental and lifestyle modifications, and cognitive rehabilitation.• Pharmacotherapies for post-traumatic cognitive impairments include uncompetitive N-methyl-D-aspartate receptor (NMDA) antagonists, medications that directly or indirectly augment cerebral catecholaminergic or acetylcholinergic function, or agents with combinations of these properties.• In the immediate post-injury period, treatment with uncompetitive NMDA receptor antagonists reduces duration of unconsciousness. The mechanism for this effect may involve attenuation of neurotrauma-induced glutamate-mediated excitotoxicity and/or stabilization of glutamate signaling in the injured brain.• During the subacute or late post-injury periods, medications that augment cerebral acetylcholinergic function may improve declarative memory. Among responders to this treatment, secondary benefits on attention, processing speed, and executive function impairments as well as neuropsychiatric disturbances may be observed. During these post-injury periods, medications that augment cerebral catecholaminergic function may improve hypoarousal, processing speed, attention, and/or executive function as well as comorbid depression or apathy.• When medications are used, a "start-low, go-slow, but go" approach is encouraged, coupled with frequent reassessment of benefits and side effects as well as monitoring for drug-drug interactions. Titration to either beneficial effect or medication intolerance should be completed before discontinuing a treatment or augmenting partial responses with additional medications.
22837982	The temporal lobe is essential in saving declarative memory and plays an important role along with the cerebral neocortex in creating and maintaining long-term memory. Damage to the temporal lobe is expected to result in cognitive impairment or dementia, which has characteristic symptoms such as cognitive and behavioral dysfunction and decreasing self-reliance in activities of daily living. We report on a patient, who suffered from dementia due to meningovascular syphilis affecting the medial temporal lobe, and on the outcome of cognitive rehabilitation.
22823125	Selective declarative memory processes are differentially compromised in chronic alcoholism (ALC) and HIV infection (HIV) and likely reflect neuropathology associated with each condition: frontocerebellar dysfunction in ALC and frontostriatal dysfunction in HIV infection. Evidence for disease overlap derives from observed exacerbated impairments in these declarative memory processes in ALC-HIV comorbidity. Less is known about nondeclarative memory processes in these disease conditions. Examination of visuomotor learning in chronic ALC and HIV infection could provide insight into the differential and combined contribution of selective disease-related injury to visuomotor procedural memory processes.We examined component processes of visuomotor learning and retention on the rotary pursuit task in 29 ALC, 23 HIV, 28 ALC + HIV, and 20 control subjects. Participants were given 4 rotary pursuit learning sessions over 2 testing days, typically separated by 1 week, to assess visuomotor learning and retention patterns. Ancillary measures of simple motor, psychomotor, explicit memory, and balance abilities were administered to test which component processes independently predicted visuomotor learning.	All clinical groups showed visuomotor learning across rotary pursuit testing sessions, despite impairment in visuomotor speed in the HIV groups and impairment in explicit memory and psychomotor speed in the alcohol groups. The 2 alcoholic groups showed retention and consolidation over time (i.e., improved performance without further training), whereas the HIV-infected group showed learning and retention but no consolidation effect. The comorbid group shared impairments associated with the ALC-only group (explicit memory and psychomotor speed) and the HIV-only group (visuomotor speed), although there was no clear compounded effect of alcohol and HIV infection on visuomotor learning performance.	This study supports the hypothesis that ALC and HIV infection exert differential effects on components of visuomotor procedural learning. Further, the results provide behavioral evidence for dissociable influences of frontocerebellar and frontostriatal disruption to visuomotor procedural learning and retention.	
22819624	A consolidated memory recalled by a specific reminder can become unstable (labile) and susceptible to facilitation or impairment for a discrete period of time. This labilization phase is followed by a process of stabilization called reconsolidation. The phenomenon has been shown in diverse types of memory, and different pharmacological agents have been used to disclose its presence. Several studies have revealed the relevance of the GABAergic system to this process. Consequently, our hypothesis is that the system is involved in the reconsolidation of declarative memory in humans. Thus, using our verbal learning task, we analyzed the effect of benzodiazepines on the re-stabilization of the declarative memory. On Day 1, volunteers learned an association between five cue- response-syllables. On Day 2, the verbal memory was labilized by a reminder presentation, and then a placebo capsule or 0.25 mg or 0.03 mg of clonazepam was administered to the subjects. The verbal memory was evaluated on Day 3. The volunteers who had received the 0.25 mg clonazepam along with the specific reminder on Day 2, exhibited memory improvement. In contrast, there was no effect when the drug was given without retrieval, when the memory was simply retrieved instead of being reactivated or when short-term memory testing was performed 4 h after reactivation. We discuss the GABAergic role in reconsolidation, which shows a collateral effect on other memories when the treatment is aimed at treating anxiety disorders. Further studies might elucidate the role of GABA in the reconsolidation process associated with dissimilar scenarios. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
22815515	Neuroanatomical and psychological evidence suggests prolonged maturation of declarative memory systems in the human brain from childhood into young adulthood. Here, we examine functional brain development during successful memory retrieval of scenes in children, adolescents, and young adults ages 8-21 via functional magnetic resonance imaging. Recognition memory improved with age, specifically for accurate identification of studied scenes (hits). Successful retrieval (correct old-new decisions for studied vs unstudied scenes) was associated with activations in frontal, parietal, and medial temporal lobe (MTL) regions. Activations associated with successful retrieval increased with age in left parietal cortex (BA7), bilateral prefrontal, and bilateral caudate regions. In contrast, activations associated with successful retrieval did not change with age in the MTL. Psychophysiological interaction analysis revealed that there were, however, age-relate changes in differential connectivity for successful retrieval between MTL and prefrontal regions. These results suggest that neocortical regions related to attentional or strategic control show the greatest developmental changes for memory retrieval of scenes. Furthermore, these results suggest that functional interactions between MTL and prefrontal regions during memory retrieval also develop into young adulthood. The developmental increase of memory-related activations in frontal and parietal regions for retrieval of scenes and the absence of such an increase in MTL regions parallels what has been observed for memory encoding of scenes.
22815509	The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups: >500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks.
22813992	Brain derived neurotrophic factor (BDNF) is a critical component of the molecular mechanism of memory formation. Variation in the BDNF gene, particularly the rs6265 (val(66)met) single nucleotide polymorphism (SNP), has been linked to variability in human memory performance and to both the structure and physiological response of the hippocampus, which plays a central role in memory processing. However, these effects have not been consistently reported, which may reflect the modest size of the samples studied to date. Employing a meta-analytic approach, we examined the effect of the BDNF val(66)met polymorphism on human memory (5922 subjects) and hippocampal structure (2985 subjects) and physiology (362 subjects). Our results suggest that variations in the rs6265 SNP of the BDNF gene have a significant effect on memory performance, and on both the structure and physiology of the hippocampus, with carriers of the met allele being adversely affected. These results underscore the role of BDNF in moderating variability between individuals in human memory performance and in mediating some of the neurocognitive impairments underlying neuropsychiatric disorders.
22808287	Sleep after learning has been shown to foster the consolidation of new memories. However, fundamental questions on the best timing of learning before night-time sleep persist. We tested the hypothesis that learning directly prior to night-time sleep compared to 7.5 hrs prior to night-time sleep provides better conditions for the consolidation of declarative and procedural memories. Fifty healthy female adolescents (aged 16-17 years) were trained on a declarative word-pair and a procedural finger-tapping task at 3 pm (afternoon group, n = 25) or at 9 pm (evening group, n = 25), followed by a sleep laboratory night. Retrieval was assessed 24 hours and 7 days after initial training. Subjects trained in the afternoon showed a significantly elevated retention rate of word-pairs compared to subjects trained in the evening after 24 hours, but not after 7 days. In contrast, off-line gains in finger-tapping performance were significantly higher in subjects trained in the evening compared to those trained in the afternoon after both retention intervals. The observed enhanced consolidation of procedural memories after training in the evening fits to current models of sleep-related memory consolidation. In contrast, the higher retention of declarative memories after encoding in the afternoon is surprising, appeared to be less robust and needs further investigation.
22806662	The hippocampus plays a central role in spatial representation, declarative and episodic memory. In this area, so-called place cells possess high spatial selectivity, firing preferentially when the individual is within a small area of the environment. Interestingly, it has been found in rats that these cells can be active also when the animal is outside the location or context of their corresponding place field producing so-called "forward sweeps". These typically occur at decision points during task execution and seem to be utilized, among other things, for the evaluation of potential alternative paths. Anticipatory firing is also found in the ventral striatum, a brain area that is strongly interconnected with the hippocampus and is known to encode value and reward. In this paper, we describe a biologically based computational model of the hippocampal-ventral striatum circuit that implements a goal-directed mechanism of choice, with the hippocampus primarily involved in the mental simulation of possible navigation paths and the ventral striatum involved in the evaluation of the associated reward expectancies. The model is validated in a navigation task in which a rat is placed in a complex maze with multiple rewarding sites. We show that the rat mentally activates place cells to simulate paths, estimate their value, and make decisions, implementing two essential processes of model-based reinforcement learning algorithms of choice: look-ahead prediction and the evaluation of predicted states.
22798956	Several studies have consistently shown that pre-sleep learning is associated to changes of sleep structure. Whereas previous research has mainly focused on sleep states, namely REM and NREM amount, very little attention has been paid to the hypothesis that pre-sleep learning might improve sleep continuity, stability, and cyclic organization, which are often impaired in aging. Thus, aim of this research was to assess, in a sample of 18 healthy elderly subjects, whether a memory task administered at bedtime would determine changes in any sleep parameter, with special regard to sleep continuity, stability, and organization. To this purpose, a baseline sleep (BL), i.e., a normal sleep with 9-h time in bed (TIB), was compared to a post-training sleep (TR), with the same TIB but preceded by an intensive training session. For the latter, a verbal declarative task was used, consisting in learning paired-word lists, rehearsed, and recalled for three times in a row. To control for individual learning abilities, subjects were administered several sets of lists with increasing difficulty, until they reached an error rate ≥20% at third recall. Relative to BL, TR shows a significant reduction in the frequency of brief awakenings, arousals, state transitions, "functional uncertainty" (FU) periods, and in the percentage of time in FU over total sleep time (TST). A significant increase in the number of complete cycles, total cycle time (TCT), and TCT/TST proportion was also found. All these changes are evenly distributed over the sleep episode. No sleep stage measure display significant changes, apart from a slight reduction in the percentage of Stage 1. Scores at retest are negatively correlated with both the frequency of arousals and of state transitions. Our data suggest that pre-sleep learning can yield a beneficial re-organizing effect on elderlies' sleep quality. The inverse correlation between recall scores and the measures of sleep continuity and stability provides further support to the role of these features in memory processes.
22794269	Memory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain.
22768272	Sleep enhances memory consolidation. Bearing in mind that food intake produces many metabolic signals that can influence memory processing in humans (e.g., insulin), the present study addressed the question as to whether the enhancing effect of sleep on memory consolidation is affected by the amount of energy consumed during the preceding daytime. Compared to sleep, nocturnal wakefulness has been shown to impair memory consolidation in humans. Thus, a second question was to examine whether the impaired memory consolidation associated with sleep deprivation (SD) could be compensated by increased daytime energy consumption. To these aims, 14 healthy normal-weight men learned a finger tapping sequence (procedural memory) and a list of semantically associated word pairs (declarative memory). After the learning period, standardized meals were administered, equaling either ∼50% or ∼150% of the estimated daily energy expenditure. In the morning, after sleep or wakefulness, memory consolidation was tested. Plasma glucose was measured both before learning and retrieval. Polysomnographic sleep recordings were performed by electroencephalography (EEG). Independent of energy intake, subjects recalled significantly more word pairs after sleep than they did after SD. When subjects stayed awake and received an energy oversupply, the number of correctly recalled finger sequences was equal to those seen after sleep. Plasma glucose did not differ among conditions, and sleep time in the sleep conditions was not influenced by the energy intake interventions. These data indicate that the daytime energy intake level affects neither sleep's capacity to boost the consolidation of declarative and procedural memories, nor sleep's quality. However, high energy intake was followed by an improved procedural but not declarative memory consolidation under conditions of SD. This suggests that the formation of procedural memory is not only triggered by sleep but is also sensitive to the fluctuations in the energy state of the body.
22760181	Intracranial recordings in subjects suffering from intractable epilepsy - made during their evaluation for an eventual surgical removal of the epileptic focus - have allowed the extraordinary opportunity to study the firing of multiple single neurons in awake and behaving human subjects. These studies have shown that neurons in the human medial temporal lobe respond in a remarkably selective and abstract manner to particular persons or objects, such as Jennifer Aniston, Luke Skywalker or the Tower of Pisa. These neurons have been named 'Jennifer Aniston neurons' or, more recently, 'concept cells'. I argue that the sparse, explicit and abstract representation of these neurons is crucial for memory functions, such as the creation of associations and the transition between related concepts that leads to episodic memories and the flow of consciousness.
22755467	This experiment investigated the effect of explicit, implicit, and sequential learning (implicit-explicit) on the acquisition and retention of decision-making skill in volleyball. The participants were 60 female novices, ages 10 to 12 years. The experimental groups followed three different methods of training: (a) explicit practice for the development of declarative knowledge, (b) implicit practice for the development of the procedural knowledge, (c) sequential practice (implicit first and then explicit), and (d) control group that participated only in the measurements. A pre-test, a post-test, and a retention test measured the response time and accuracy of the decision-making skill. Analysis indicated that all experimental groups improved over time while the control group did not. The sequential group was faster and more accurate than the implicit group, and the latter was faster and more accurate than the explicit one. The sequential group outperformed implicit and explicit groups on both speed and accuracy of decision. It seems that both explicit and implicit processes, when they take place in sequence, interact positively, and this method improves speed and accuracy of decision making rather than when each mode of learning (implicit or explicit) occurs separately. If the role of working memory is reduced at the early stages of learning, the accumulation of declarative knowledge (explicit learning) may benefit from accumulation of procedural knowledge and enhance decision-making skill.
22754045	Studies have shown that sleep shelters old verbal memories from associative interference arising from new, more recently acquired memories. Our objective is to extend the forms of interference for which sleep provides a sheltering benefit to non-associative and prospective interference, and to examine experimental conditions and memory strengths for which sleep before or after learning particularly affects verbal memory consolidation.Acquiring paired word associates, retention across intervening sleep and wake, training on new, interfering word associates, and test recall of both sets.	University laboratory.	Healthy volunteers.	N/A.	Comparing recall before and after intervening periods of sleep versus wake, we found that: (i) Sleep preferentially shields weakly encoded verbal memories from retroactive interference. (ii) Sleep immediately following learning helps shelter memory from associative and non-associative forms of retroactive interference. (iii) Sleep protects new verbal memories from prospective interference. (iv) Word associations acquired for the first time in the evening after a day spent in the wake state are encoded more strongly than word associations acquired in the morning following a night of sleep.	The findings extend the known sleep protection from interference to non-associative as well as prospective interference, and limit the protection to weakly encoded word associations. Combined, our results suggest that sleep immediately after verbal learning isolates newly formed memory traces and renders them inaccessible, except by specific contextual cues. Memory isolation in sleep is a passive mechanism that can reasonably account for several experimental findings.	
22750359	Two groups of students aged between 12 and 14 years--27 with attention deficit/hyperactivity disorder (ADHD) and 28 with both ADHD and learning problems--were compared to a sample of 29 typically developing students in terms of the acquisition and retention of declarative, conditional and procedural knowledge either in a hypermedia learning or in a traditional instructional setting. Hypermedia instruction produced better learning outcomes than traditional instruction did; the benefits concerned prevalently procedural knowledge and emerged mainly in the retention phase. Hypermedia instruction led ADHD students to reach achievement levels similar to those of typically developing students. Furthermore, hypermedia instruction contrasted the decay of knowledge from the acquisition to the retention phase in both clinical groups. On the basis of these findings, hypermedia instruction is proposed as an approach that may help ADHD learners to overcome attention deficits.
22750121	Various studies suggest that non-rapid eye movement (NREM) sleep, especially slow-wave sleep (SWS), is vital to the consolidation of declarative memories. However, sleep stage 2 (S2), which is the other NREM sleep stage besides SWS, has gained only little attention. The current study investigated whether S2 during an afternoon nap contributes to the consolidation of declarative memories. Participants learned associations between faces and cities prior to a brief nap. A cued recall test was administered before and following the nap. Spindle, delta and slow oscillation activity was recorded during S2 in the nap following learning and in a control nap. Increases in spindle activity, delta activity, and slow oscillation activity in S2 in the nap following learning compared to the control nap were associated with enhanced retention of face-city associations. Furthermore, spindles tended to occur more frequently during up-states than down-states within slow oscillations during S2 following learning versus S2 of the control nap. These findings suggest that spindles, delta waves, and slow oscillations might promote memory consolidation not only during SWS, as shown earlier, but also during S2.
22749926	Perceptual learning is a special type of non-declarative learning that involves experience-dependent plasticity in sensory cortices. The cholinergic system is known to modulate declarative learning. In particular, reduced levels or efficacy of the neurotransmitter acetylcholine were found to facilitate declarative memory consolidation. However, little is known about the role of the cholinergic system in memory consolidation of non-declarative learning. Here we compared two groups of non-smoking men who learned a visual texture discrimination task (TDT). One group received chewing tobacco containing nicotine for 1 h directly following the TDT training. The other group received a similar tasting control substance without nicotine. Electroencephalographic recordings during substance consumption showed reduced alpha activity and P300 latencies in the nicotine group compared to the control group. When re-tested on the TDT the following day, both groups responded more accurately and more rapidly than during training. These improvements were specific to the retinal location and orientation of the texture elements of the TDT suggesting that learning involved early visual cortex. A group comparison showed that learning effects were more pronounced in the nicotine group than in the control group. These findings suggest that oral consumption of nicotine enhances the efficacy of nicotinic acetylcholine receptors. Our findings further suggest that enhanced efficacy of the cholinergic system facilitates memory consolidation in perceptual learning (and possibly other types of non-declarative learning). In that regard acetylcholine seems to affect consolidation processes in perceptual learning in a different manner than in declarative learning. Alternatively, our findings might reflect dose-dependent cholinergic modulation of memory consolidation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
22745496	Neural circuits associated with motivated declarative encoding and active threat avoidance have both been described, but the relative contribution of these systems to punishment-motivated encoding remains unknown. The current study used functional magnetic resonance imaging in humans to examine mechanisms of declarative memory enhancement when subjects were motivated to avoid punishments that were contingent on forgetting. A motivational cue on each trial informed participants whether they would be punished or not for forgetting an upcoming scene image. Items associated with the threat of shock were better recognized 24 h later. Punishment-motivated enhancements in subsequent memory were associated with anticipatory activation of right amygdala and increases in its functional connectivity with parahippocampal and orbitofrontal cortices. On a trial-by-trial basis, right amygdala activation during the motivational cue predicted hippocampal activation during encoding of the subsequent scene; across participants, the strength of this interaction predicted memory advantages due to motivation. Of note, punishment-motivated learning was not associated with activation of dopaminergic midbrain, as would be predicted by valence-independent models of motivation to learn. These data are consistent with the view that motivation by punishment activates the amygdala, which in turn prepares the medial temporal lobe for memory formation. The findings further suggest a brain system for declarative learning motivated by punishment that is distinct from that for learning motivated by reward.
22743169	The search for a unitary model of sleep-memory relationships seems still far from accomplished, despite the huge body of data produced in the latest twenty years. So far, inconsistent results have been mainly addressed by parcelling out memory through a continuous refinement of its classification systems, with a major focus on dichotomic distinctions such as the one concerning the declarative vs. procedural memory systems, or the implicit vs. explicit nature of learning. Although this approach has provided a remarkable contribution, it has somehow resulted in an extreme fragmentation of the scenario, where it is even more complex to get a clear picture of the way sleep and memory are connected. This article, starting from a review of the most recent literature on sleep-memory relationships, is intended to provide a compass in this frantically moving landscape. By sorting out the most promising research lines, we highlight some crucial "ongoing" theoretical developments, such as: the rediscovery of the classical notion in psychology of memory that learning has a reconstructive rather than a reproductive nature, with the need of addressing phenomena such as the delicate balance between remembering and forgetting and the integration of different items of knowledge; the growing interest in the role of additional factors influencing memory processes, such as intentionality and learning strategies; the possibility that organizational rather than structural features of sleep are essential to sleep-dependent memory consolidation. We will also discuss how these recent perspectives disclose a number of relevant methodological caveats to be carefully taken into account when conceiving experimental designs.
22732649	While it is now generally accepted that sleep facilitates the processing of newly acquired declarative information, questions still remain as to the type and length of sleep necessary to best benefit declarative memories. A better understanding could lend support in one direction or another as to the much-debated role of sleep, be it passive, permissive, or active, in memory processing. The present study employed a napping paradigm and compared performance on a bimodal paired-associates task of those who obtained a 10-min nap, containing only Stages 1 and 2 sleep, to those whose nap contained slow-wave sleep (SWS) and rapid eye movement (REM) sleep (60-min nap), as well as to subjects who remained awake. Measurements were obtained for baseline performance at training, after a sleep/no sleep interval for short-term retention, after a subsequent stimulus-related interference task, and again after a weeklong retention period. While all groups learned the information similarly, both nap groups performed better than the Wake group when examining short-term retention, approximately 1.5h after training (10-min p=.052, 60-min p=.002). However, performance benefits seen in the 10-min nap group proved to be temporary. Performance after a stimulus-related interference task revealed significantly better memory retention in the 60-min nap group, with interference disrupting the memory trace far less than both the Wake and 10-min nap groups (p<.001, p=.006, respectively). After a weeklong retention period, sleep's benefit to memory persisted in the 60-min nap group, with performance significantly greater than both the Wake and 10-min nap groups (p<.001, p=.004, respectively). It is our conclusion that SWS, obtained only by those in the 60-min nap group, served to actively facilitate the consolidation of learned bimodal paired-associates, supported by theories such as the Standard Theory of Consolidation as well as the Synaptic Homeostasis Hypothesis.
22705480	Even though it is known that sleep benefits declarative memory consolidation, the role of sleep in the storage of temporal sequences has rarely been examined. Thus we explored the influence of sleep on temporal order in an episodic memory task followed by sleep or sleep deprivation. Thirty-four healthy subjects (17 men) aged between 19 and 28 years participated in the randomized, counterbalanced, between-subject design. Parameters of interests were NREM/REM cycles, spindle activity and spindle-related EEG power spectra. Participants of both groups (sleep group/sleep deprivation group) performed retrieval in the evening, morning and three days after the learning night. Results revealed that performance in temporal order memory significantly deteriorated over three days only in sleep deprived participants. Furthermore our data showed a positive relationship between the ratios of the (i) first NREM/REM cycle with more REM being associated with delayed temporal order recall. Most interestingly, data additionally indicated that (ii) memory enhancers in the sleep group show more fast spindle related alpha power at frontal electrode sites possibly indicating access to a yet to be consolidated memory trace. We suggest that distinct sleep mechanisms subserve different aspects of episodic memory and are jointly involved in sleep-dependent memory consolidation.
22700468	Both sleep spindles and slow oscillations have been implicated in sleep-dependent memory consolidation. Whereas spindles occur during both light and deep sleep, slow oscillations are restricted to deep sleep, raising the possibility of greater consolidation-related spindle involvement during deep sleep. We assessed declarative memory retention over an interval containing a nap and determined spindle density for light and deep sleep separately. In deep sleep, spindle density was considerably higher and showed a strong and robust positive correlation with retention. This relation was absent for light sleep, suggesting that the potentiating effects of spindles are tied to their co-occurrence with slow oscillations.
22683286	One hundred and forty-four people with convulsive seizures (CS) and 144 healthy controls were evaluated for cognitive function, using a battery of neuropsychological tests. People with CS performed significantly worse than the controls on the Mini-Mental State Examination, Hamilton Depression Rating Scale, auditory verbal learning test, digit span test, verbal fluency test, and digit cancellation test. The percentage of patients who had abnormal scores on the Hamilton Depression Rating Scale was higher than that of controls (54.9% vs. 7.6%, p<0.001). Cognitive functional impairment was detected in 65.3% of the patients and 29.2% of the controls (p<0.001). People with CS presented with depressive mood and a wide range of cognitive deficits, particularly deficits in episodic declarative memory, attentional capacity, semantic memory, and mental speed. Years in education were positively associated with the cognitive performance of people with CS (OR=0.655, 95% CI: 0.486-0.882, p=0.005).
22659110	In general, declarative learning is associated with the activation of the medial temporal lobes (MTL), while the basal ganglia (BG) are considered the substrate for procedural learning. More recently it has been demonstrated the distinction of these systems may not be as absolute as previously thought and that not only the explicit or implicit nature of the memory task alone is important for the distinction of MTL or BG systems. Nevertheless, patients with BG dysfunction - such as patients with Parkinson's disease (PD) or Huntington's disease (HD) - are considered to be impaired at implicit learning. However, a more recent study demonstrated that one implicit learning task, probabilistic classification learning (examples include the weather prediction (WPT) and Mr. Potato Head tasks) is only impaired in PD when it involves learning with corrective feedback (FB) but not when it involves learning in a paired associate (PA) manner, without feedback. Therefore, it has been argued that the presence of feedback rather than the implicit nature of these tasks determines whether or not the BG are recruited. As patients with HD as well as those with PD, have also been shown to be impaired on the standard FB based version of probabilistic classification learning, the question remains as to whether or not there is a similar selective deficit in FB but not PA based probabilistic classification learning in HD. 18 patients with early HD and 18 healthy controls completed FB and PA versions of the WPT task. Relative to controls, HD patients were selectively impaired at WPT learning with feedback. These findings are consistent with previous evidence from studies of probabilistic classification learning in PD. Unlike PD, selective deficits in WPT learning in HD cannot be attributed to the effects of dopaminergic medication and must be directly related to BG dysfunction; for instance even in early HD, only 50% of the neurons in the medial head of caudate remain. We conclude that the striatum is important for WPT learning with feedback. Our findings are consistent with imaging evidence showing recruitment of the caudate during FB based WPT learning, while the MTL is associated with PA based learning.
22652523	The objective of the present study was to examine the influence of prenatal drug exposure (PDE) on memory performance and supporting brain structures (i.e., hippocampus) during adolescence. To achieve this goal, declarative memory ability and hippocampal volume were examined in a well-characterized sample of 138 adolescents (76 with a history of PDE and 62 from a non-exposed comparison group recruited from the same community, mean age=14 years). Analyses were adjusted for: age at time of the assessments, gender, IQ, prenatal exposure to alcohol and tobacco, and indices of early childhood environment (i.e., caregiver depression, potential for child abuse, and number of caregiver changes through 7 years of age). Results revealed that adolescents with a history of PDE performed worse on the California Verbal Learning Test-Child Version (CVLT-C), and story recall from the Children's Memory Scale (CMS), and had larger hippocampal volumes, even after covariate adjustment. Hippocampal volume was negatively correlated with memory performance on the CVLT-C, with lower memory scores associated with larger volumes. These findings provide support for long-term effects of PDE on memory function and point to neural mechanisms that may underlie these outcomes.
22649213	Investigating in a case-control study whether the performance scores of a group of patients with Parkinson disease (PD) without dementia on tests of declarative memory could be predicted by hippocampal volume reduction (as assessed by automatic segmentation of cerebral magnetic resonance [MR] images) or by the rate of microstructural alterations (as evaluated by diffusion tensor analysis of MR images).Twenty-five individuals with PD and 25 matched healthy control subjects underwent a 3-T MRI protocol with whole-brain T1-weighted and diffusion tensor imaging and a neuropsychological assessment. Images were processed to obtain indices of macrostructural (volume) and microstructural (mean diffusivity [MD]) variation of bilateral hippocampi. Neuropsychological evaluation included tests of verbal memory (15-minute delayed recall of a 15-word list) and visuospatial memory (20-minute delayed reproduction of Rey complex figure).	MD in the hippocampi of patients with PD was significantly increased with respect to that of the group of control subjects. Moreover, patients with high hippocampal MD values obtained low memory scores. In contrast, no difference emerged between patients with PD and healthy control subjects for hippocampal size, and no relationship could be found between hippocampal volumes and memory scores.	These data confirm that the declarative memory impairment in patients with PD without dementia may be predicted by the rate of microstructural alterations in the hippocampal formation as detected by diffusion tensor imaging analysis.	
22796971	Neurodevelopment is a highly complex process, influenced by a wide range of interacting genetic and environmental factors. Recent developments in fetal, neonatal and infant behavioural genetics and brain imaging methods have allowed for more detailed investigation of the effects of early adverse environment on the developing brain. This review aims to provide background for neurobiological understanding of how the prolonged exposure to stress or trauma during early childhood affects subsequent cognitive, emotional and social development. Initially, a brief overview of brain development is provided - focusing, in particular, on the limbic system structures, which are closely linked to emotional experiences and reactions, learning and memory. Emphasis is placed on the concept of neural plasticity, which is the biological base of memory and learning - the two most important mechanisms through which the environment affects the behavior. Moreover, the concept of sensitive periods, that is to say periods of "vulnerability" or "opportunity" during which particular experiences affect brain growth, functional organization and maturation, is discussed. Brief overview of the neuroendocrine stress response system and the long-term effects of prolonged exposure to stress hormones on early brain development clarify further why children are more vulnerable than adults to the effects of stress. The section dealing with the memory, which is closely linked to the limbic system, attempts to discuss how early exposure to chronic stress or psychological trauma, through neurobiological effects and the process of learning, can lead to dysfunctional behaviors, which in its extreme form can be mental disorders. The two types of memory are discussed: (a) the implicit (nondeclarative), which develops during the prelingual stage of child's development and refers to unconscious memories of previous experiences, and (b) the explicit (declarative) memory, which is closely linked to language development and refers to memories that can be consciously recalled. Given that prenatal or postnatal early experiences can alter the course of brain development, the exposure to maltreatment, whether it takes the form of physical, sexual or emotional abuse, or the kind of extreme neglect and deprivation during the early years of life, is related to alterations in brain structure and function, which in turn contributes to development of chronic post-traumatic disorder (PTSD), anxiety, mood and attachment disorders, memory and learning problems, and other psychopathological conditions. Finally, it is pointed out that a comprehensive and detailed diagnostic assessment of young children who are referred to the child and adolescent mental health services because of presenting with behavioural and emotional disturbances should be an established good clinical practice, given that a wrong diagnosis may have further deleterious effects on the child's psychosocial development. The need for neuropsychological assessment of children who have been exposed to early trauma or stress is thought to have important implications for the recognition and the neurobiological understanding of early trauma, which in turn allows for the development and implementation of appropriate interventions.
22644546	A profound anterograde memory deficit for information, regardless of the nature of the material, is the hallmark of Korsakoff syndrome, an amnesic condition resulting from severe thiamine (vitamin B1) deficiency. Since the late nineteenth century when the Russian physician, S. S. Korsakoff, initially described this syndrome associated with "polyneuropathy," the observed global amnesia has been a primary focus of neuroscience and neuropsychology. In this review we highlight the historical studies that examined anterograde episodic memory processes in KS, present a timeline and evidence supporting the myriad theories proffered to account for this memory dysfunction, and summarize what is known about the neuroanatomical correlates and neural systems presumed affected in KS. Rigorous study of KS amnesia and associated memory disorders of other etiologies provide evidence for distinct mnemonic component processes and neural networks imperative for normal declarative and nondeclarative memory abilities and for mnemonic processes spared in KS, from whence emerged the appreciation that memory is not a unitary function. Debate continues regarding the qualitative and quantitative differences between KS and other amnesias and what brain regions and neural pathways are necessary and sufficient to produce KS amnesia.
22626934	This review concentrates on two different language dimensions: lexical/semantic and grammatical. This distinction between a lexical/semantic system and a grammatical system is well known in linguistics, but in cognitive neurosciences it has been obscured by the assumption that there are several forms of language disturbances associated with focal brain damage and hence language includes a diversity of functions (phoneme discrimination, lexical memory, grammar, repetition, language initiation ability, etc.), each one associated with the activity of a specific brain area. The clinical observation of patients with cerebral pathology shows that there are indeed only two different forms of language disturbances (disturbances in the lexical/semantic system and disturbances in the grammatical system); these two language dimensions are supported by different brain areas (temporal and frontal) in the left hemisphere. Furthermore, these two aspects of the language are developed at different ages during child's language acquisition, and they probably appeared at different historical moments during human evolution. Mechanisms of learning are different for both language systems: whereas the lexical/semantic knowledge is based in a declarative memory, grammatical knowledge corresponds to a procedural type of memory. Recognizing these two language dimensions can be crucial in understanding language evolution and human cognition.
22616657	Extensive research has shown that psychosocial stress can induce cognitive impairment. However, few studies have explored impairment following acute stress exposure in individuals with central obesity. Central obesity co-occurs with glucocorticoid excess and can lead to elevated cortisol responses to stress. It is not clear whether centrally obese individuals exhibit greater cognitive impairment following acute stress. Cortisol responses to stress versus no-stress control were compared in 66 high- and low waist to hip ratio (WHR) middle-aged adults (mean age of 46 ± 7.17 years). Cognitive performance post exposure was assessed using Cambridge Automated Neuropsychological Test Battery. It was hypothesised that high WHR would exhibit greater cortisol in response to stress exposure and would show poorer cognitive performance. Males, particularly of high WHR, tended to secrete greater cortisol during stress exposure. Exposure to stress and increasing WHR were specifically associated with poorer performance on declarative memory tasks (spatial recognition memory and paired associates learning). These data tentatively suggest a reduction in cognitive performance in those with central obesity following exposure to acute stress. Further research is needed to elucidate the effects of stress on cognition in this population.
22591117	Previous studies suggest that sleep-specific brain activity patterns such as sleep spindles and electroencephalographic slow-wave activity contribute to the consolidation of novel memories. The generation of both sleep spindles and slow-wave activity relies on synchronized oscillations in a thalamo-cortical network that might be implicated in synaptic strengthening (spindles) and downscaling (slow-wave activity) during sleep. This study further examined the association between electroencephalographic power during non-rapid eye movement sleep in the spindle (sigma, 12-16 Hz) and slow-wave frequency range (0.1-3.5 Hz) and overnight memory consolidation in 20 healthy subjects (10 men, 27.1 ± 4.6 years). We found that both electroencephalographic sigma power and slow-wave activity were positively correlated with the pre-post-sleep consolidation of declarative (word list) and procedural (mirror-tracing) memories. These results, although only correlative in nature, are consistent with the view that processes of synaptic strengthening (sleep spindles) and synaptic downscaling (slow-wave activity) might act in concert to promote synaptic plasticity and the consolidation of both declarative and procedural memories during sleep.
22588014	Chemotherapy has been reported to produce cognitive impairments in a significant number of cancer patients. These deficits frequently involve aspects of spatial or declarative memory which can persist for up to several years after completion of the treatment. We have recently shown that 5-fluorouracil (5-FU), a commonly used chemotherapy drug, induces cognitive impairment and a reduction in hippocampal neurogenesis using a rat model of chemotherapy (Elbeltagy et al. [17]). The present study examines the effects of two weeks of 5-FU treatment on cell proliferation in the sub granular zone (SGZ) of the dentate gyrus and the survival of newly dividing cells over a six week period after the end of treatment. Cell proliferation at each time point was quantified by staining for the cell proliferation marker Ki67 while the survival of cells, dividing at the start of treatment, was determined by quantification of BrdU positive cell numbers after pulse labelling with BrdU at the start of drug treatment. The results show that 2 weeks of 5-FU treatment did not significantly reduce cell proliferation in the SGZ immediately after treatment. However cell proliferation was significantly reduced, compared to saline treated controls, two weeks after the end of treatment and remained significantly reduced at 6 weeks. The survival of cells, dividing at the start of treatment, was significantly reduced when quantified immediately after the end of treatment and continued to decline compared with control animals over the following 2 weeks but no further change occurred at 6 weeks. Quantification of COX-2 positive cell numbers in the hippocampus did not correlate with the reduction in cell proliferation or survival suggesting that inflammation is not responsible for these changes. These results demonstrate that 5-FU has delayed and prolonged effects on hippocampal neurogenesis after the end of chemotherapy treatment. This correlates with patient reports of continued cognitive impairment after treatment and indicates that changes in neurogenesis may underlie these effects.
22585743	Experimental studies support a neurotrophic hypothesis of major depressive disorder (MDD). The aim of this study was to determine the effect of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism on the white matter fiber tracts connecting hippocampus and amygdala with the prefrontal lobe in a sample of patients with MDD and healthy controls. Thirty-seven patients with MDD and 42 healthy volunteers were recruited. Diffusion tensor imaging (DTI) data with 61 diffusion directions were obtained with MRI 3 Tesla scanner. Deterministic tractography was applied with ExploreDTI and Val66Met BDNF SNP (rs6265) was genotyped. Fiber tracts connecting the hippocampus and amygdala with the prefrontal lobe, namely uncinate fasciculus (UF), fornix, and cingulum were analyzed. A significant interaction was found in the UF between BDNF alleles and diagnosis. Patients carrying the BDNF met-allele had smaller fractional anisotropy (FA) in the UF compared to those patients homozygous for val-allele and compared to healthy subjects carrying the met-allele. A significant three-way interaction was detected between region of the cingulum (dorsal, rostral, and parahippocampal regions), brain hemisphere and BDNF genotype. Larger FA was detectable in the left rostral cingulum for met-allele carriers when compared to val/val alelle carriers. We provide evidence for the importance of the neurotrophic involvement in limbic and prefrontal connections. The met-allele of the BDNF polymorphism seems to render subjects more vulnerable for dysfunctions associated with the UF, a tract known to be related to negative emotional-cognitive processing bias, declarative memory problems, and autonoetic self awareness.
22583753	The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory.
22579682	The activity and regulation of the hypothalamus-pituitary-adrenal axis has been related to cognitive decline during aging. This study investigated whether the cortisol awakening response (CAR) is related to memory performance among older adults. The sample was composed of 88 participants (44 men and 44 women) from 55 to 77 years old. The memory assessment consisted of two tests measuring declarative memory (a paragraph recall test and a word list learning test) and two tests measuring working memory (a spatial span test and a spatial working memory test). Among those participants who showed the CAR on two consecutive days, we found that a greater CAR was related to poorer declarative memory performance in both men and women, and to better working memory performance only in men. The results of our study suggest that the relationship between CAR and memory performance is negative in men and women when memory performance is largely dependent on hippocampal functioning (i.e. declarative memory), and positive, but only in men, when memory performance is largely dependent on prefrontal cortex functioning (i.e. working memory).
22562440	Depressive disorder is a multifactorial diseases, that one of the typical feature are cognitive impairments. The aim of this study was to determine the total antioxidant status (TAS) in patients with recurrent depressive disorder (rDD) and to define relationship between plasma levels of TAS and the cognitive performance.the study comprised 74 subjects: patients with rDD (n = 45) and healthy subjects (n = 29). Cognitive function assessment was based on: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. Statistically significant differences were found in the intensity of depression symptoms, measured by the Hamilton Depression Rating Scale (HDRS) on therapy onset versus the examination results after 8 weeks of treatment (p < 0.001). The level of TAS was substantially higher in patients with rDD (p = 0.01). For rDD patients, elevated TAS levels were associated with worse cognitive test performance. The higher was the concentration of plasma TAS, the greater was the severity of depressive symptoms measured by HDRS before and after pharmacotherapy. (1) Higher concentration of plasma TAS in rDD patients is associated with the severity of depressive symptoms. (2) Elevated levels of plasma TAS are related to impairment of short-term declarative memory, long-term declarative-memory, verbal fluency and working memory.	
22561731	The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP-induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalo-cortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3mg/kg) on neural activation as reflected by transcriptional activation of c-fos in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-fos mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-fos mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-fos mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalo-cortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons.
22551681	Global deficits in declarative memory are commonly reported in individuals with schizophrenia and psychotic bipolar disorder, and in their biological relatives. However, it remains unclear whether there are specific components within the global declarative memory dysfunction that are unique to schizophrenia and bipolar disorder, or whether these impairments overlap the two psychoses. This study sought to characterize differential components of learning and memory in individuals within the psychosis dimension: probands with schizophrenia (SZP, n=33), probands with psychotic bipolar I disorder (BDP, n=20), and biological relatives of SZP (SZR, n=21), contrasted with healthy controls (HC, n=26). A computerized cognitive paradigm, the Acquired Equivalence test, with probes for associative learning, memory for learned associations, and memory generalization was administered, along with standardized neuropsychological measures of declarative memory. All study groups were able to learn and remember the associations, although SZP were slower than HC in the initial learning stages. Both SZP (significantly) and BDP (at a trend level) showed altered memory generalization compared to HC (SZP vs. HC, p=.038, d=.8; BDP vs. HC, p=.069, d=.95). SZR showed memory generalization intermediate between SZP and HC, although their performance did not differ significantly from either group. These findings indicate that probands with schizophrenia and bipolar psychoses have similar alteration in the ability to flexibly generalize learned knowledge when probed with novel stimuli, despite overall sufficient associative learning and memory for what they learned. These results suggest that the two disorders present a clinical continuum with overlapping hippocampus-mediated memory generalization dysfunction underlying the psychosis phenotype.
22545614	In the present study, we investigated the functional characteristics of task sets that were never applied before and were formed only on the basis of instructions. We tested if such task sets could elicit a task-rule congruency effect, which implies the automatic activation of responses in the context of another task. To this end, a novel procedure was developed that revealed instruction-based task-rule congruency effects in 2 experiments. Although the effect seems quite general (Experiment 1), it still necessitates the formation of a task set, as it cannot be induced by the mere maintenance of instructions in declarative working memory (Experiment 2). We conclude that a task set representing only key features of an upcoming task can be formed on the basis of instructions alone to such a degree that it can automatically trigger a response tendency in another task. Implications of our results for the impact of instructions on performance in general and for the occurrence of task-rule congruency effects in particular are discussed.
26301468	A large number of criteria have been proposed for determining when a behavior has become automatic. Almost all of these were developed before the widespread acceptance of multiple memory systems. Consequently, popular frameworks for studying automaticity often neglect qualitative differences in how different memory systems guide initial learning. Unfortunately, evidence suggests that automaticity criteria derived from these frameworks consistently misclassify certain sets of initial behaviors as automatic. Specifically, criteria derived from cognitive science mislabel much behavior still under the control of procedural memory as automatic, and criteria derived from animal learning mislabel some behaviors under the control of declarative memory as automatic. Even so, neither set of criteria make the opposite error-that is, both sets correctly identify any automatic behavior as automatic. In fact, evidence suggests that although there are multiple memory systems and therefore multiple routes to automaticity, there might nevertheless be only one common representation for automatic behaviors. A number of possible cognitive and cognitive neuroscience models of this single automaticity system are reviewed. WIREs Cogn Sci 2012, 3:363-376. doi: 10.1002/wcs.1172 For further resources related to this article, please visit the WIREs website. 
22534623	Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamine-conditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise.
22531200	Mental dysfunction and especially gait disorders, such as freezing and postural instability in "on phase," are partially unresponsive to dopaminergic therapy late in the course of Parkinson disease (PD). Some of them have been related to decreased sensitivity of postsynaptic dopaminergic receptors, and it is known that electroconvulsive therapy (ECT) enhances the sensitivity of these receptors. The aim of this study was to determine the efficacy and safety of ECT in patients with advanced Parkinson disease with symptoms partially unresponsive to L-dopa.Neurologic (Parkinson's Disease Questionnaire, Unified Parkinson's Disease Rating Scale, Tinetti Scale, and the Sit-to-Stand test), psychiatric (structured interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Hamilton Depression Rating Scale) and neuropsychological (Mini Mental State Examination, executive functions, declarative and procedural memory, visual processing, and reaction time) evaluation was performed on 9 patients with a diagnosis of L-dopa-resistant PD by the Movement Disorders Working Group. This evaluation was done before and after 8 sessions of bitemporal ECT. Six patients completed the study.	Statistically significant differences were found in the number of steps and freezing episodes in the on phase when they were compared before and after the ECT administration. However, no statistically significant differences were found in the "off" phenomena, motor fluctuations, or dyskinesias before and after ECT administration. No patient showed psychiatric symptoms before, during, or after the ECT. No statistically significant differences were observed in the neuropsychological results between the pretreatment and posttreatment evaluations. All patients showed transient amnesia after the ECT administration, which lasted for 48 hours.	Electroconvulsive therapy could be a safe and effective therapeutic option in L-dopa-resistant patients with PD with predominantly axial "on" phenomena; nevertheless, it needs to be confirmed in later studies.	
22529835	The recent spread of intracranial electroencephalographic (EEG) recording techniques for presurgical evaluation of drug-resistant epileptic patients is providing new information on the activity of different brain structures during both wakefulness and sleep. The interest has been mainly focused on the medial temporal lobe, and in particular the hippocampal formation, whose peculiar local sleep features have been recently described, providing support to the idea that sleep is not a spatially global phenomenon. The study of the hippocampal sleep electrophysiology is particularly interesting because of its central role in the declarative memory formation. Recent data indicate that sleep contributes to memory formation. Therefore, it is relevant to understand whether specific patterns of activity taking place during sleep are related to memory consolidation processes. Fascinating similarities between different states of consciousness (wakefulness, REM sleep, non-REM sleep) in some electrophysiological mechanisms underlying cognitive processes have been reported. For instance, large-scale synchrony in gamma activity is important for waking memory and perception processes, and its changes during sleep may be the neurophysiological substrate of sleep-related deficits of declarative memory. Hippocampal activity seems to specifically support memory consolidation during sleep, through specific coordinated neurophysiological events (slow waves, spindles, ripples) that would facilitate the integration of new information into the pre-existing cortical networks. A few studies indeed provided direct evidence that rhinal ripples as well as slow hippocampal oscillations are correlated with memory consolidation in humans. More detailed electrophysiological investigations assessing the specific relations between different types of memory consolidation and hippocampal EEG features are in order. These studies will add an important piece of knowledge to the elucidation of the ultimate sleep function.
22525744	Spatial navigation attracts the attention of neuroscientists as an animal analogue of human declarative memory. The Carousel maze is a dry-land navigational paradigm, which proved to be useful in studying neurobiological substrates of learning. The task involves avoidance of a stable sector on a rotating arena and is highly dependent upon the hippocampus. The present study aims at testing hypothesis that sulpiride (a centrally-active dopamine D2-like receptor antagonist) and propranolol (a beta-blocker) impair spatial learning in the Carousel maze after combined systemic administration. These doses were previously shown to be subthreshold in this task. Results showed that both substances affected behavior and significantly potentiated their negative effects on spatial learning. This suggests central interaction of both types of receptors in influencing acquisition of this dynamic-environment task.
22493573	Fundamental to all human languages is an unlimited expressive capacity and creative flexibility that allow speakers to rapidly generate novel and complex utterances. In turn, listeners interpret language "on-line," incrementally integrating multiple sources of information as words unfold over time. A challenge for theories of language processing has been to understand how speakers and listeners generate, gather, integrate, and maintain representations in service of language processing. We propose that many of the processes by which we use language place high demands on and receive contributions from the hippocampal declarative memory system. The hippocampal declarative memory system is long known to support relational binding and representational flexibility. Recent findings demonstrate that these same functions are engaged during the real-time processes that support behavior in-the-moment. Such findings point to the hippocampus as a potentially key contributor to cognitive functions that require on-line integration of multiple sources of information, such as on-line language processing. Evidence supporting this view comes from findings that individuals with hippocampal amnesia show deficits in the use of language flexibly and on-line. We conclude that the relational binding and representational flexibility afforded by the hippocampal declarative memory system positions the hippocampus as a key contributor to language use and processing.
22487365	Genetic variants that are related to the dopaminergic system have been frequently found to be associated with various neurological and mental disorders. Here, we studied the relationships between some of these genetic variants and some cognitive and psychophysiological processes that are implicated in such disorders. Two single nucleotide polymorphisms were chosen: one in the dopamine D2 receptor gene (rs6277-C957T) and one in the catechol-O-methyltransferase gene (rs4680-Val158Met), which is involved in the metabolic degradation of dopamine. The performance of participants on two long-term memory tasks was assessed: free recall (declarative memory) and mirror drawing (procedural motor learning). Heart rate (HR) was also monitored during the initial trials of the mirror-drawing task, which is considered to be a laboratory middle-stress generator (moderate stress), and during a rest period (low stress). Data were collected from 213 healthy Caucasian university students. The C957T C homozygous participants showed more rapid learning than the T allele carriers in the procedural motor learning task and smaller differences in HR between the moderate- and the low-stress conditions. These results provide useful information regarding phenotypic variance in both healthy individuals and patients.
22485133	Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation.
22483294	Alzheimer's disease (AD) is the leading cause of dementia worldwide and is associated with a marked individual, familial and social burden. Catechol-O-mehyltransferase (COMT) is surfacing with a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters and estrogen. COMT gene regulates dopamine levels in the prefrontal cortex which are involved in working memory and executive functioning. Impaired executive functioning is reported in a subgroup of AD patients and is associated with a more severe disorder, a more rapid disease progression and a shorter survival. The COMT rs4680 gene polymorphism has been investigated as a susceptibility factor for AD. No statistically significant results were found in meta-analysis but one study reported that the rs4680 Val allele was associated with AD-related psychosis. The COMT rs4680 polymorphism was also found to modulate declarative episodic memory in normal people and schizophrenic subjects. COMT inhibitors, that are adjunctive drugs in Parkinson's disease treatment, lower homocysteine levels and improve executive memory processes in normal subjects. A preliminary study, which needs replication, demonstrates that COMT inhibitors block beta-amyloid fibrils in vitro. Taken together, these findings suggest that research should focus on the role of COMT in AD pathogenesis and on the feasibility of targeting COMT activity in AD treatment.
22482692	We investigated structural brain damage in subjects who had suffered severe and diffuse traumatic brain injury (TBI), and examined its relationship with declarative memory impairment. Cortical thickness, diffusion tensor imaging (DTI), and volumetric and shape data of the hippocampus were assessed in a group of 26 adults with severe TBI in the chronic stage and 22 healthy matched controls. Declarative memory was evaluated by Rey's Auditory Verbal Learning Test (RAVLT). TBI patients performed significantly worse than controls on all RAVLT measures. The group comparison for cortical thickness and DTI revealed a pattern of widespread atrophy in TBI patients. In the TBI group DTI measures correlated with cortical thickness in the prefrontal and parietal regions, including the precuneus. Declarative memory correlated with both cortical thickness and DTI measures. However, although hippocampal volume was significantly decreased in TBI patients, no correlations were found. Multiple regression analysis of all the structural measures revealed that decreases in Fractional anisotropy (FA) and thinning of the left parietal region were the best predictors of memory impairment. In conclusion, cortical thickness reductions in the left hemisphere and a lack of white matter integrity are the main contributors to long-term impairment in declarative memory among patients suffering from severe and diffuse TBI. In this study the hippocampus did not make a significant contribution to memory dysfunctions, suggesting that damage to this structure is compensated for by other regions, with the definitive sequelae being mainly explained by alterations in cortico-subcortical connectivity.
22480490	Sleep can improve the off-line memory consolidation of new items of declarative and non-declarative information in healthy subjects, whereas acute sleep loss, as well as sleep restriction and fragmentation, impair consolidation. This suggests that, by modifying the amount and/or architecture of sleep, chronic sleep disorders may also lead to a lower gain in off-line consolidation, which in turn may be responsible for the varying levels of impaired performance at memory tasks usually observed in sleep-disordered patients. The experimental studies conducted to date have shown specific impairments of sleep-dependent consolidation overall for verbal and visual declarative information in patients with primary insomnia, for verbal declarative information in patients with obstructive sleep apnoeas, and for visual procedural skills in patients with narcolepsy-cataplexy. These findings corroborate the hypothesis that impaired consolidation is a consequence of the chronically altered organization of sleep. Moreover, they raise several novel questions as to: a) the reversibility of consolidation impairment in the case of effective treatment, b) the possible negative influence of altered prior sleep also on the encoding of new information, and c) the relationships between altered sleep and memory impairment in patients with other (medical, psychiatric or neurological) diseases associated with quantitative and/or qualitative changes of sleep architecture.
22471636	Recent work in neuroscience has highlighted the contrast between 'procedural' memory for bodily experiences and skills, which is unconscious though unrepressed, and verbalizable, 'declarative' memory, which includes autobiographical memory. Autobiographical memory is weak in people with autistic spectrum disorder, who frequently turn to self-generated sensations for reassurance that they continue to exist. The author suggests that, instead of internalizing shared experiences leading to growth, children with autism can feel that they add to themselves by taking over the qualities of others through the 'annexation' of physical properties that leads to a damaged object and can trigger a particular sort of negative therapeutic reaction. Clinical illustrations drawn from the treatment of two children on the autistic spectrum illustrate some ramifications of these processes in relation to the sense of a separate identity and the capacity to access memories.
22470434	Although learning a second language (L2) as an adult is notoriously difficult, research has shown that adults can indeed attain native language-like brain processing and high proficiency levels. However, it is important to then retain what has been attained, even in the absence of continued exposure to the L2--particularly since periods of minimal or no L2 exposure are common. This event-related potential (ERP) study of an artificial language tested performance and neural processing following a substantial period of no exposure. Adults learned to speak and comprehend the artificial language to high proficiency with either explicit, classroom-like, or implicit, immersion-like training, and then underwent several months of no exposure to the language. Surprisingly, proficiency did not decrease during this delay. Instead, it remained unchanged, and there was an increase in native-like neural processing of syntax, as evidenced by several ERP changes--including earlier, more reliable, and more left-lateralized anterior negativities, and more robust P600s, in response to word-order violations. Moreover, both the explicitly and implicitly trained groups showed increased native-like ERP patterns over the delay, indicating that such changes can hold independently of L2 training type. The results demonstrate that substantial periods with no L2 exposure are not necessarily detrimental. Rather, benefits may ensue from such periods of time even when there is no L2 exposure. Interestingly, both before and after the delay the implicitly trained group showed more native-like processing than the explicitly trained group, indicating that type of training also affects the attainment of native-like processing in the brain. Overall, the findings may be largely explained by a combination of forgetting and consolidation in declarative and procedural memory, on which L2 grammar learning appears to depend. The study has a range of implications, and suggests a research program with potentially important consequences for second language acquisition and related fields.
22457736	Numerous studies have examined sleep's influence on a range of hippocampus-dependent declarative memory tasks, from text learning to spatial navigation. In this study, we examined the impact of sleep, wake, and time-of-day influences on the processing of declarative information with strong semantic links (semantically related word pairs) and information requiring the formation of novel associations (unrelated word pairs). Participants encoded a set of related or unrelated word pairs at either 9 am or 9 pm, and were then tested after an interval of 30 min, 12 hr, or 24 hr. The time of day at which subjects were trained had no effect on training performance or initial memory of either word pair type. At 12 hr retest, memory overall was superior following a night of sleep compared to a day of wakefulness. However, this performance difference was a result of a pronounced deterioration in memory for unrelated word pairs across wake; there was no sleep-wake difference for related word pairs. At 24 hr retest, with all subjects having received both a full night of sleep and a full day of wakefulness, we found that memory was superior when sleep occurred shortly after learning rather than following a full day of wakefulness. Lastly, we present evidence that the rate of deterioration across wakefulness was significantly diminished when a night of sleep preceded the wake period compared to when no sleep preceded wake, suggesting that sleep served to stabilize the memories against the deleterious effects of subsequent wakefulness. Overall, our results demonstrate that 1) the impact of 12 hr of waking interference on memory retention is strongly determined by word-pair type, 2) sleep is most beneficial to memory 24 hr later if it occurs shortly after learning, and 3) sleep does in fact stabilize declarative memories, diminishing the negative impact of subsequent wakefulness.
22440335	Although increased anxiety and cortisol reactivity can disrupt neural activity and impact cognition, little research has evaluated associations between anxiety, cortisol, and performance on neuropsychological instruments. The current study investigated the relationship between exogenous salivary cortisol activity and self-report state anxiety on measures tapping a variety of cognitive domains. Fifty-eight male participants were randomly assigned to either a control (no stress induction) or an experimental condition simulating testing anxiety. Self-report state anxiety measures and saliva samples were jointly collected on three occasions. The experimental group generally performed worse than controls on declarative memory and working memory tests. Cortisol and self-report anxiety were not correlated. Inverse relationships were demonstrated between self-report anxiety and neuropsychological test scores. Baseline levels of cortisol at session arrival were positively associated with facilitative memory effects, though there was little association between changes in cortisol and cognitive performance. This study highlights the importance of considering the impact of anxiety during neuropsychological evaluations.
22430027	Extensive research has been accumulated demonstrating that sleep is essential for processes of memory consolidation in adults. In children and infants, a great capacity to learn and to memorize coincides with longer and more intense sleep. Here, we review the available data on the influence of sleep on memory consolidation in healthy children and infants, as well as in children with attention-deficit/hyperactivity disorder (ADHD) as a model of prefrontal impairment, and consider possible mechanisms underlying age-dependent differences. Findings indicate a major role of slow wave sleep (SWS) for processes of memory consolidation during early development. Importantly, longer and deeper SWS during childhood appears to produce a distinctly superior strengthening of hippocampus-dependent declarative memories, but concurrently prevents an immediate benefit from sleep for procedural memories, as typically observed in adults. Studies of ADHD children point toward an essential contribution of prefrontal cortex to the preferential consolidation of declarative memory during SWS. Developmental studies of sleep represent a particularly promising approach for characterizing the supra-ordinate control of memory consolidation during sleep by prefrontal-hippocampal circuitry underlying the encoding of declarative memory.
22415192	Thalamo-cortical feedback loops play a key role in the processing and coordination of processing and integration of perceptual inputs and outputs, and disruption in this connection has long been hypothesized to contribute significantly to neuropsychological disturbances in schizophrenia. To test this hypothesis, we applied diffusion tensor tractography to 18 patients suffering schizophrenia and 20 control subjects. Fractional anisotropy (FA) was evaluated in the bilateral anterior and posterior limbs of the internal capsule, and correlated with clinical and neurocognitive measures. Patients diagnosed with schizophrenia showed significantly reduced FA bilaterally in the anterior but not the posterior limb of the internal capsule, compared with healthy control subjects. Lower FA correlated with lower scores on tests of declarative episodic memory in the patient group only. These findings suggest that disruptions, bilaterally, in thalamo-cortical connections in schizophrenia may contribute to disease-related impairment in the coordination of mnemonic processes of encoding and retrieval that are vital for efficient learning of new information.
22410753	Volumetric measures of mesial temporal lobe structures on MRI scans recently have been explored as potential biomarkers of dementia in patients with PD, with investigations primarily focused on hippocampal volume. Both in vivo MRI and postmortem tissue studies in Alzheimer's disease, however, demonstrate that the entorhinal cortex (ERC) is involved earlier in disease-related pathology than the hippocampus. The ERC, a region integral in declarative memory function, projects multimodal sensory information to the hippocampus through the perforant path. In PD, ERC atrophy, as measured on MRI, however, has received less attention, compared to hippocampal atrophy. We compared ERC and hippocampal atrophy in 12 subjects with PD dementia including memory impairment, 14 PD subjects with normal cognition, and 14 healthy controls with normal cognition using manual segmentation methods on MRI scans. Though hippocampal volumes were similar in the two PD cognitive groups, ERC volumes were substantially smaller in the demented PD subjects, compared to cognitively normal PD subjects (P < 0.05). In addition, normalized ERC and hippocampal volumes for right and left hemispheres were significantly lower in the demented PD group, compared to healthy controls. Our findings suggest that ERC atrophy differentiates demented and cognitively normal PD subjects, in contrast to hippocampal atrophy. Thus, ERC atrophy on MRI may be a potential biomarker for dementia in PD, particularly in the setting of memory impairment.
22409507	Behavioral evidence concerning memory in forms of high-functioning autism (HFA) and in moderately low-functioning autism (M-LFA) is reviewed and compared. Findings on M-LFA are sparse. However, it is provisionally concluded that memory profiles in HFA and M-LFA (relative to ability-matched controls) are similar but that declarative memory impairments are more extensive in M-LFA than in HFA. Specifically, both groups have diminished memory for emotion- or person-related stimuli. Regarding memory for nonsocial stimuli, both groups probably have mental-age-appropriate nondeclarative memory, and within declarative memory, both groups have mental-age-appropriate immediate free recall of within-span or supraspan lists of unrelated items, as well as cued recall and paired associate learning. By contrast, recognition is largely unimpaired in HFA but moderately impaired in M-LFA, and free recall of meaningful or structured stimuli is moderately impaired in HFA but more severely impaired in M-LFA. Theoretical explanations of data on declarative memory in HFA identify problems in the integrative processing, or the consolidation and storage, of complex stimuli or a specific problem of recollection. Proposed neural substrates include the following: disconnectivity of primary sensory and association areas; dysfunctions of medial prefrontal cortex, hippocampus, or posterior parietal lobe; or combinations of these associated with neural disconnectivity. Hypothetically, perirhinal dysfunction might explain the more extensive declarative memory impairments in M-LFA. Foreseeable consequences of uneven memory abilities in HFA and M-LFA are outlined, including possible effects on language and learning in M-LFA. Finally, priorities for future research are identified, highlighting the urgent need for research on memory in lower functioning individuals.
22403534	Working memory (WM) is the ability to transiently maintain and manipulate internal representations beyond its external availability to the senses. This process is thought to support high level cognitive abilities and been shown to be strongly predictive of individual intelligence and reasoning abilities. While early models of WM have relied on a modular perspective of brain functioning, more recent evidence suggests that cognitive functions emerge from the interactions of multiple brain regions to generate large-scale networks. Here we will review the current research on functional connectivity of WM processes to highlight the critical role played by neural interactions in healthy and pathological brain states. Recent findings demonstrate that WM abilities are not determined solely by local brain activity, but also rely on the functional coupling of neocortical-hippocampal regions to support WM processes. Although the hippocampus has long been held to be important for long-term declarative memory, recent evidence suggests that the hippocampus may also be necessary to coordinate disparate cortical regions supporting the periodic reactivation of internal representations in WM. Furthermore, recent brain imaging studies using connectivity measures, have shown that changes in cortico-limbic interactions can be useful to characterize WM impairments observed in different neuropathological conditions. Recent advances in electrophysiological and neuroimaging techniques to model network activity has led to important insights into how neocortical and hippocampal regions support WM processes and how disruptions along this network can lead to the memory impairments commonly reported in many neuropathological populations.
22401298	Focal bilateral hippocampal damage typically causes severe and selective amnesia for new declarative information (facts and events), a cognitive deficit that greatly impacts the ability to live a normal, fully independent life. We describe the case of 1846, a 48-year-old woman with profound hippocampal amnesia following status epilepticus and an associated anoxic episode at age 30. Patient 1846 has undergone extensive neuropsychological testing on many occasions over the 18 years since her injury, and we present data indicating that her memory impairment has remained severe and stable during that time. New, high-resolution, structural MRI studies of 1846's brain reveal substantial bilateral hippocampal atrophy resembling that of other well-known amnesic patients. In spite of severe amnesia 1846 lives a full and mostly independent adult life, facilitated by an extensive social support network of family and friends. Her case provides an example of a rare and unlikely positive outcome in the face of severe memory problems.
22389627	The hippocampus is crucial for episodic or declarative memory and the theta rhythm has been implicated in mnemonic processing, but the functional contribution of theta to memory remains the subject of intense speculation. Recent evidence suggests that the hippocampus might function as a network hub for volitional learning. In contrast to human experiments, electrophysiological recordings in the hippocampus of behaving rodents are dominated by theta oscillations reflecting volitional movement, which has been linked to spatial exploration and encoding. This literature makes the surprising cross-species prediction that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. We examined the links between theta, spatial exploration, and memory encoding by designing an interactive human spatial navigation paradigm combined with multimodal neuroimaging. We used both non-invasive whole-head Magnetoencephalography (MEG) to look at theta oscillations and Functional Magnetic Resonance Imaging (fMRI) to look at brain regions associated with volitional movement and learning. We found that theta power increases during the self-initiation of virtual movement, additionally correlating with subsequent memory performance and environmental familiarity. Performance-related hippocampal theta increases were observed during a static pre-navigation retrieval phase, where planning for subsequent navigation occurred. Furthermore, periods of the task showing movement-related theta increases showed decreased fMRI activity in the parahippocampus and increased activity in the hippocampus and other brain regions that strikingly overlap with the previously observed volitional learning network (the reverse pattern was seen for stationary periods). These fMRI changes also correlated with participant's performance. Our findings suggest that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. These findings directly extend the role of the hippocampus in spatial exploration in rodents to human memory and self-directed learning.
22374914	To evaluate the role of gender on the hearing performance of postlingually deafened adult patients with cochlear implants.Individual retrospective cohort study.	There were 638 postlingually deafened adults (280 men and 358 women) selected for a retrospective evaluation of their hearing performance with cochlear implants. Both genders underwent the same surgical and rehabilitative procedures and benefited from the latest technological advances available. There was no significant difference in the age, duration of deafness, and preoperative hearing performance between the genders. The test battery was composed of the Freiburger Monosyllabic Test, Speech Tracking, and the Hochmair-Schulz-Moser (HSM) sentence test in quiet and in 10-dB noise. The results of 5 years of follow-up are presented here.	Genders showed a similar performance in Freiburger Monosyllabic Test and Speech Tracking Test. However, in the HSM test in noise, men performed slightly better than women in all of the follow-up sessions, which was statistically significant at 2 and 4 years after implantation.	Although normal-hearing women use more predictive cognitive strategies in speech comprehension and are supposed to have a more efficient declarative memory system, this may not necessarily lead to a better adaptation to the altered auditory information delivered by a cochlear implant. Our study showed that in more complex listening situations such as speech tests in noise, men tend to perform slightly better than women. Gender may have an influence on the hearing performance of postlingually deafened adults with cochlear implants.	
22366337	Changes in the cortisol awakening response (CAR) have been reportedly associated with older age and may reflect changes in cognitive performance. However methodological issues around adherence, in regard to careful timing of the CAR, suggest caution in drawing firm conclusions. More investigation is also needed regarding which cognitive domains may be most relevant. Executive Function (EF) is linked strongly to functioning of the frontal cortex, itself linked to cortisol secretion via regulation of the Hypothalamic Adrenocortical Axis. In this study, cortisol profiles, cognitive performance and adherence were carefully assessed in a sample of 50 older participants, aged 60-91 years (mean=74 years). Key aspects of EF were assessed using Form B of the standard Trail-making Test controlling for time taken to complete the simpler Trail-A form of the test. Strong associations between CAR profiles and EF were evident. Cortisol measures significantly predictive of superior EF-related performance in a regression analysis were: earlier peaking and greater magnitude of the CAR. Together these measures explained fully a quarter of all the variance in test performance (R(2)=0.25; F=7.90; df=2,47; p<.001). Cognitive tests of declarative memory, often linked to hippocampal functioning, were not associated with CAR profiles. We conclude that in a population of healthy older adults aspects of the CAR may be strongly, and perhaps with some degree of specificity, associated with that domain of cognitive functioning, EF, which seems to depend crucially on the integrity of frontal cortex circuitry.
22366054	Learning and memory of declarative knowledge and relational information are dependent on the integrity of medial temporal lobe (MTL). Numerous studies suggest that left lobectomy impairs verbal memory while right lobectomy impairs non-verbal memory. In order to instrumentally quantify material-specific memory impairment after temporal lobe excision, we compared, using a computerized conditional motor associative learning task, patients with surgically treated drug-resistant temporal lobe epilepsy to age-matched controls. We enrolled seven epileptic patients with left (LTR), seven with right (RTR) temporal lobe resection and fourteen controls. During the task, abstract visual stimuli had to be associated, by trial and error, with a spatially oriented joystick motor response. Response and decision time were analyzed. Statistical analysis disclosed that the learning curve slopes of both RTR and LTR patients were significantly shallower compared to controls, LTR patients needed a number of test trials significantly increased compared to RTR patients and controls, the average probability of success in the test trials was significantly lower in LTR patients compared to RTR patients and controls, and RTR patients' decision times were significantly longer than LTR patients and controls. The results suggest that RTR patients, using the preserved verbalization strategy, achieved higher learning scores than LTR patients, which were forced to use a visuo-spatial representation of the stimuli-response association. Accordingly, RTR patients were significantly slower, compared to LTR patients and controls, indicating that processes involving recall were partially impaired, and non-canonical networks for executing a non-verbal task could be in action.
26301397	Damage to the hippocampus and related brain regions causes a profound amnesic syndrome, in which patients are unable to form new memories about their experiences and about facts about the world. A number of theories have been proposed to explain hippocampal function. The theories that are currently most influential propose that the hippocampus is the substrate of declarative or episodic memory and that the hippocampus is the neural locus of a cognitive map. Anatomical, physiological, and behavioral studies of the hippocampal system have enabled a rich understanding of a number of general principles of information processing and storage in the brain. In this article, we describe key anatomical and physiological features of hippocampal function as well as the most influential theories of hippocampal function. WIREs Cogn Sci 2012, 3:231-251. doi: 10.1002/wcs.1164 For further resources related to this article, please visit the WIREs website. 
22359397	The self has been the topic of philosophical inquiry for centuries. Neuropsychological data suggest that the declarative self can be fractionated into three functionally independent systems processing personal information at several levels of abstraction, including episodic memories of one's own life (episodic autobiographical memory, EAM), semantic knowledge of facts about one's own life (semantic autobiographical memory, SAM), and semantic summary representations of one's personal identity (conceptual self, CS). Our proposal here was to present a comprehensive description of the neural networks underpinning self-representations. To this aim, we performed three meta-analyses, one each for EAM, SAM, and CS, using the activation likelihood estimation (ALE) method. We expected a shift from posterior to anterior structures associated with the incrementally increasing level of abstraction of self-representations. The key finding was that EAM predominantly activates posterior and limbic regions including hippocampus. SAM is associated with anterior activations and also posterior and limbic activations in a lesser degree than EAM. CS mainly recruits medial prefrontal structures. Interestingly, medial prefrontal cortex is activated irrespective of the level of abstraction, but a more caudal part is recruited during CS, while SAM and EAM activate more rostral portions. To conclude, in line with the previous proposals, our results corroborate the idea that the declarative self is not monolithic but a multidimensional construct comprising distinct representations at different levels of abstraction.
22350434	In patients with cerebral tumors, deficits in declarative episodic memory typically result from damage to structures of the Papez circuit. These deficits can arise directly from the action of the tumor mass or indirectly from the surgical intervention. Memory deficits are also frequently seen in patients who show no direct involvement of the Papez circuit. In these patients, the memory impairment probably results from disruption of frontal lobe functioning (caused by localization of the tumor at this level or disconnection from subcortical afferents). Here, I review the neuropsychological tools used to differentiate amnesic syndromes resulting from lack of consolidation of new memory traces (as a consequence of damage to the Papez circuit) from amnesias resulting from reduced efficiency of elaborative encoding and/or strategic retrieval processes (as a consequence of frontal lobe damage). The clinical and rehabilitative implications of this distinction are briefly discussed.
22350217	Several studies, showing that attention disorders during encoding reduce later memory performance, have stressed the critical role of attention for the formation of durable memory traces. Accordingly, some studies suggest that attentive disturbances, together with declarative memory defects, can constitute the earliest cognitive disorders in Alzheimer's disease. Therefore, the analysis of these disorders can contribute to identify different forms of dementia and to detect demented patients characterized by a faster cognitive decline. In this study, we report the normative data (gathered in a large Italian population) of a short test that assess the ability to detect stimuli characterized by a conjunction of features: the 'Multiple Features Targets Cancellation' task (MFTC). Our sample of 465 subjects was composed by urban and rural people. Multiple linear regression analyses revealed significant relation of false alarms with age and educational level, and of time of execution with age, educational level and gender. Regression analyses on accuracy scores did not show any significant correlation with demographics variables. Based on non-parametric techniques, cutoff scores were obtained on the corrected scores of the patients, and equivalent scores were derived for each measure. The MFTC task represents a useful tool that explores attentional disorders (and in particular conjunction search disturbances) and that could be helpful both in discriminating different forms of dementia and to detect mild cognitive impairment patients at risk of conversion to dementia.
22345366	We examined social cognition in a sample of healthy participants who had prior magnetic resonance imaging (MRI) gray matter volume studies of the orbital frontal cortex (OFC) that was parcellated into three regions: gyrus rectus, middle orbital gyrus and lateral orbital gyrus. These subjects also completed a self-report measure of Machiavelli personality traits, along with psychometric tests of social comprehension and declarative episodic memory, all of which we used as proxy measures to examine various features of social cognition. The data pointed to distinct functional-anatomical relationships highlighted by strong correlations of left lateral orbital gyrus and Machiavellian scores and right middle orbital gyrus with social comprehension and declarative episodic memory. In addition, hierarchical regression analyses revealed statistical evidence of a double dissociation between Machiavellian scores and left lateral orbital gyrus on one hand, and social comprehension with right middle orbital gyrus, on the other hand. To our knowledge, these findings are the first to show evidence linking normal variation in OFC subregions and different aspects of social cognition.
22342122	This study sought to characterize the psychosis phenotype, contrasting cognitive features within traditional diagnosis and psychosis dimension in a family sample containing both schizophrenia and psychotic bipolar I disorder. Seventy-six probands with psychosis [44 probands with schizophrenia, 32 probands with psychotic bipolar I disorder] and 55 first-degree relatives [30 relatives of schizophrenia probands, 25 relatives of bipolar probands] were recruited. Standardized clinical and neuropsychological measures were administered. No differences in cognitive performance emerged between probands with schizophrenia and probands with psychotic bipolar disorder, or between relatives of probands with schizophrenia and relatives of probands with bipolar disorder in the domains of working and declarative memory, executive function and attention. Relatives overall showed higher cognitive performance compared to probands, as expected. However, when we segmented the probands and relatives along a psychosis dimension, independent of diagnostic groups, results revealed lower cognitive performance in probands compared to relatives without psychosis spectrum disorders, whereas relatives with psychosis spectrum disorders showed an intermediate level of performance across all cognitive domains. In this study, cognitive performance did not distinguish either probands or their first-degree relatives within traditional diagnostic groups (schizophrenia and psychotic bipolar disorder), but distinguished probands and relatives with and without lifetime psychosis manifestations independent of diagnostic categories. These data support the notion that schizophrenia and psychotic bipolar disorder present a clinical continuum with overlapping cognitive features defining the psychosis phenotype.
22332900	The article investigates the relation between declarative and procedural working memory (WM; Oberauer, 2009). Two experiments test the assumption that representations in the two subsystems are selected for processing in analogous ways. Participants carried out a series of decisions on memorized lists of digits. For each decision, they had to select declarative and procedural representations. Regarding declarative representations, participants selected a memory set and a digit within this set as the input to each decision. With respect to the procedural representations, they selected a task set to be applied to the selected digit and a response within that task set. We independently manipulated the number of lists and the number of tasks to be switched among (one, two, or three; Experiment 1) and preparation time for a list switch (Experiment 2). For three effects commonly observed in task-switch studies, analogues in declarative WM were found: list-switch costs, mixing costs, and residual switch costs. List- and task-switch costs were underadditive, suggesting that declarative and procedural representations are selected separately and in parallel. The findings support the hypothesis of two analogous WM subsystems.
22302828	How information is manipulated and segregated within local circuits in the frontal cortex remains mysterious, in part because of inadequate knowledge regarding the connectivity of diverse pyramidal cell subtypes. The frontal cortex participates in the formation and retrieval of declarative memories through projections to the perirhinal cortex, and in procedural learning through projections to the striatum/pontine nuclei. In rat frontal cortex, we identified two pyramidal cell subtypes selectively projecting to distinct subregions of perirhinal cortex (PRC). PRC-projecting cells in upper layer 2/3 (L2/3) of the frontal cortex projected to perirhinal area 35, while neurons in L5 innervated perirhinal area 36. L2/3 PRC-projecting cells partially overlapped with those projecting to the basolateral amygdala. L5 PRC-projecting cells partially overlapped with crossed corticostriatal cells, but were distinct from neighboring corticothalamic (CTh)/corticopontine cells. L5 PRC-projecting and CTh cells were different in their electrophysiological properties and dendritic/axonal morphologies. Within the frontal cortex, L2/3 PRC-projecting cells innervated L5 PRC-projecting and CTh cells with similar probabilities, but received feedback excitation only from PRC-projecting cells. These data suggest that specific neuron subtypes in different cortical layers are reciprocally excited via interlaminar loops. Thus, two interacting output channels send information from the frontal cortex to different hierarchical stages of the parahippocampal network, areas 35 and 36, with additional collaterals selectively targeting the amygdala or basal ganglia, respectively. Combined with the hierarchical connectivity of PRC-projecting and CTh cells, these observations demonstrate an exquisite diversification of frontal projection neurons selectively connected according to their participation in distinct memory subsystems.
22300710	Whereas patients with Alzheimer's disease (AD) experience difficulties forming and retrieving memories, their memory impairments may also partially reflect an unrecognized dysfunction in sleep-dependent consolidation that normally stabilizes declarative memory storage across cortical areas. Patients with amnestic mild cognitive impairment (aMCI) exhibit circumscribed declarative memory deficits, and many eventually progress to an AD diagnosis. Whether sleep is disrupted in aMCI and whether sleep disruptions contribute to memory impairment is unknown. We measured sleep physiology and memory for two nights and found that aMCI patients had fewer stage-2 spindles than age-matched healthy adults. Furthermore, aMCI patients spent less time in slow-wave sleep and showed lower delta and theta power during sleep compared to controls. Slow-wave and theta activity during sleep appear to reflect important aspects of memory processing, as evening-to-morning change in declarative memory correlated with delta and theta power during intervening sleep in both groups. These results suggest that sleep changes in aMCI patients contribute to memory impairments by interfering with sleep-dependent memory consolidation.
22273980	Depressive disorders are multifactorial diseases, in which cognitive impairment is one of the characteristic feature. One of the molecules that regulate of various cognitive, emotional and behavioural processes is nitric oxide (NO), synthesized from l-arginine by a family of isoformic enzymes known as nitric oxide synthases (NOS). NO is a gaseous compounds that acts as a biological second messenger in a number of organ system. In addition, NO is a ubiquitous free radical (NO) that affects many normal physiologic functions but is also implicated in the etiology and progression of many diseases. The aim of the study was to determine the concentration of NO in patients with recurrent depressive disorder (rDD) and to define relationship between plasma NO levels and the cognitive performance.The study comprised 78 subjects: patients with rDD (n=45), healthy controls (CG, n=33). Cognitive function assessment was based on: TMT, The Stroop Test, VFT, AVLT.	Statistically significant differences were found among patients with rDD in the intensity of depression symptoms, measured by the HDRS on therapy onset vs. the examination results after 8 weeks of treatment (p<0.001). The level of NO was substantially higher in patients with rDD compared to CG. For all examined subjects (p<0.001), elevated levels of NO in blood plasma adversely affect the efficiency of visual-spatial and auditory-verbal working memory as well as short-term declarative memory. For rDD patients, elevated NO levels were associated with worse cognitive test performance. The higher was the concentration of plasma NO, the greater was the severity of depressive symptoms measured by HDRS (p=0.03).	(1) Higher concentration of plasma NO in rDD patients is associated with the severity of depressive symptoms. (2) Elevated levels of plasma NO are related to impairment of visual-spatial and auditory-verbal working memory as well as to impairment of short-term declarative memory.	
22269006	The aim of this article is to review neuroimaging studies of autism spectrum disorders (ASD) that examine declarative, socio-emotional, and procedural learning and memory systems.We conducted a search of PubMed from 1996 to 2010 using the terms 'autism,''learning,''memory,' and 'neuroimaging.' We limited our review to studies correlating learning and memory function with neuroimaging features of the brain.	The early literature supports the following preliminary hypotheses: (1) abnormalities of hippocampal subregions may contribute to autistic deficits in episodic and relational memory; (2) disturbances to an amygdala-based network (which may include the fusiform gyrus, superior temporal cortex, and mirror neuron system) may contribute to autistic deficits in socio-emotional learning and memory; and (3) abnormalities of the striatum may contribute to developmental dyspraxia in individuals with ASD.	Characterizing the disturbances to learning and memory systems in ASD can inform our understanding of the neural bases of autistic behaviors and the phenotypic heterogeneity of ASD.	
22257534	The aim of this study was to study cognitive procedural learning in early Alzheimer's disease (AD).Cognitive procedural learning was assessed using the Tower of Hanoi (TH) task. In order to take account of possible interactions between different systems during cognitive procedural learning, we also measured non-verbal intellectual functions, working memory, and declarative memory.	Our results showed an apparent preservation of cognitive procedural learning in AD and a deleterious effect of the disease on verbal intelligence and declarative memory. Correlational analyses revealed a difference between AD patients and control participants in the type of processing they applied to the task.	The non-involvement of declarative memory would appear to be partly responsible for a slowdown in the cognitive procedural dynamics of AD patients. As the AD patients were unable to use their declarative memory, they were still in a problem-solving mode at the end of the learning protocol and had to implement higher order cognitive processes (i.e., compensatory mechanisms) to perform the procedural task.	
22252785	A progressive accumulation of amyloid β-protein (Aβ) is widely recognized as a pathological hallmark of Alzheimer's disease (AD). Substantial progress has been made toward understanding the neurodegenerative cascade initiated by small soluble species of Aβ and recent evidence supports the notion that microtubule rearrangements may be proximate to neuritic degeneration and deficits in episodic declarative memory. Here, we examined primary cortical neurons for changes in markers associated with synaptic function following exposure to sublethal concentrations of non-aggregated Aβ-peptide. This data show that soluble Aβ species at a sublethal concentration induce degradation of the microtubule-associated protein 1A (MAP1A) without concurrently affecting dendritic marker MAP2 and/or the pre-synaptic marker synaptophysin. In addition, MAP1A was found to highly co-localize with the postsynaptic density-95 (PSD-95) protein, proposing that microtubule perturbations might be central for the Aβ-induced neuronal dysfunctions as PSD-95 plays a key role in synaptic plasticity. In conclusion, this study suggests that disruption of MAP1A could be a very early manifestation of Aβ-mediated synaptic dysfunction-one that presages the clinical onset of AD by years. Moreover, our data support the notion of microtubule-stabilizing agents as effective AD drugs.
22244090	Sleep benefits memory across a range of tasks for young adults. However, remarkably little is known of the role of sleep on memory for healthy older adults. We used 2 tasks, 1 assaying motor skill learning and the other assaying nonmotor/declarative learning, to examine off-line changes in performance in young (20-34 years), middle-aged (35-50 years), and older (51-70 years) adults without disordered sleep. During an initial session, conducted either in the morning or evening, participants learned a motor sequence and a list of word pairs. Memory tests were given twice, 12 and 24 hours after training, allowing us to analyze off-line consolidation after a break that included sleep or normal wake. Sleep-dependent performance changes were reduced in older adults on the motor sequence learning task. In contrast, sleep-dependent performance changes were similar for all 3 age groups on the word pair learning task. Age-related changes in sleep or networks activated during encoding or during sleep may contribute to age-related declines in motor sequence consolidation. Interestingly, these changes do not affect declarative memory.
22232393	Considerable research has investigated the role of verbal working memory in language development in children with and without language problems. Much less is currently known about the relationship between language and the declarative and procedural memory systems. This study examined whether these 2 memory systems were related to typically developing children's past tense and lexical knowledge.Fifty-eight typically developing children approximately 5 years of age completed a battery of linguistic and nonlinguistic tasks, including tests of vocabulary, past tense production, and procedural and declarative memory.	The results showed that declarative and procedural memory were not correlated with either regular or irregular past tense use. A significant correlation was observed between declarative memory and vocabulary.	The results of the study were not consistent with the view that the declarative and procedural memory systems support children's use of the regular and irregular past tense. However, evidence was found suggesting that declarative memory supports vocabulary in this age group.	
22220356	Memory can be defined as the ability to acquire, process, store, and retrieve information. Memory is indispensable for learning, adaptation, and survival of every living organism. In humans, the remembering process has acquired great flexibility and complexity, reaching close links with other mental functions, such as thinking and emotions. Changes in synaptic connectivity and interactions among multiple neural networks provide the neurobiological substrates for memory encoding, retention, and consolidation. Memory may be categorized as short-term and long-term memory (according to the storage temporal duration), as implicit and explicit memory (with respect to the consciousness of remembering), as declarative (knowing that [fact]) and procedural (knowing how [skill]) memory, or as sensory (echoic, iconic and haptil), semantic, and episodic memory (according to the various remembering domains). Significant advances have been obtained in understanding memory neurobiology, but much remains to be learned in its cognitive, psychological, and phenomenological aspects.
22207008	The positive impact of sleep on memory consolidation has been shown for human subjects in numerous studies, but there is still sparse knowledge on this topic in rats, one of the most prominent model species in neuroscience research. Here, we examined the role of sleep in the object-place recognition task, a task closely comparable to tasks typically applied for testing human declarative memory: It is a one-trial task, hippocampus-dependent, not stressful and can be repeated within the same animal. A test session consisted of the Sample trial, followed by a 2-h retention interval and a Test trial, the latter examining the memory the rat had for the places of two objects presented at the Sample trial. In Experiment 1, each rat was tested twice, with the retention interval taking place either in the morning or evening, i.e., in the inactive or active phase, respectively. Rats showed significantly (p<0.01) better memory for object place after the Morning session. To control for confounding circadian factors, in Experiment 2 rats were tested four times, i.e., in the morning or in the evening while sleep was or was not deprived. Sleep during the retention interval was recorded polysomnographically. Rats only showed significant memory for the target object place in the Test trial after the Morning retention interval in the absence of sleep deprivation, and recognition performance in this condition was significantly superior to that in the three other conditions (p<0.05). EEG recordings during spontaneous morning sleep revealed increased slow oscillation (0.85-2.0 Hz) and upper delta (2.0-4.0 Hz), but reduced spindle band (10.5-13.5 Hz) activity, as compared to evening sleep. However, spindle band power was increased in the Morning retention interval in comparison to a Morning Baseline period (p<0.05). We conclude that consolidation of object-place memory depends on sleep, and presumably requires NonREM sleep rich in both slow wave and spindle activity.
22197003	In the present study, we aimed to compare the effect of exogenous cortisol on memory retrieval in posttraumatic stress disorder (PTSD) with the effects in healthy controls. In healthy participants, administration of cortisol impairs declarative memory retrieval. Only a few studies have investigated these effects in PTSD yielding mixed results.In a placebo-controlled crossover study, 44 patients with PTSD and 65 healthy controls received either placebo or 10mg of hydrocortisone orally before memory testing. In addition to declarative memory retrieval (word list learning), we also tested autobiographical memory retrieval specificity.	In both tasks opposing effects of cortisol on memory were observed when comparing patients with controls. In controls, cortisol had impairing effects on memory retrieval, while in PTSD patients cortisol had enhancing effects on memory retrieval in both memory domains.	The present results suggest beneficial effects of acute cortisol elevations on hippocampal mediated memory processes in PTSD. Possible neurobiological mechanisms underlying these findings are discussed.	
22194717	Interactions between the cerebral cortex, thalamus, and basal ganglia form the basis of cognitive information processing in the mammalian brain. Understanding the principles of neuroanatomical organization in these structures is critical to understanding the functions they perform and ultimately how the human brain works. We have manually distilled and synthesized hundreds of primate neuroanatomy facts into a single interactive visualization. The resulting picture represents the fundamental neuroanatomical blueprint upon which cognitive functions must be implemented. Within this framework we hypothesize and detail 7 functional circuits corresponding to psychological perspectives on the brain: consolidated long-term declarative memory, short-term declarative memory, working memory/information processing, behavioral memory selection, behavioral memory output, cognitive control, and cortical information flow regulation. Each circuit is described in terms of distinguishable neuronal groups including the cerebral isocortex (9 pyramidal neuronal groups), parahippocampal gyrus and hippocampus, thalamus (4 neuronal groups), basal ganglia (7 neuronal groups), metencephalon, basal forebrain, and other subcortical nuclei. We focus on neuroanatomy related to primate non-primary cortical systems to elucidate the basis underlying the distinct homotypical cognitive architecture. To display the breadth of this review, we introduce a novel method of integrating and presenting data in multiple independent visualizations: an interactive website (http://www.frontiersin.org/files/cognitiveconsilience/index.html) and standalone iPhone and iPad applications. With these tools we present a unique, annotated view of neuroanatomical consilience (integration of knowledge).
22194237	Negative feedback can signal poor performance, but it also provides information that can help learners reach the goal of task mastery. The primary aim of this study was to test the hypothesis that the amount of information provided by negative feedback during a paired-associate learning task influences feedback-related processing in the caudate nucleus. To do this, we manipulated the number of response options: With two options, positive and negative feedback provide equal amounts of information, whereas with four options, positive feedback provides more information than does negative feedback. We found that positive and negative feedback activated the caudate similarly when there were two response options. With four options, the caudate's response to negative feedback was reduced. A secondary goal was to investigate the link between brain-based measures of feedback-related processing and behavioral indices of learning. Analysis of the posttest measures showed that trials with positive feedback were associated with higher posttest confidence ratings. Additionally, when positive feedback was delivered, caudate activity was greater for trials with high than with low posttest confidence. This experiment demonstrated the context sensitivity of feedback processing and provided evidence that feedback processing in the striatum can contribute to the strengthening of the representations available within declarative memory.
22182823	Does normal aging inexorably lead to diminished motor learning abilities? This article provides an overview of the literature on the question, with particular emphasis on the functional dissociation between two sets of memory processes: declarative, effortful processes, and non-declarative, automatic processes. There is abundant evidence suggesting that aging does impair learning when past memories of former actions are required (episodic memory) and recollected through controlled processing (working memory). However, other studies have shown that aging does not impair learning when motor actions are performed non verbally and automatically (tapping procedural memory). These findings led us to hypothesize that one can minimize the impact of aging on the ability to learn new motor actions by favouring procedural learning. Recent data validating this hypothesis are presented. Our findings underline the importance of developing new motor learning strategies, which "bypass" declarative, effortful memory processes.
22180166	The hippocampus is necessary for the normal formation of enduring declarative memories, but its role in cognitive processes spanning short intervals is less well understood. Within the last decade, several reports have described modest behavioral deficits in medial temporal lobe (MTL)-lesion patients when they perform tasks that do not seem likely to rely on enduring memory. An intriguing but sparsely-tested implication of such results is that the MTL is involved in the online representation of information, possibly of an associative/relational nature, irrespective of delay. We administered several tests that simultaneously presented all information necessary for accurate responses to a group of MTL-lesion patients with severe declarative memory deficits but otherwise normal cognition, and to matched brain-damaged and healthy comparison participants. MTL-lesion patients performed less well than either comparison group in the Hooper Visual Organization Test, and several patients performed outside the normal range on the Overlapping Figures Test. A novel follow-up borrowing characteristics of the Overlapping Figures Test revealed impaired identification of novel items by MTL-lesion patients when target items were obscured by distracters, and two additional novel tests of fragmented object identification further implicated the hippocampus/MTL in the integration of information across very brief intervals. These findings suggest that MTL structures including the hippocampus contribute similarly to cognition irrespective of timescale.
22172579	The medial temporal lobes (MTLs) have been thought to function exclusively in service of declarative memory. Recent research shows that damage to the perirhinal cortex (PRC) of the MTL impairs the discrimination of objects sharing many similar parts/features, leading to the hypothesis that the PRC contributes to the perception when the feature configurations, rather than the individual features, are required to solve the task. It remains uncertain, however, whether the previous research demands a slight extension of PRC function to include working memory or a more dramatic extension to include perception. We present 2 experiments assessing the implicit effects of familiar configuration on figure assignment, an early and fundamental perceptual outcome. Unlike controls, PRC-damaged individuals failed to perceive the regions portraying familiar configurations, as figure more often, than the regions comprising the same parts rearranged into novel configurations. They were also impaired in identifying the familiar objects. In a third experiment, PRC-damaged individuals performed poorly when asked to choose a familiar object from pairs of familiar and novel objects comprising the same parts. Our results demonstrate that the PRC is involved in both implicit and explicit perceptual discriminations of novel and familiar configurations. These results reveal that complex object representations in the PRC subserve both perception and memory.
22170602	Oxidative stress has been implicated in the cognitive decline, especially in memory impairment. The purpose of this study was to determine the concentration of malondialdehyde (MDA) in patients with recurrent depressive disorders (rDD) and to define relationship between plasma levels of MDA and the cognitive performance. The study comprised 46 patients meeting criteria for rDD. Cognitive function assessment was based on: The Trail Making Test , The Stroop Test, Verbal Fluency Test and Auditory-Verbal Learning Test. The severity of depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Statistically significant differences were found in the intensity of depression symptoms, measured by the HDRS on therapy onset versus the examination results after 8 weeks of treatment (P < 0.001). Considering the 8-week pharmacotherapy period, rDD patients presented better outcomes in cognitive function tests. There was no statistically significant correlation between plasma MDA levels, and the age, disease duration, number of previous depressive episodes and the results in HDRS applied on admission and on discharge. Elevated levels of MDA adversely affected the efficiency of visual-spatial and auditory-verbal working memory, short-term declarative memory and the delayed recall declarative memory. 1. Higher concentration of plasma MDA in rDD patients is associated with the severity of depressive symptoms, both at the beginning of antidepressants pharmacotherapy, and after 8 weeks of its duration. 2. Elevated levels of plasma MDA are related to the impairment of visual-spatial and auditory-verbal working memory and short-term and delayed declarative memory.
22169884	Methylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate.In the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers.	In a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40 mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test.	Declarative memory consolidation was significantly improved relative to placebo after 20 and 40 mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning.	To the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.	
22156722	Post-traumatic stress disorder (PTSD) is associated with impaired memory performance coupled with functional changes in brain areas involved in declarative memory and emotion regulation. It is not yet clear how symptom severity and comorbidity affect neurocognitive functioning in PTSD. We performed a functional magnetic resonance imaging (fMRI) study with an emotional declarative memory task in 28 Complex PTSD patients with comorbid depressive and personality disorders, and 21 healthy non-trauma-exposed controls. In Complex PTSD patients--compared to controls--encoding of later remembered negative words vs baseline was associated with increased blood oxygenation level dependent (BOLD) response in the left ventral anterior cingulate cortex (ACC) and dorsal ACC extending to the dorsomedial prefrontal cortex (dmPFC) together with a trend for increased left hippocampus activation. Patients tended to commit more False Alarms to negative words compared to controls, which was associated with enhanced left ventrolateral prefrontal and orbitofrontal cortex (vlPFC/OFC) responses. Severity of child abuse was positively correlated with left ventral ACC activity and severity of depression with (para) hippocampal and ventral ACC activity. Presented results demonstrate functional abnormalities in Complex PTSD in the frontolimbic brain circuit also implicated in fear conditioning models, but generally in the opposite direction, which may be explained by severity of the trauma and severity of comorbid depression in Complex PTSD.
22153362	The benefit of sleep in general for memory consolidation is well known. The relevance of sleep characteristics and the influence of hormones are not well studied. We explored the effects of a nap on memory consolidation of motor (finger-tapping-task) and verbal (associated-word-pairs) tasks in following settings: A: young, healthy males and females during early-follicular phase (n=40) and B: females during mid-luteal and early-follicular phase in the menstrual cycle (n=15). We found a sex and in women a menstrual cycle effect on memory performance following a nap. Men performed significantly better after a nap and women did so only in the mid-luteal phase of their menstrual cycle. Only the men and the women in their mid-luteal phase experienced a significant increase in spindle activity after learning. Furthermore, in women estrogen correlated significantly with the offline change in declarative learning and progesterone with motor learning. The ratio of the 2nd and 4th digit, which has been associated to fetal sex hormones and cognitive sex differences, significantly predicted the average performance of the female subjects in the learning tasks. Our results demonstrate that sleep-related memory consolidation has a higher complexity and more influencing factors than previously assumed. There is a sex and menstrual cycle effect, which seems to be mediated by female hormones and sleep spindles. Further, contrary to previous reports, consolidation of a simple motor task can be induced by a 45 min NREM sleep nap, thus not dependent on REM sleep.
22125545	Our daily experiences are incidentally and rapidly encoded as episodic memories. Episodic memories consist of numerous associations (e.g., who gave what to whom where and when) that can be expressed flexibly in new situations. Key features of episodic memory are speed of encoding, its associative nature, and its representational flexibility. Another defining feature of human episodic memory has been consciousness of encoding/retrieval. Here, we show that humans can rapidly form associations between subliminal words and minutes later retrieve these associations even if retrieval words were conceptually related to, but different from encoding words. Because encoding words were presented subliminally, associative encoding, and retrieval were unconscious. Unconscious association formation and retrieval were dependent on a preceding understanding of task principles. We conclude that key computations underlying episodic memory - rapid encoding and flexible expression of associations - can operate outside consciousness.
22123775	Communication is aided greatly when speakers and listeners take advantage of mutually shared knowledge (i.e., common ground). How such information is represented in memory is not well known. Using a neuropsychological-psycholinguistic approach to real-time language understanding, we investigated the ability to form and use common ground during conversation in memory-impaired participants with hippocampal amnesia. Analyses of amnesics' eye fixations as they interpreted their partner's utterances about a set of objects demonstrated successful use of common ground when the amnesics had immediate access to common-ground information, but dramatic failures when they did not. These findings indicate a clear role for declarative memory in maintenance of common-ground representations. Even when amnesics were successful, however, the eye movement record revealed subtle deficits in resolving potential ambiguity among competing intended referents; this finding suggests that declarative memory may be critical to more basic aspects of the on-line resolution of linguistic ambiguity.
22114672	While a role for sleep in declarative memory processing is established, the qualitative nature of this consolidation benefit, and the physiological mechanisms mediating it, remain debated. Here, we investigate the impact of sleep physiology on characteristics of episodic memory using an item- (memory elements) and context- (contextual details associated with those elements) learning paradigm; the latter being especially dependent on the hippocampus. Following back-to-back encoding of two word lists, each associated with a different context, participants were assigned to either a Nap-group, who obtained a 120-min nap, or a No Nap-group. Six hours post-encoding, participants performed a recognition test involving item-memory and context-memory judgments. In contrast to item-memory, which demonstrated no between-group differences, a significant benefit in context-memory developed in the Nap-group, the extent of which correlated both with the amount of stage-2 NREM sleep and frontal fast sleep-spindles. Furthermore, a difference was observed on the basis of word-list order, with the sleep benefit and associated physiological correlations being selective for the second word-list, learned last (most proximal to sleep). These findings suggest that sleep may preferentially benefit contextual (hippocampal-dependent) aspects of memory, supported by sleep-spindle oscillations, and that the temporal order of initial learning differentially determines subsequent offline consolidation.
22096266	Definite references signal a speaker's belief that a listener can uniquely identify the referent (e.g., the dog, as the only dog among a group of animals). Clark's (1992) collaborative referencing model provides a way to examine the speaker's display of confidence that his/her reference will be understood by the listener without further clarification. We previously found that amnesia participants, as directors in a barrier task with a familiar partner, used referencing forms that displayed less confidence than forms used by comparison participants. If this is an interactional consequence of managing the memory impairment (as opposed to a language deficit), we should also expect a decrease in definite referencing by their partners.To examine the use of definite references by healthy non-brain-damaged participants when speaking to their memory-impaired partner during repeated trials of a barrier task. METHODS #ENTITYSTARTX00026; PROCEDURES: We replicated our previous work with 11 of the same participant pairs-6 individuals with hippocampal amnesia and 5 comparison participants-each of whom was paired with a familiar partner of their choosing. Focusing on the productions of the partners (i.e., partners became directors) we (1) coded referential expressions as definite or indefinite; (2) tracked changes in the use of indefinite and definite references across trials; and (3) compared data to previous analyses (when amnesia participants were directors). OUTCOMES #ENTITYSTARTX00026; RESULTS: The productions of comparison pairs were overwhelming definite (95%, 1359). In sharp contrast, partners of the amnesia participants used a definite initiating reference less than half the time (48%, 825), when speaking to their memory-impaired partner and used definite references that signalled a lack of confidence more often and across more trials.	These findings support the assumption that disruptions in language-and-memory-in-use are not limited to the productions of the individuals with amnesia, but rather extend to the discourse of their communication partners. Observing disruptions in the use of definite references of individuals with intact language and declarative memory, when communicating with their partner with amnesia, points to the complex interaction of memory and language. Even when attention is paid to grammatical forms, the decisions are never linguistic alone.	
22090478	The multiple memory systems hypothesis posits that different neural circuits function in parallel and may compete for information processing and storage. For example, instrumental conditioning would depend on the striatum, whereas spatial memory may be mediated by a circuit centered on the hippocampus. However, the nature of the task itself is not sufficient to select durably one system over the other. In this study, we investigated the effects of natural and pharmacological rewards on the selection of a particular memory system during learning. We compared the effects of food- or drug-induced activation of the reward system on cue-guided versus spatial learning using a Y-maze discrimination task. Drug-induced reward severely impaired the acquisition of a spatial discrimination task but spared the cued version of the task. Immunohistochemical analysis of the phosphorylated form of the cAMP response element binding (CREB) protein and c-Fos expression induced by behavioral testing revealed that the spatial deficit was associated with a decrease of both markers within the hippocampus and the prefrontal cortex. In contrast, drug reward potentiated the cued learning-induced CREB phosphorylation within the dorsal striatum. Administration of the protein kinase A inhibitor 8-Bromo-adenosine-3',5'-cyclic monophosphorothioate Rp isomer (Rp-cAMPS) into the dorsal striatum before training completely reversed the drug-induced spatial deficit and restored CREB phosphorylation levels within the hippocampus and the prefrontal cortex. Therefore, drug-induced striatal hyperactivity may underlie the declarative memory deficit reported here. This mechanism could represent an important early step toward the development of addictive behaviors by promoting conditioning to the detriment of more flexible forms of memory.
22078257	Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.
22068745	In this study, the sequence learning performance of 16 non-demented patients with Parkinson's disease (PD) was compared with 18 age-matched healthy controls on a verbal version of the serial reaction time (SRT) task intended to encapsulate both visuomotor- and judgment-linked learning processes. Visuomotor sequence performance in PD patients was closely related to baseline response speed, with robust learning demonstrated by patients who responded with comparable speed to controls but severely impaired performance in patients who responded slowly. In contrast, both fast- and slow-responding PD patients were able to successfully categorise patterns according to their sequential status, a performance that was linked to declarative memory for the sequence. The findings highlight the important role of event timing in SRT performance and are in accord with the hypothesis that, despite the important role played by the basal ganglia in motor sequence learning, basal ganglionic dysfunction may not substantially impair sequence order learning so much as the translation of sequence knowledge into rapid motor performance for some PD patients. Intact pattern judgment on the SRT experiment suggests that the integrity of the neostriatum is not essential for learning judgment-linked categorical information about sequences of temporal stimulus movement.
22043868	Social stress affects cognitive processes in general, and memory performance in particular. However, the direction of these effects has not been clearly established, as it depends on several factors. Our aim was to determine the impact of the hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) reactivity to psychosocial stress on short-term non-declarative memory and declarative memory performance. Fifty-two young participants (18 men, 34 women) were subjected to the Trier Social Stress Task (TSST) and a control condition in a crossover design. Implicit memory was assessed by a priming test, and explicit memory was assessed by the Rey Auditory Verbal Learning Test (RAVLT). The TSST provoked greater salivary cortisol and salivary alpha-amylase (sAA) responses than the control task. Men had a higher cortisol response to stress than women, but no sex differences were found for sAA release. Stress was associated with an enhancement of priming but did not affect declarative memory. Additionally, the enhancement on the priming test was higher in those whose sAA levels increased more in response to stress (r(48) = 0.339, p = 0.018). Our results confirm an effect of acute stress on priming, and that this effect is related to SNS activity. In addition, they suggest a different relationship between stress biomarkers and the different memory systems.
22037418	Newly acquired declarative memory traces are believed to be reactivated during NonREM sleep to promote their hippocampo-neocortical transfer for long-term storage. Yet it remains a major challenge to unravel the underlying neuronal mechanisms. Using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings in humans, we show that sleep spindles play a key role in the reactivation of memory-related neocortical representations. On separate days, participants either learned face-scene associations or performed a visuomotor control task. Spindle-coupled reactivation of brain regions representing the specific task stimuli was traced during subsequent NonREM sleep with EEG-informed fMRI. Relative to the control task, learning face-scene associations triggered a stronger combined activation of neocortical and hippocampal regions during subsequent sleep. Notably, reactivation did not only occur in temporal synchrony with spindle events but was tuned by ongoing variations in spindle amplitude. These learning-related increases in spindle-coupled neocortical activity were topographically specific because reactivation was restricted to the face- and scene-selective visual cortical areas previously activated during pre-sleep learning. Spindle-coupled hippocampal activation was stronger the better the participant had performed at prior learning. These results are in agreement with the notion that sleep spindles orchestrate the reactivation of new hippocampal-neocortical memories during sleep.
22033732	Declarative memory dysfunction is associated with post-traumatic stress disorder (PTSD). This paper reviews this literature and presents two frameworks to explain the nature of this dysfunction: that memory deficits are a product of neurobiological abnormalities caused by PTSD and/or that pre-existing memory deficits serve as a risk factor for the development of PTSD following trauma exposure. Brain regions implicated in declarative memory deficits include the hippocampus and prefrontal cortex, and imaging and biochemistry studies as they relate to memory dysfunction are described. Prospective and twin studies provide support for a risk factor model.
22028091	We used a sequence-learning task to assess whether: 1. The time interval between awakening and training equally affects the rate of acquisition of sequence order, a declarative component, and the kinematic optimization process, an implicit component; 2. Sleep enhances the retention of both these aspects of sequence learning.For aim 1, we compare the acquisition rate of a new motor sequence in a group trained in the morning and another in the evening. For aim 2., we tested retention of the same motor sequence twelve hours later, either without sleep (normal day activity or a night of sleep deprivation) or with interposed sleep (afternoon napping or regular full night sleep).	Training and Testing were performed in a controlled laboratory setting.	Thirty-six right-handed normal subjects (age range 18-24 years; 16 women).	During the training, acquisition rate of the sequence order was significantly higher in the AM-trained than in the PM-trained group, without differences in the kinematic optimization processes. Both declarative and implicit learning indices were significantly higher in the subjects tested after sleep compared to those tested without interposed sleep.	The best time for fast and efficient acquisition of new declarative material is the morning, while the kinematic aspects of skill acquisition are not sensitive to the time of day. However, better retention of both declarative material and motor skills requires two conditions: a period of post-training sleep and the achievement of performance saturation during training.	
22024432	Intrinsic and historical weaknesses delayed the spread of a sound neurobiological investigation on dreaming. Nevertheless, recent independent findings confirm the hypothesis that the neurophysiological mechanisms of encoding and recall of episodic memories are largely comparable across wakefulness and sleep. Brain lesion and neuroimaging studies converge in indicating that temporo-parieto-occipital junction and ventromesial prefrontal cortex play a crucial role in dream recall. Morphoanatomical measurements disclose some direct relations between volumetric and ultrastructural measures of the hippocampus-amygdala on the one hand, and some specific qualitative features of dreaming on the other. Intracranial recordings of epileptic patients also provide support for the notion that hippocampal nuclei mediate memory formation during sleep as well as in wakefulness. Finally, surface EEG studies showed that sleep cortical oscillations associated to a successful dream recall are the same involved in encoding and recall of episodic memories during wakefulness. Although preliminary, these converging pieces of evidence strengthen the general view that the neurophysiological mechanisms underlying episodic/declarative memory formation may be the same across different states of consciousness.
22021253	The present study investigated the effects of approach versus avoidance motivation on declarative learning. Human participants navigated a virtual reality version of the Morris water task, a classic spatial memory paradigm, adapted to permit the experimental manipulation of motivation during learning. During this task, participants were instructed to navigate to correct platforms while avoiding incorrect platforms. To manipulate motivational states participants were either rewarded for navigating to correct locations (approach) or punished for navigating to incorrect platforms (avoidance). Participants' skin conductance levels (SCLs) were recorded during navigation to investigate the role of physiological arousal in motivated learning. Behavioral results revealed that, overall, approach motivation enhanced and avoidance motivation impaired memory performance compared to nonmotivated spatial learning. This advantage was evident across several performance indices, including accuracy, learning rate, path length, and proximity to platform locations during probe trials. SCL analysis revealed three key findings. First, within subjects, arousal interacted with approach motivation, such that high arousal on a given trial was associated with performance deficits. In addition, across subjects, high arousal negated or reversed the benefits of approach motivation. Finally, low-performing, highly aroused participants showed SCL responses similar to those of avoidance-motivation participants, suggesting that for these individuals, opportunities for reward may evoke states of learning similar to those typically evoked by threats of punishment. These results provide a novel characterization of how approach and avoidance motivation influence declarative memory and indicate a critical and selective role for arousal in determining how reinforcement influences goal-oriented learning.
22019073	Higher cognitive functioning is mediated by frontal-subcortical cognitive and limbic feedback sub-loops. The thalamo-cortical projection through the anterior limb of the internal capsule (ALIC) serves as the final step in these feedback sub-loops. We evaluated abnormalities in the ALIC fiber tract in schizophrenia using both structural MRI and diffusion tensor imaging (DTI).20 chronic schizophrenia patients and 22 male, normal controls group matched for handedness, age, and parental SES, underwent structural and DTI brain imaging on a 1.5 Tesla GE system. We manually measured ALIC volume normalized for intracranial contents (ICC) using structural brain images and then registered these high resolution structural brain scan derived ALIC label maps to DTI space allowing for the measurement in the ALIC of diffusion indices including, fractional anisotropy (FA) mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD).	We found in the ALIC of chronic schizophrenia subjects, compared with normal controls, bilaterally lower FA and bilaterally higher RD, but no differences in AD, MD, or relative volume. Cognitive correlations in schizophrenia patients showed, in particular, that higher left ALIC FA correlated positively with better verbal and nonverbal declarative/episodic memory performance.	Using a novel approach to assess both diffusion and volume measures in the ALIC in schizophrenia, we found abnormalities in measures of diffusion, but not volume, supporting their importance as sensitive indices of abnormalities in white matter fiber bundles in schizophrenia. Our findings also support the role of ALIC white matter tract FA abnormalities in declarative/episodic memory in schizophrenia.	
22000901	It has been proposed that the language problems in specific language impairment (SLI) arise from basal ganglia abnormalities that lead to impairments with procedural and working memory but not declarative memory. In SLI, this profile of memory functioning has been hypothesized to underlie grammatical impairment but leave lexical knowledge relatively unaffected. The current study examined memory and language functioning in 13 Danish-speaking children with SLI and 20 typically developing (TD) children. Participants were administered tasks assessing declarative, procedural and verbal working memory as well as knowledge of past tense and vocabulary. The SLI group performed significantly poorer than the TD group on the measure of verbal working memory. Non-significant differences between groups were observed on the measure of declarative memory, after controlling for verbal working memory. The groups were found to perform at comparable levels on the procedural memory task. On the language measures, the SLI group performed significantly poorer than the TD group on the past tense and vocabulary tasks. However, the magnitude of the difference was larger on the task assessing past tense. These results indicate grammatical knowledge is relatively more affected than lexical knowledge in Danish speaking children with SLI. However, the results were not consistent with the proposal linking impaired grammar to impairments with procedural memory. At the same time, the study does not rule out that other aspects of procedural learning and memory contribute to the language problems in SLI.The reader will be introduced to (1) different memory systems, in particular the declarative, procedural and working memory systems and (2) also research examining the relationship between these different memory systems and language in children with SLI.	
21997601	Recent evidence suggests that the sleep-dependent consolidation of declarative memory relies on the nonrapid eye movement rather than the rapid eye movement phase of sleep. In addition, it is known that aging is accompanied by changes in sleep and memory processes. Hence, the purpose of this study was to investigate the overnight consolidation of declarative memory in healthy elderly women.Sleep laboratory of University.	Nineteen healthy elderly women (age range: 61-74 years).	We used laboratory-based measures of sleep. To test declarative memory, the Rey-Osterrieth Complex Figure Test was performed.	Declarative memory performance in elderly women was associated with Stage 2 sleep spindle density. Women characterized by high memory performance exhibited significantly higher numbers of sleep spindles and higher spindle density compared with women with generally low memory performance.	The data strongly support theories suggesting a link between sleep spindle activity and declarative memory consolidation.	
21964564	A review of medial temporal lobe connections reveals three distinct groupings of hippocampal efferents. These efferent systems and their putative memory functions are: (1) The 'extended-hippocampal system' for episodic memory, which involves the anterior thalamic nuclei, mammillary bodies and retrosplenial cortex, originates in the subicular cortices, and has a largely laminar organisation; (2) The 'rostral hippocampal system' for affective and social learning, which involves prefrontal cortex, amygdala and nucleus accumbens, has a columnar organisation, and originates from rostral CA1 and subiculum; (3) The 'reciprocal hippocampal-parahippocampal system' for sensory processing and integration, which originates from the length of CA1 and the subiculum, and is characterised by columnar, connections with reciprocal topographies. A fourth system, the 'parahippocampal-prefrontal system' that supports familiarity signalling and retrieval processing, has more widespread prefrontal connections than those of the hippocampus, along with different thalamic inputs. Despite many interactions between these four systems, they may retain different roles in memory which when combined explain the importance of the medial temporal lobe for the formation of declarative memories.
21957237	Traditionally, the medial temporal lobe (MTL) was linked to explicit or declarative memory in associative learning. However, recent studies have reported MTL involvement even when volunteers are not consciously aware of the learned contingencies. Therefore, the mechanism of the MTL-related learning process cannot be described sufficiently by the explicit/implicit distinction, and the underlying process in the MTL for associative learning needs a more functional characterization. A possible feature that would allow a functional specification also for implicit learning is the nature of the material that is learned. Given that implicit memory tasks often comprise a combination of perceptual and motor learning, we hypothesized that implicit learning of the perceptual but not the motor component entails MTL activation in these studies. To directly test this hypothesis, we designed a purely perceptual and a purely motor variant of the serial reaction time task. In two groups of human volunteers, behavioral results clearly showed that both variants were learned without awareness. Neuronal recordings using fMRI revealed that bilateral hippocampal activation was observed only for implicit learning of the perceptual sequence, not for the motor sequence. This dissociation clearly shows that the functional role of the hippocampus for learning is determined by the domain of the learned association and that the function of the medial temporal lobe system is the processing of contingencies between perceptual features regardless of the explicit or implicit nature of the ensuing memory.
21954386	This study focuses on the early cerebral base of speech perception by examining functional lateralization in neonates for processing segmental and suprasegmental features of speech. For this purpose, auditory evoked responses of full-term neonates to phonemic and prosodic contrasts were measured in their temporal area and part of the frontal and parietal areas using near-infrared spectroscopy (NIRS). Stimuli used here were phonemic contrast /itta/ and /itte/ and prosodic contrast of declarative and interrogative forms /itta/ and /itta?/. The results showed clear hemodynamic responses to both phonemic and prosodic changes in the temporal areas and part of the parietal and frontal regions. In particular, significantly higher hemoglobin (Hb) changes were observed for the prosodic change in the right temporal area than for that in the left one, whereas Hb responses to the vowel change were similarly elicited in bilateral temporal areas. However, Hb responses to the vowel contrast were asymmetrical in the parietal area (around supra marginal gyrus), with stronger activation in the left. These results suggest a specialized function of the right hemisphere in prosody processing, which is already present in neonates. The parietal activities during phonemic processing were discussed in relation to verbal-auditory short-term memory. On the basis of this study and previous studies on older infants, the developmental process of functional lateralization from birth to 2 years of age for vowel and prosody was summarized.
21945835	It has long been known that memory is not a single process. Rather, there are different kinds of memory that are supported by distinct neural systems. This idea stemmed from early findings of dissociable patterns of memory impairments in patients with selective damage to different brain regions. These studies highlighted the role of the basal ganglia in non-declarative memory, such as procedural or habit learning, contrasting it with the known role of the medial temporal lobes in declarative memory. In recent years, major advances across multiple areas of neuroscience have revealed an important role for the basal ganglia in motivation and decision making. These findings have led to new discoveries about the role of the basal ganglia in learning and highlighted the essential role of dopamine in specific forms of learning. Here we review these recent advances with an emphasis on novel discoveries from studies of learning in patients with Parkinson's disease. We discuss how these findings promote the development of current theories away from accounts that emphasize the verbalizability of the contents of memory and towards a focus on the specific computations carried out by distinct brain regions. Finally, we discuss new challenges that arise in the face of accumulating evidence for dynamic and interconnected memory systems that jointly contribute to learning.
21942825	Episodic and autobiographical memory are clearly related, yet in both the adult and developmental literatures it is difficult to compare them because of differences in how the constructs are assessed, including differences in content, levels of control, and time since experience. To address these issues, we directly compared children's and adults' autobiographical and episodic memory using the same controlled paradigm. Participants engaged in a photo-taking activity in a museum (autobiographical encoding) and viewed others' photographs of the same museum exhibits (episodic encoding). At test, participants classified photos as ones they took, viewed, or novel. In the autobiographical condition older children and adults performed similarly; younger children's performance was lower than adults'. In contrast, in the episodic condition both groups of children performed more poorly than adults. The findings suggest the developmental primacy of autobiographical relative to episodic memory, and that traditional episodic tasks may underestimate older children's declarative memory abilities.
21940453	Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF₁), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF₁ knock-out (CRF₁-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF₁ in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF₁ deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF₁-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF₁ signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.
21910555	Decades of research have established that "online" cognitive processes, which operate during conscious encoding and retrieval of information, contribute substantially to individual differences in memory. Furthermore, it is widely accepted that "offline" processes during sleep also contribute to memory performance. However, the question of whether individual differences in these two types of processes are related to one another remains unanswered. We investigated whether working memory capacity (WMC), a factor believed to contribute substantially to individual differences in online processing, was related to sleep-dependent declarative memory consolidation. Consistent with previous studies, memory for word pairs reliably improved after a period of sleep, whereas performance did not improve after an equal interval of wakefulness. More important, there was a significant, positive correlation between WMC and increase in memory performance after sleep but not after a period of wakefulness. The correlation between WMC and performance during initial test was not significant, suggesting that the relationship is specific to change in memory due to sleep. This suggests a fundamental underlying ability that may distinguish individuals with high memory capacity.
21895365	To assess predictive relations between joint attention skills, intention understanding, and mental state vocabulary, 88 children were tested with measures of comprehension of gaze and referential pointing, as well as the production of declarative gestures and the comprehension and production of imperative gestures, at the ages of 7-18 months. Infants' intention-based imitation skills were assessed at 12, 15, and 18 months. At the ages of 24 and 36 months, toddlers' internal state lexicon was evaluated by parents with a German adaptation of the Mental State Language Questionnaire (Olineck & Poulin-Dubois, 2005). Regression analyses revealed that 9-months-olds' comprehension of referential pointing contributed significantly to the prediction of intention-based imitation skills at 15 months, as well as to children's volition and cognition vocabularies at 24 and 36 months, respectively. Moreover, 12-month-olds' comprehension of an imperative motive was shown to selectively predict toddlers' use of volition terms at 24 months. Overall, these results provide empirical evidence for both general and specific developmental relations between preverbal communication skills and mental state language, thus implying developmental continuity within the social domain in the first 3 years of life.
21889806	The hippocampal formation and striatum subserve declarative and procedural memory, respectively. However, experimental evidence suggests that the ventral striatum, as opposed to the dorsal striatum, does not lend itself to being part of either system. Instead, it may constitute a system integrating inputs from the amygdala, prefrontal cortex and hippocampus to generate motivational, outcome-predicting signals that invigorate goal-directed behaviors. Inspired by reinforcement learning models, we suggest an alternative scheme for computational functions of the striatum. Dorsal and ventral striatum are proposed to compute outcome predictions largely in parallel, using different types of information as input. The nature of the inputs to striatum is furthermore combinatorial, and the specificity of predictions transcends the level of scalar value signals, incorporating episodic information.
21889375	Non-rapid eye movement (NREM) sleep has recently garnered support for its role in consolidating hippocampus-based declarative memories in humans. We provide a brief review of the latest research on NREM sleep activity and its association with declarative memory consolidation. Utilizing empirical findings from sleep studies on schizophrenia, Alzheimer's disease, and fibromyalgia, we argue that a significant reduction of slow-wave sleep and sleep spindle activity contribute to the development of deficits in declarative memory consolidation along with concomitant sleep disturbances commonly experienced in the aforementioned disorders. A tentative model is introduced to describe the mediating role of the thalamocortical network in disruptions of both declarative memory consolidation and NREM sleep. The hope is to stimulate new research in further investigating the intimate link between these two very important functions.
21875653	Dysregulated cholinergic neurotransmission has been implicated in the pathophysiology of schizophrenia, particularly negative symptoms and cognitive deficits. The aim of the present study was to evaluate the role of neocortical cholinergic innervation and of the N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on social interaction and novel object recognition (NOR), a declarative memory task. The cholinergic corticopetal projection was lesioned by local infusion of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis of adult male Lister hooded rats. Behavior was assessed 2.5 weeks later in a social interaction paradigm followed by the NOR task. We found that selective cholinergic denervation of neocortex led to a significant reduction in duration of social interaction, specifically active social interaction. Acute administration of PCP (1.0 mg/kg, s.c.) caused a marked decrease of active social interaction, such that there was no longer a difference between intact and denervated animals. Neither cholinergic denervation alone, nor PCP (1.0 mg/kg, s.c.) alone blocked the ability of rats to recognize a novel object. However, when animals lacking cortical cholinergic innervation were challenged by PCP, they were no longer able to recognize a novel object. This study indicates that rats lacking cholinergic innervation of neocortex have impaired social interaction and specifically that the duration of active contact is shortened. Animals with severe cortical cholinergic hypofunction maintain the ability to perform in a declarative memory test, although the task is carried out less intensively. However, a provocation of psychosis-like behavior by a dose of PCP that does not by itself impair performance in normal animals, will abolish the ability to recognize novel objects in animals lacking cortical cholinergic innervation. The present findings support a possible role for cortical cholinergic hypofunction in the negative and cognitive symptoms of schizophrenia, and the potential for cholinergic augmentation as part of the pharmacological profile of antipsychotic drugs.
21875215	Dissociable prototype learning systems have been demonstrated behaviorally and with neuroimaging in younger adults as well as with patient populations. In A/not-A (AN) prototype learning, participants are shown members of category A during training, and during test are asked to decide whether novel items are in category A or are not in category A. Research suggests that AN learning is mediated by a perceptual learning system. In A/B (AB) prototype learning, participants are shown members of category A and B during training, and during test are asked to decide whether novel items are in category A or category B. In contrast to AN, research suggests that AB learning is mediated by a declarative memory system. The current study examined the effects of normal aging on AN and AB prototype learning. We observed an age-related deficit in AB learning, but an age-related advantage in AN learning. Computational modeling supports one possible interpretation based on narrower selective attentional focus in older adults in the AB task and broader selective attention in the AN task. Neuropsychological testing in older participants suggested that executive functioning and attentional control were associated with better performance in both tasks. However, nonverbal memory was associated with better AN performance, while visual attention was associated with worse AB performance. The results support an interactive memory systems approach and suggest that age-related declines in one memory system can lead to deficits in some tasks, but to enhanced performance in others.
21872533	We investigated sleep-related declarative memory consolidation in four children with focal idiopathic epilepsy. In a population of healthy control children, recall of learned pairs of words was increased after a night of sleep, but not after a daytime wakefulness period. In children with epilepsy (1 case of benign epilepsy with centro-temporal spikes, 1 case of benign childhood epilepsy with occipital paroxysms, and 2 cases of epileptic encephalopathy (EE) with continuous spike and waves during slow-wave sleep, CSWS), recall performance significantly decreased overnight, suggesting impairment in sleep-related declarative memory consolidation. Hydrocortisone treatment in one patient with EE with CSWS resulted in normalization of the sleep EEG together with normalization of overnight memory performance, which was not the case in the other EE/CSWS patient whose sleep EEG was only partially improved. These preliminary results suggest that interictal epileptiform discharges in idiopathic focal epilepsies may disrupt the brain processes underlying sleep-related memory consolidation.
21864847	Sleep benefits the consolidation of both declarative and nondeclarative memories, however the question if these two memory systems profit from sleep in more or less similar ways is still under debate. Studying the on-line and off-line consolidation of declarative and nondeclarative memory tasks in depressed patients and healthy controls, we here present a clear double dissociation between memory systems and consolidation phases, suggesting radically different ways how sleep benefits memory consolidation. 37 medicated inpatients with an acute episode of major depression and 31 healthy controls were assessed using a nondeclarative (sequential finger tapping) memory task before and after a night with polysomnography, 27 of the depressed and 22 of the control subjects additionally performed a declarative (paired associates) task. Although depressed patients and control subjects did not differ in practice-dependent learning of the nondeclarative motor task in the wake state, healthy subjects showed overnight improvements in tapping performance of 11.4%, while the patients' performance decreased overnight by 11.5%. This pattern was reversed for the declarative task: While patients learned 33.5% less word pairs than controls in the wake state, overnight changes did not differ between the two groups. These results suggest a double dissociation of memory consolidation processes in major depression: Off-line memory consolidation in major depression is impaired for nondeclarative, but not declarative tasks. The same tasks in the wake state show a reversed pattern, with performance in declarative but not nondeclarative tasks being impaired in major depression.
21859174	Use of prescription stimulants by normal healthy individuals to enhance cognition is said to be on the rise. Who is using these medications for cognitive enhancement, and how prevalent is this practice? Do prescription stimulants in fact enhance cognition for normal healthy people? We review the epidemiological and cognitive neuroscience literatures in search of answers to these questions. Epidemiological issues addressed include the prevalence of nonmedical stimulant use, user demographics, methods by which users obtain prescription stimulants, and motivations for use. Cognitive neuroscience issues addressed include the effects of prescription stimulants on learning and executive function, as well as the task and individual variables associated with these effects. Little is known about the prevalence of prescription stimulant use for cognitive enhancement outside of student populations. Among college students, estimates of use vary widely but, taken together, suggest that the practice is commonplace. The cognitive effects of stimulants on normal healthy people cannot yet be characterized definitively, despite the volume of research that has been carried out on these issues. Published evidence suggests that declarative memory can be improved by stimulants, with some evidence consistent with enhanced consolidation of memories. Effects on the executive functions of working memory and cognitive control are less reliable but have been found for at least some individuals on some tasks. In closing, we enumerate the many outstanding questions that remain to be addressed by future research and also identify obstacles facing this research.
21856335	Until recently, it was believed that the introduction of new neurons in neuronal networks was incompatible with memory function. Since the rediscovery of adult hippocampal neurogenesis, behavioral data demonstrate that adult neurogenesis is required for memory processing. We examine neurocomputational studies to identify which basic mechanisms involved in memory might be mediated by adult neurogenesis. Mainly, adult neurogenesis might be involved in the reduction of catastrophic interference and in a time-related pattern separation function. Artificial neuronal networks suggest that the selective recruitment of new-born or old neurons is not stochastic, but depends on environmental requirements. This leads us to propose the novel concept of "soft-supervision". Soft-supervision would be a biologically plausible process, by which the environment is able to influence activation and learning rules of neurons differentially.
21854967	Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks measuring sustained attention or vigilance. We here report how a selective disruption of deep sleep only, that is, selective slow-wave activity (SWA) reduction, affects the performance of healthy well-sleeping subjects on several tasks: a "simple" and a "complex" vigilance task, a declarative learning task, and an implicit learning task despite unchanged duration of sleep. We used automated electroencephalogram (EEG) dependent acoustic feedback aimed at selective interference with-and reduction of-SWA. In a within-subject repeated measures crossover design, performance on the tasks was assessed in 13 elderly adults without sleep complaints after either SWA-reduction or after normal sleep. The number of vigilance lapses increased as a result of SWA reduction, irrespective of the type of vigilance task. Recognition on the declarative memory task was also affected by SWA reduction, associated with a decreased activation of the right hippocampus on encoding (measured with fMRI) suggesting a weaker memory trace. SWA reduction, however, did not affect reaction time on either of the vigilance tasks or implicit memory task performance. These findings suggest a specific role of slow oscillations in the subsequent daytime ability to maintain sustained attention and to encode novel declarative information but not to maintain response speed or to build implicit memories. Of particular interest is that selective SWA reduction can mimic some of the effects of total sleep deprivation, while not affecting sleep duration.
21854958	Slow-wave sleep (SWS) facilitates the consolidation of hippocampus-dependent declarative memory. Based on the standard two-stage memory model, we propose that memory consolidation during SWS represents a process of system consolidation which is orchestrated by the neocortical <1Hz electroencephalogram (EEG) slow oscillation and involves the reactivation of newly encoded representations and their subsequent redistribution from temporary hippocampal to neocortical long-term storage sites. Indeed, experimental induction of slow oscillations during non-rapid eye movement (non-REM) sleep by slowly alternating transcranial current stimulation distinctly improves consolidation of declarative memory. The slow oscillations temporally group neuronal activity into up-states of strongly enhanced neuronal activity and down-states of neuronal silence. In a feed-forward efferent action, this grouping is induced not only in the neocortex but also in other structures relevant to consolidation, namely the thalamus generating 10-15Hz spindles, and the hippocampus generating sharp wave-ripples, with the latter well known to accompany a replay of newly encoded memories taking place in hippocampal circuitries. The feed-forward synchronizing effect of the slow oscillation enables the formation of spindle-ripple events where ripples and accompanying reactivated hippocampal memory information become nested into the single troughs of spindles. Spindle-ripple events thus enable reactivated memory-related hippocampal information to be fed back to neocortical networks in the excitable slow oscillation up-state where they can induce enduring plastic synaptic changes underlying the effective formation of long-term memories.
21853284	Patients with amnesia have deficits in declarative memory but intact memory for motor and perceptual skills, which suggests that explicit memory and implicit memory are distinct. However, the evidence that implicit motor learning is intact in amnesic patients is contradictory. This study investigated implicit sequence learning in amnesic patients with Korsakoff's syndrome (N = 20) and matched controls (N = 14), using the classical Serial Reaction Time Task and a newly developed Pattern Learning Task in which the planning and execution of the responses are more spatially demanding. Results showed that implicit motor learning occurred in both groups of participants; however, on the Pattern Learning Task, the percentage of errors did not increase in the Korsakoff group in the random test phase, which is indicative of less implicit learning. Thus, our findings show that the performance of patients with Korsakoff's syndrome is compromised on an implicit learning task with a strong spatial response component.
21850272	Contributions of somatotropic hormonal activity to memory functions in humans, which are suggested by clinical observations, have not been systematically examined. With previous experiments precluding a direct effect of systemic growth hormone (GH) on acute memory formation, we assessed the role of central nervous somatotropic signaling in declarative memory consolidation. We examined the effect of intranasally administered growth hormone releasing-hormone (GHRH; 600 µg) that has direct access to the brain and suppresses endogenous GHRH via an ultra-short negative feedback loop. Twelve healthy young men learned word-pair associates at 2030 h and were administered GHRH and placebo, respectively, at 2100 h. Retrieval was tested after 11 hours of wakefulness. Compared to placebo, intranasal GHRH blunted GH release within 3 hours after substance administration and reduced the number of correctly recalled word-pairs by ∼12% (both P<0.05). The impairment of declarative memory consolidation was directly correlated to diminished GH concentrations (P<0.05). Procedural memory consolidation as examined by the parallel assessment of finger sequence tapping performance was not affected by GHRH administration. Our findings indicate that intranasal GHRH, by counteracting endogenous GHRH release, impairs hippocampal memory processing. They provide first evidence for a critical contribution of central nervous somatotropic activity to hippocampus-dependent memory consolidation.
21850268	The idea that memories are immutable after consolidation has been challenged. Several reports have shown that after the presentation of a specific reminder, reactivated old memories become labile and again susceptible to amnesic agents. Such vulnerability diminishes with the progress of time and implies a re-stabilization phase, usually referred to as reconsolidation. To date, the main findings describe the mechanisms associated with the labilization-reconsolidation process, but little is known about its functionality from a biological standpoint. Indeed, two functions have been proposed. One suggests that destabilization of the original memory after the reminder allows the integration of new information into the background of the original memory (memory updating), and the other suggests that the labilization-reconsolidation process strengthens the original memory (memory strengthening). We have previously reported the reconsolidation of human declarative memories, demonstrating memory updating in the framework of reconsolidation. Here we deal with the strengthening function attributed to the reconsolidation process. We triggered labilization-reconsolidation processes successively by repeated presentations of the proper reminder. Participants learned an association between five cue-syllables and their respective response-syllables. Twenty-four hours later, the paired-associate verbal memory was labilized by exposing the subjects to one, two or four reminders. The List-memory was evaluated on Day 3 showing that the memory was improved when at least a second reminder was presented in the time window of the first labilization-reconsolidation process prompted by the earlier reminder. However, the improvement effect was revealed on Day 3, only when at least two reminders were presented on Day 2 and not as a consequence of only retrieval. Therefore, we propose central concepts for the reconsolidation process, emphasizing its biological role and the parametrical constrains for this function to be operative.
21840287	Previous studies have claimed that weak transcranial direct current stimulation (tDCS) induces persisting activity changes in the human motor cortex and working memory, but to date no studies have evaluated the effects of tDCS on declarative memory.Our aim was to determine whether anodal and cathodal transcranial direct current stimulation would differentially modify performance in a word memorization task during encoding or recognition when administered over the left dorsolateral prefrontal cortex (DLPFC).	In two experiments, 32 participants underwent a series of word memorization tasks. This task was performed during sham, anodal, and cathodal stimulation applied over the left DLPFC. Moreover, participants in the first experiment performed the same task with anodal tDCS of the primary motor cortex (M1).	During encoding, anodal stimulation of the left DLPFC improved memory, whereas cathodal stimulation of the same area impaired memory performance in later recognition. Anodal stimulation of M1 had no effect on later recognition. During recognition cathodal stimulation of the left DLPFC impaired recognition compared with sham stimulation of the same area and anodal stimulation had a trend toward improving the recognition.	The results indicated that active stimulation of the left DLPFC leads to an enhancement or impairment of verbal memorization depending on the polarity of the stimulation. Furthermore, this effect was specific to the site of stimulation.	
21832260	Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene disorders, which provide insight into the molecular mechanisms underlying the genetic basis of human memory function.
21820271	Sleep supports the consolidation of declarative and procedural memory. While prefrontal cortex (PFC) activity supports the consolidation of declarative memory during sleep, opposite effects of PFC activity are reported with respect to the consolidation of procedural memory during sleep. Patients with attention-deficit/hyperactivity disorder (ADHD) are characterised by a prefrontal hypoactivity. Therefore, we hypothesised that children with ADHD benefit from sleep with respect to procedural memory more than healthy children. Sixteen children with ADHD and 16 healthy controls (aged 9-12) participated in this study. A modification of the serial-reaction-time task was conducted. In the sleep condition, learning took place in the evening and retrieval after a night of sleep, whereas in the wake condition learning took place in the morning and retrieval in the evening without sleep. Children with ADHD showed an improvement in motor skills after sleep compared to the wake condition. Sleep-associated gain in reaction times was positively correlated with the amount of sleep stage 4 and REM-density in ADHD. As expected, sleep did not benefit motor performance in the group of healthy children. These data suggest that sleep in ADHD normalizes deficits in procedural memory observed during daytime. It is discussed whether in patients with ADHD attenuated prefrontal control enables sleep-dependent gains in motor skills by reducing the competitive interference between explicit and implicit components within a motor task.
21805395	In the present chapter, we describe our own attempts to improve our understanding of the pathophysiology of memory in aging. First, we tried to improve animal models of memory degradations occurring in aging, and develop common behavioral tools between mice and humans. Second, we began to use these behavioral tools to identify the molecular/intracellular changes occurring within the integrate network of memory systems in order to bridge the gap between the molecular and system level of analysis. The chapter is divided into three parts (i) modeling aging-related degradation in declarative memory (DM) in mice, (ii) assessing the main components of working memory (WM) with a common radial-maze task in mice and humans and (iii) studying the role of the retinoid cellular signaling path in aging-related changes in memory systems.
21803373	Polysomnograhic (PSG) studies in Alzheimer's disease (AD) show REM sleep abnormalities, which may be indicative for the deterioration of cholinergic pathways and probably closely linked to declarative memory impairment. To clarify the specificity of the association between sleep and cognitive impairment in dementia, we compared AD patients with patients suffering from frontotemporal dementia (FTD) with regard to PSG and neuropsychological variables. 15 AD and 6 FTD patients underwent polysomonography and a neuropsychological battery (CERAD-NB). Group differences (age: AD > FTD; education level: AD < FTD) were considered as covariates. Polysomnography revealed a trend towards increased REM latency and reduced REM sleep in AD, as well as a decrease of stage 2 sleep, however, at least partly due to effects of age. Declarative memory was more impaired in AD than in FTD, but this difference disappeared when adjusted for covariates. While no relationship was found between REM sleep and CERAD-NB parameters, strong positive correlations between stage 2 sleep and declarative memory measures were observed, which were also detectable when analyzing both groups separately. Based on these results we conclude that REM sleep alterations may be specific for AD, distinguishable from other dementia diagnoses, whereas NonREM stage 2 sleep may be related to declarative memory formation in dementia independent of subtype.
21800251	Sleep after learning is often beneficial for memory. Reinstating an environmental context that was present at learning during subsequent retrieval also leads to superior declarative memory performance. This study examined how post-learning sleep, relative to wakefulness, impacts upon context-dependent memory effects. Thirty-two participants encoded word lists in each of two rooms (contexts), which were different in terms of size, odour and background music. Immediately after learning and following a night of sleep or a day of wakefulness, memory for all previously studied words was tested using a category-cued recall task in room one or two alone. Accordingly, a comparison could be made between words retrieved in an environmental context which was the same as, or different to, that of the learning phase. Memory performance was assessed by the difference between the number of words remembered at immediate and delayed retrieval. A 2 × 2 × 2 mixed ANOVA revealed an interaction between retrieval context (same/different to learning) and retention interval (sleep/wakefulness), which was driven by superior memory after sleep than after wake when learning and retrieval took place in different environmental contexts. Our findings suggest a sleep-related reduction in the extent to which context impacts upon retrieval. As such, these data provide initial support for the possibility that sleep dependent processes may promote a decontextualisation of recently formed declarative representations.
21799746	While numerous studies have shown that a night of sleep profits memory relative to wake, we still have little understanding about what factors mediate this effect of sleep. A clear understanding of the dynamics of this effect of sleep beyond the initial night of sleep is also lacking. Here, we examined the effect of extrinsic rewards on sleep-dependent declarative memory processing across 12 and 24 hr training-retest intervals. Subjects were either paid based on their performance at retest ($1 for each correct answer), or received a flat fee for participation. After a 12 hr interval we observed pronounced benefits of both sleep and reward on memory. Over an extended 24 hr interval we found 1) that an initial night of sleep partially protects memories from subsequent deterioration during wake, and 2) that sleep blocks further deterioration, and may even have a restorative effect on memory, when it follows a full day of wake. Interestingly, the benefit imparted to rewarded (relative to unrewarded) stimuli was equal for sleep and wake subjects, suggesting that the sleeping brain may not differentially process rewarded information, relative to wake. However, looking at the overall impact of sleep relative to reward in this protocol, it was apparent that sleep both imparted a stronger mnemonic boost than reward, and provided a benefit to memory regardless of whether it occurred in the first or the second 12 hrs following task training.
21799485	Testing declarative memory in laboratory rodents can provide insights into the fundamental mechanisms underlying this type of learning and memory processing, and these insights are likely to be applicable to humans. Here we provide a detailed description of the social discrimination procedure used to investigate recognition memory in rats and mice, as established during the last 20 years in our laboratory. The test is based on the use of olfactory signals for social communication in rodents; this involves a direct encounter between conspecifics, during which the investigatory behavior of the experimental subject serves as an index for learning and memory performance. The procedure is inexpensive, fast and very reliable, but it requires well-trained human observers. We include recent modifications to the procedure that allow memory extinction to be investigated by retroactive and proactive interference, and that enable the dissociated analysis of the central nervous processing of the volatile fraction of an individual's olfactory signature. Depending on the memory retention interval under study (short-term memory, intermediate-term memory, long-term memory or long-lasting memory), the protocol takes ~10 min or up to several days to complete.
21774924	Interest is being shown in a componential analysis of performance on declarative memory tasks that distinguishes two different kinds of access to stored memories, recollection and familiarity. From a developmental perspective, it has been hypothesized that recollection emerges later and shows more developmental changes than familiarity. Nevertheless, the contribution of recollection and familiarity to the recognition performance of individuals with intellectual disabilities (ID) has been rarely examined. The present study was aimed at investigating the qualitative profile of declarative long-term memory in a group of individuals with Williams syndrome (WS). We compared 13 individuals with WS and 13 mental-age-matched typically developing children in two different experimental paradigms to assess the contribution of familiarity and recollection to recognition performance. We adopted a modified version of the process dissociation procedure and a task dissociation procedure, both of which are suited to individuals with ID. Results of both experimental paradigms demonstrated reduced recollection and spared familiarity in the declarative memory performances of individuals with WS. These results provide direct evidence of a dissociation between recollection and familiarity in a neurodevelopmental disorder and are discussed in relation to alternative approaches for explaining abnormal cognition in individuals with ID.
21774923	According to the Procedural Deficit Hypothesis (PDH), abnormalities of brain structures underlying procedural memory largely explain the language deficits in children with specific language impairment (SLI). These abnormalities are posited to result in core deficits of procedural memory, which in turn explain the grammar problems in the disorder. The abnormalities are also likely to lead to problems with other, non-procedural functions, such as working memory, that rely at least partly on the affected brain structures. In contrast, declarative memory is expected to remain largely intact, and should play an important compensatory role for grammar. These claims were tested by examining measures of working, declarative and procedural memory in 51 children with SLI and 51 matched typically-developing (TD) children (mean age 10). Working memory was assessed with the Working Memory Test Battery for Children, declarative memory with the Children's Memory Scale, and procedural memory with a visuo-spatial Serial Reaction Time task. As compared to the TD children, the children with SLI were impaired at procedural memory, even when holding working memory constant. In contrast, they were spared at declarative memory for visual information, and at declarative memory in the verbal domain after controlling for working memory and language. Visuo-spatial short-term memory was intact, whereas verbal working memory was impaired, even when language deficits were held constant. Correlation analyses showed neither visuo-spatial nor verbal working memory was associated with either lexical or grammatical abilities in either the SLI or TD children. Declarative memory correlated with lexical abilities in both groups of children. Finally, grammatical abilities were associated with procedural memory in the TD children, but with declarative memory in the children with SLI. These findings replicate and extend previous studies of working, declarative and procedural memory in SLI. Overall, we suggest that the evidence largely supports the predictions of the PDH.
21773811	Mild cognitive impairment (MCI) is a heterogeneous condition characterized by the presence in an otherwise healthy elderly individual of cognitive deficits involving specific domains in the absence of significant functional impairments. Reports indicate that prospective memory (PM), that is, the ability to remember to execute delayed intentions, is impaired in individuals with MCI. The present review discusses the current debate in the literature on PM functioning in MCI by focusing on the relationship between prospective retrieval and retrospective memory functioning. Analysis of the reported evidence revealed that both the prospective component and the retrospective component of PM can be impaired in MCI. Declarative memory dysfunction may account for the retrospective memory impairment, while either reduced executive abilities or a deficit of reflexive mechanisms could explain the prospective component impairment.
21764294	Recent studies of upper limb movements have provided insights into the computations, mechanisms, and taxonomy of human sensorimotor learning. Motor tasks differ with respect to how they weight different learning processes. These include adaptation, an internal-model based process that reduces sensory-prediction errors in order to return performance to pre-perturbation levels, use-dependent plasticity, and operant reinforcement. Visuomotor rotation and force-field tasks impose systematic errors and thereby emphasize adaptation. In skill learning tasks, which for the most part do not involve a perturbation, improved performance is manifest as reduced motor variability and probably depends less on adaptation and more on success-based exploration. Explicit awareness and declarative memory contribute, to varying degrees, to motor learning. The modularity of motor learning processes maps, at least to some extent, onto distinct brain structures.
21763643	It is proposed that thinking is simulated interaction with the environment. Three assumptions underlie this 'simulation' theory of cognitive function. Firstly, behaviour can be simulated in the sense that we can activate motor structures, as during a normal overt action, but suppress its execution. Secondly, perception can be simulated by internal activation of sensory cortex in a way that resembles its normal activation during perception of external stimuli. The third assumption ('anticipation') is that both overt and simulated actions can elicit perceptual simulation of their most probable consequences. A large body of evidence, mainly from neuroimaging studies, that supports these assumptions, is reviewed briefly. The theory is ontologically parsimonious and does not rely on standard cognitivist constructs such as internal models or representations. It is argued that the simulation approach can explain the relations between motor, sensory and cognitive functions and the appearance of an inner world. It also unifies and explains important features of a wide variety of cognitive phenomena such as memory and cognitive maps. Novel findings from recent developments in memory research on the similarity of imaging and memory and on the role of both prefrontal cortex and sensory cortex in declarative memory and working memory are predicted by the theory and provide striking support for it. This article is part of a Special Issue entitled "The Cognitive Neuroscience".
21748823	It is commonly accepted that the hippocampus plays a major role in declarative memory across species and that it is of particular relevance for spatial memory in rodents. However, the interplay between hippocampal function and nondeclarative memory systems, such as procedural stimulus-response (S-R) or sequential learning, is less clear: depending on task requirements, an interaction, dissociation or interference between hippocampal function and other memory systems may occur. This study was conducted to investigate the influence of dorsal ibotenic hippocampal lesions on learning and performance of sequential behavior in a rat version of the serial reaction time task (SRTT). Magnetic resonance imaging (MRI) analyses of the lesions revealed a bilateral volume reduction of ≈ 46% (histological analyses: ≈ 59%) of the total hippocampus. They were largely confined to its dorsal part and led to an expected spatial memory deficits in an object place recognition test as compared to healthy controls, even though sham lesions had the same effect. Our earlier studies on sequential learning had revealed substantial impairments in case of dorsal striatal dopaminergic lesions. In the present study, however, hippocampal lesioned animals unexpectedly showed superior performance throughout SRTT testing and training as compared to controls, which resulted in a higher degree of subsequent automated sequential behavior. Thus, our data reveal the infrequent case where hippocampal lesions lead to long-term improvements in test performance of a type of rather complex procedural behavior. One possible explanation for this effect is that hippocampal activity in rodents can interfere with other memory systems during the acquisition of procedural tasks with very low spatial requirements, as used here. Alternative explanations for the observed superior SRTT performance in lesioned animals, such as hyperactivity or increased exploratory drive are also topic of the discussion.
21747764	Emotional content/context enhances declarative memory through modulation of encoding and retrieval mechanisms. At encoding, neurophysiological data have consistently demonstrated the subsequent memory effect in theta and gamma oscillations. Yet, the existing studies were focused on the emotional content effect and let the emotional context effect unexplored. We hypothesized that theta and gamma oscillations show higher evoked/induced activity during the encoding of visual stimuli when delivered in an emotionally arousing context. Twenty-five healthy volunteers underwent evoked potentials (EP) recordings using a 21 scalp electrodes montage. They attended to an audiovisual test of emotional declarative memory being randomly assigned to either emotionally arousing or neutral context. Visual stimulus presentation was used as the time-locking event. Grand-averages of the EP and evoked spectral perturbations were calculated for each volunteer. EP showed a higher negative deflection from 80 to 140 ms for the emotional condition. Such effect was observed over central, frontal and prefrontal locations bilaterally. Evoked theta power was higher in left parietal, central, frontal, and prefrontal electrodes from -50 to 300 ms in the emotional condition. Evoked gamma power was higher in the emotional condition with a spatial distribution that overlapped at some points with the theta topography. The early theta power increase could be related to expectancy induced by auditory information processing that facilitates visual encoding in emotional contexts. Together, our results suggest that declarative memory enhancement for both emotional content and emotional context are supported by similar neural mechanisms at encoding, and offer new evidence about the brain processing of relevant environmental stimuli.
21741545	Healthy aging is characterized by a diminished quality of sleep with decreased sleep duration and increased time awake after sleep onset. Older adults awaken more frequently and tend to awaken less from rapid eye movement (REM) sleep and more from non-REM (nREM) sleep than young adults. Sleep architecture also begins changing in middle age leading to a dramatic decrease in the deepest stage of nREM-slow wave sleep (SWS)-as aging progresses. Other less marked nREM changes include reduced numbers of sleep spindles and K-complexes. In contrast, the amount of REM diminishes only slightly. Both circadian and homeostatic sleep-regulatory processes are affected by aging. Circadian rhythms of temperature, melatonin, and cortisol are phase advanced and their amplitude diminished. An increased number of nocturnal awakenings and diminished daytime sleepiness suggest diminished homeostatic sleep pressure. A variety of endocrine and neuromodulatory changes (e.g., reduced growth hormone and dopamine levels) also accompany healthy aging. Healthy aging is characterized by declines in working memory and new episodic memory performance with relative sparing of semantic memory, recognition memory, and priming. Memory systems impacted by aging are associated with volumetric and functional changes in fronto-striatal circuits along with more limited changes in medial temporal structures (in which larger aging-related changes suggest neuropathology). Cross-sectional studies generally associate poorer sleep quality with poorer neuropsychological functioning. However, paradoxically, older adults appear to be more resistant to the cognitive effects of sleep deprivation, restriction, and fragmentation than younger adults. A new and expanding field examines the interaction between aging and sleep-dependent memory consolidation. Among forms of learning displaying prominent sleep-dependent consolidation in young adults, motor-sequence learning displays loss of sleep-dependent consolidation with aging whereas sleep-dependent consolidation of verbal declarative memory appears spared. Findings suggest that improving sleep through behavioral or pharmacological treatments may enhance cognition and performance in older adults.
21736777	The macronutrient composition of a breakfast that could facilitate performance after an overnight fast remains unclear. As glucose is the brain's major energy source, the interest is in investigating meals differing in their blood glucose-raising potential. Findings vary due to unaccounted differences in glucoregulation, arousal and cortisol secretion. We investigated the effects of meals differing in glycaemic index (GI) and glycaemic load (GL) on cognition and mood in school children. A total of seventy-four school children were matched and randomly allocated either to the high-GL or low-GL group. Within each GL group, children received high-GI and low-GI breakfasts. Cognitive function (CF) and mood were measured 95-140 min after breakfast. Blood glucose and salivary cortisol were measured at baseline, before and after the CF tests. Repeated-measures ANOVA was used to identify differences in CF, mood, glucose and cortisol levels between the breakfasts. Low-GI meals predicted feeling more alert and happy, and less nervous and thirsty (P < 0·05 for each); high-GL meals predicted feeling more confident, and less sluggish, hungry and thirsty (P < 0·05 for each). High-GL (P < 0·001) and high-GI (P = 0·05) meals increased glucose levels 90 min after breakfast, and high-GI meals increased cortisol levels (P < 0·01). When baseline mood, glucose and cortisol levels were considered, low-GI meals predicted better declarative-verbal memory (P = 0·03), and high-GI meals better vigilance (P < 0·03); observed GI effects were valid across GL groups. GI effects on cognition appear to be domain specific. On balance, it would appear that the low-GI high-GL breakfast may help to improve learning, and of potential value in informing government education policies relating to dietary recommendations and implementation concerning breakfast.
21736452	Memory functions involve three stages: encoding, consolidation, and retrieval. Modulating effects of glucocorticoids (GCs) have been consistently observed for declarative memory with GCs enhancing encoding and impairing retrieval, but surprisingly, little is known on how GCs affect memory consolidation. Studies in rats suggest a beneficial effect of GCs that were administered during postlearning wake periods, whereas in humans, cortisol impaired memory consolidation when administered during postlearning sleep. These inconsistent results raise the question whether effects of GCs critically depend on the brain state during consolidation (sleep vs. wake). Here, we compare for the first time directly the effects of cortisol on memory consolidation during postlearning sleep and wakefulness in different measures of declarative memory. Cortisol (13 mg vs. placebo) was intravenously infused during a postlearning nap or a time-matched period of wakefulness after participants had encoded neutral and emotional text material. Memory for the texts was tested (a) by asking for the contents of the texts ("item" memory) and (b) for the temporal order of the contents within the texts ("relational" memory). Neither postlearning infusion of cortisol during sleep nor during wakefulness affected retention of content words of emotional or neutral texts. Critically, however, the retention of temporal order within the texts, known to rely most specifically on the hippocampus proper within the medial-temporal lobe memory system, was distinctly improved by cortisol infusion during the wake phase but impaired by cortisol during sleep. These results point toward fundamentally different mechanisms of hippocampal memory consolidation, depending on the brain state.
21736434	Can motor learning be equivalent in younger and older adults? To address this question, 48 younger (M = 23.5 years) and 48 older (M = 65.0 years) participants learned to perform a golf-putting task in two different motor learning situations: one that resulted in infrequent errors or one that resulted in frequent errors. The results demonstrated that infrequent-error learning predominantly relied on nondeclarative, automatic memory processes whereas frequent-error learning predominantly relied on declarative, effortful memory processes: After learning, infrequent-error learners verbalized fewer strategies than frequent-error learners; at transfer, a concurrent, attention-demanding secondary task (tone counting) left motor performance of infrequent-error learners unaffected but impaired that of frequent-error learners. The results showed age-equivalent motor performance in infrequent-error learning but age deficits in frequent-error learning. Motor performance of frequent-error learners required more attention with age, as evidenced by an age deficit on the attention-demanding secondary task. The disappearance of age effects when nondeclarative, automatic memory processes predominated suggests that these processes are preserved with age and are available even early in motor learning.
21728453	Squire and colleagues have proposed that trace and delay eyeblink conditioning are fundamentally different kinds of learning: trace conditioning requires acquisition of a conscious declarative memory for the stimulus contingencies whereas delay conditioning does not. Declarative memory in trace conditioning is thought to generate conditioned responding through the activation of a conscious expectancy for when the unconditioned stimulus (US) is going to occur. Perruchet (1985) has previously shown that in a 50% partial reinforcement design it is possible to dissociate single cue delay eyeblink conditioning from conscious expectancy for the US by examining performance over runs of reinforced and nonreinforced trials. Clark, Manns, and Squire (2001) claim that this dissociation does not occur in trace eyeblink conditioning. In the present experiment we examined the Perruchet effect for short, moderate, and long trace intervals (600, 1000, and 1400 ms) and for the equivalent interstimulus intervals (ISIs) in a delay conditioning procedure. We found evidence for a dissociation of eyeblink CRs and US expectancy over runs regardless of whether there was a delay or a trace arrangement of cues. The reasons for the Perruchet effect are still unclear, but the present data suggest that it does not depend on a separate nondeclarative system of the type proposed by Squire and colleagues.
21722740	Spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) signal, as measured by functional magnetic resonance imaging (fMRI) at rest, exhibit a temporally coherent activity thought to reflect functionally relevant networks. Antero-mesial temporal structures are the site of early pathological changes in Alzheimer's disease and have been shown to be critical for declarative memory. Our study aimed at exploring the functional impact of basal connectivity of an anterior temporal network (ATN) on declarative memory. A heterogeneous group of subjects with varying performance on tasks assessing memory was therefore selected, including healthy subjects and patients with isolated memory complaint, amnestic Mild Cognitive Impairment (aMCI) and mild Alzheimer's disease (AD). Using Independent Component Analysis on resting-state fMRI, we extracted a relevant anterior temporal network (ATN) composed of the perirhinal and entorhinal cortex, the hippocampal head, the amygdala and the lateral temporal cortex extending to the temporal pole. A default mode network and an executive-control network were also selected to serve as control networks. We first compared basal functional connectivity of the ATN between patients and control subjects. Relative to controls, patients exhibited significantly increased functional connectivity in the ATN during rest. Specifically, voxel-based analysis revealed an increase within the inferior and superior temporal gyrus and the uncus. In the patient group, positive correlations between averaged connectivity values of ATN and performance on anterograde and retrograde object-based memory tasks were observed, while no correlation was found with other evaluated cognitive measures. These correlations were specific to the ATN, as no correlation between performance on memory tasks and the other selected networks was found. Taken together, these findings provide evidence that basal connectivity inside the ATN network has a functional role in object-related, context-free memory. They also suggest that increased connectivity at rest within the ATN could reflect compensatory mechanisms that occur in response to early pathological insult.
21714740	A current debate in the literature is whether all declarative memories and associated memory processes rely on the same neural substrate. Here, we show that H.C., a developmental amnesic person with selective bilateral hippocampal volume loss, has a mild deficit in personal episodic memory, and a more pronounced deficit in public event memory; semantic memory for personal and general knowledge was unimpaired. This was accompanied by a subtle difference in impairment between recollection and familiarity on lab-based tests of recognition memory. Strikingly, H.C.'s recognition did not benefit from a levels-of-processing manipulation. Thus, not all types of declarative memory and related processes can exist independently of the hippocampus even if it is damaged early in life.
21706019	When learned in quick succession, declarative and motor skill tasks interfere with one another and subsequent recall is impaired. Depending on the order of the tasks, we were able to prevent memory interference in humans by applying transcranial magnetic stimulation to either the dorsolateral prefrontal or the primary motor cortex, and neither memory was impaired. Our observations suggest that distinct mechanisms support the communication between different types of memory processing.
21697007	Sleep supports the consolidation of declarative memory. Patients with attention-deficit/hyperactivity disorder (ADHD) are not only characterized by sleep problems but also by declarative memory deficits. Given that the consolidation of declarative memory during sleep is supported by slow oscillations, which are predominantly generated by the prefrontal cortex, and that ADHD patients display low prefrontal brain activity, we assumed that ADHD patients show reduced sleep-associated consolidation of declarative memory.The impact of sleep on the consolidation of declarative memory was examined with a picture recognition task. Twelve ADHD patients (10-16 years) and 12 healthy controls participated in two experimental conditions: in the sleep condition, learning was performed in the evening and picture recognition was tested after nocturnal sleep; in the wake condition, learning was conducted in the morning while retrieval took place after a day of wakefulness.	Analyses of recognition accuracy revealed reduced sleep-associated enhancement of recognition accuracy in ADHD. While sleep-associated enhancement of recognition accuracy was correlated with slow oscillation power during non-REM sleep in healthy controls, no such correlations were observed in ADHD.	These data indicate a deficit in sleep-associated consolidation of declarative memory in ADHD. Moreover, our results suggest reduced functionality of slow oscillations in sleep-associated consolidation of declarative memory in ADHD.	
21691889	Transfer of knowledge is the cornerstone of any educational organisation, with senior staff expected to participate in the training of less experienced colleagues and students. Teaching in the field is, however, slightly different, and a less theoretical approach is usually recommended. In terms of Disaster Victim Identification (DVI) activities, practical work under supervision of a field team stimulates tactile memory. A more practical approach is also useful when multiple organizations from a variety of countries are involved, as language barriers make it easier to manually show someone how to solve a problem, instead of attempting to explain complex concepts verbally. "See one, do one, teach one" is an approach that can be used to ensure that teaching is undertaken with the teacher grasping the essentials of a situation before passing on the information to someone else. The key principles of adult learning that need to be applied to DVI situations include the following: participants need to know why they are learning and to be motivated to learn by the need to solve problems; previous experience must be respected and built upon and learning approaches should match participants' background and diversity; and finally participants need to be actively involved in the learning process. Active learning involves the active acquisition of knowledge and/or skills during the performance of a task and characterizes DVI activities. Learning about DVI structure, activities and responsibilities incorporates both the learning of facts ("declarative knowledge") and practical skills ("procedural knowledge"). A fundamental requirement of all DVI exercises should be succession planning with involvement of less experienced colleagues at every opportunity so that essential teaching and learning opportunities are maximized. DVI missions provide excellent teaching opportunities and international agencies have a responsibility to teach less experienced colleagues and local staff during deployment.
21687470	For a long time alpha oscillations have been functionally linked to the processing of visual information. Here we propose an new theory about the functional meaning of alpha. The central idea is that synchronized alpha reflects a basic processing mode that controls access to information stored in a complex long-term memory system, which we term knowledge system in order to emphasize that it comprises not only declarative memories but any kind of knowledge comprising also procedural information. Based on this theoretical background, we assume that during early stages of perception, alpha "directs the flow of information" to those neural structures which represent information that is relevant for encoding. The physiological function of alpha is interpreted in terms of inhibition. We assume that alpha enables access to stored information by inhibiting task-irrelevant neuronal structures and by timing cortical activity in task relevant neuronal structures. We discuss a variety findings showing that evoked alpha and phase locking reflect successful encoding of global stimulus features in an early post-stimulus interval of about 0-150 ms.
21684235	Emotional dysfunction is a core feature of psychotic disorders. One expression of such dysfunction is a reduction of the emotion-induced enhancement of memory which is normally found in healthy individuals. Less severe disruption of emotional processing may also be present in individuals prone to 'unusual' psychosis-like experiences. In this study we investigate voluntary declarative (i.e. explicit or episodic) emotional memory performance, primarily in relation to positive schizotypy (as measured by the unusual experiences scale of the O-LIFE). The effect of negative schizotypy (introvertive anhedonia scale of the O-LIFE) was also explored. We hypothesized that schizotypal individuals (scoring highly on Unusual Experiences) would show reduced memory enhancement.One hundred and two healthy participants viewed a narrated slide-show containing neutral and negative emotional content. They rated the story on a number of affective dimensions and completed a variety of trait measures, including a multi-dimensional measure of schizotypy. Seven days later, a memory test was performed and frequency of involuntary memories related to the slide-show assessed.	The voluntary declarative emotional memory advantage in recall seen in low scorers (25%ile) on unusual experiences was absent in high scorers (75%ile), despite greater subjective fearfulness and emotionality in that group. However, the high scoring group did report experiencing more involuntary memories related to the story. There was no effect of negative schizotypy on declarative emotional memory.	The emotional memory difficulties seen in studies of schizophrenia may extend to those with a vulnerability to positive psychosis-like experiences. This vulnerability may be expressed in both voluntary declarative - as well as involuntary - emotional memory performance.	
21677375	A key symptom in the early stages of Alzheimer's disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients.
21675222	We studied effects of a daytime nap (1 hour) with including only NREM sleep on performance of declarative memory task (60 semantically unrelated word pairs) and general functional state. During training, procedure of learning of 30 word pairs was presented once, and that of the other 30 pairs was repeated twice. Strength of the task acquisition was tested. Subjects participated in two experiments: basic and control one. After learning participants either took a nap (basic experiment) or kept awake looking movies (control experiment). In 4.5 hours after the training session all the subjects were retested. As compared to the subjects who stayed awake during the training-retesting interval, subjects who had a NREM nap demonstrated enhanced performance. Concerning the strength of task acquisition, sleep-dependent performance was observed only for the word pairs learned once. Naps did not affect the functional state assessed by the reaction time dynamics and psychological testing.
21656872	A radial maze concurrent spatial discrimination learning paradigm consisting of two stages was previously designed to assess the flexibility property of relational memory in mice, as a model of human declarative memory. Aged mice and young adult mice with damage to the hippocampus, learned accurately Stage 1 of the task which required them to learn a constant reward location in a specific set of arms (i.e., learning phase). In contrast, they were impaired relative to healthy young adult mice in a second stage when faced with rearrangements of the same arms (i.e., flexibility probes). This mnemonic inflexibility in Stage 2 is thought to derive from insufficient relational processing by the hippocampus during initial learning (Stage 1) which favors stimulus-response learning, a form of procedural learning. This was proposed as a model of the selective declarative and relational memory decline classically described in elderly people. As a first step to examine the validity of this model, we adapted this protocol to humans using a virtual radial-maze. (1) We showed that performance in the flexibility probes in young and older adults positively correlated with performance in a wayfinding task, suggesting that our paradigm assesses relational memory. (2) We demonstrated that older healthy participants displayed a deficit in the performance of the flexibility probes (Stage 2), similar to the one previously seen in aged mice. This was associated with a decline in the wayfinding task. (3) Our fMRI data in young adults confirmed that hippocampal activation during early discrimination learning in Stage 1 correlated with memory flexibility in Stage 2, whereas caudate nucleus activation in Stage 1 negatively correlated with subsequent flexibility. By enabling relational memory assessment in mice and humans, our radial-maze paradigm provides a valuable tool for translational research.
21645527	Transient receptor potential vanilloid 1 (TRPV1) was shown to modulate hippocampal CA1 pyramidal cell synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Synaptic plasticity is the cellular mechanism thought to mediate declarative learning and memory in the hippocampus. Although TRPV1 is involved in modulating hippocampal plasticity, it has yet to be determined how TRPV1 mediates its effects. Using field electrophysiology in hippocampal CA1 stratum radiatum we investigated how TRPV1 agonists modulate LTP, low frequency stimulation-induced LTD, and (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD. First we confirmed that TRPV1 agonists induce enhancement of CA1 pyramidal cell LTP in the absence the GABA(A) receptor antagonist picrotoxin. Because it was recently determined that TRPV1 mediates a novel form of LTD in CA1 inhibitory GABAergic interneurons, which can disinhibit CA1 pyramidal cells, we used picrotoxin to block the effect of the GABAergic circuitry on CA1 LTP. When using picrotoxin, the TRPV1 agonist-induced enhancement of CA1 LTP was eliminated suggesting that the GABAergic circuitry is required for TRPV1 agonist mediated increases. Regarding LTD, in contrast to previously reported data, we did not see TRPV1 agonist-mediated effect on low frequency-induced stimulus LTD. However, during DHPG-induced LTD, TRPV1 was involved in the acute, but not the long-term depression phase of this plasticity. In summary, our findings support TRPV1 agonist involvement in hippocampal synaptic plasticity, including its enhancement of CA1 LTP. We demonstrate that the enhancement mediated by TRPV1 agonists requires GABA input to pyramidal cells thus providing a mechanism for how TRPV1 agonists modulate hippocampal synaptic plasticity.
21632621	Following encoding, memory remains temporarily vulnerable to disruption. Consolidation refers to offline time-dependent processes that continue after encoding and stabilize, transform or enhance the memory trace. Memory consolidation resulting from sleep has been reported for declarative and non-declarative memories in humans. We first investigated the temporal course of memory retrieval in chimpanzees, bonobos and orangutans. We found that the amount of retrieved information was time dependent: apes' performance degraded after 1 and 2 h, stabilized after 4 h, started to increase after 8 and 12 h and fully recovered after 24 h. Second, we show that although memories during wakefulness were highly vulnerable to interference from events similar to those witnessed during the original encoding event, an intervening period of sleep not only stabilized apes' memories into more permanent ones but also protected them against interference.
21624479	Ample evidence in animals and humans supports the noradrenergic modulation in the formation of emotional memory. However, in humans the effects of stress on emotional memory are traditionally investigated by declarative memory tests (e.g., recall, recognition) for non-associative emotional stimuli (e.g., stories, pictures). Given that anxiety disorders are thought to originate from associative learning processes and are characterized by distressing emotional responses, the existing literature seems to be inconclusive for the understanding of these disorders. Here, we tested whether noradrenaline strengthens the emotional expression of associative fear memory by using a differential fear conditioning procedure in humans. Stimulation of the noradrenergic system by the administration of yohimbine HCl (20mg) during memory formation did not directly augment the differential startle fear response 48 h later. Yet, the other retention tests uncovered that the administration of yohimbine HCl contrary to placebo pill extensively delayed the process of extinction learning and generated a superior recovery of fear (i.e., reinstatement and reacquisition). Conversely, the yohimbine HCl manipulation did not affect the skin conductance responding and the US expectancy ratings, emphasizing the concept of multiple memory systems. To our knowledge this is the first demonstration in humans that increased noradrenaline release during or shortly after a stressful event strengthens the formation of associative fear memory traces. The present findings suggest that noradrenaline may play an important role in the etiology and maintenance of anxiety disorders.
21621549	Sleep plays a role in the consolidation of declarative memories. Although this influence has attracted much attention at the level of behavioural performance, few reports have searched for neural correlates. Here, we studied the impact of sleep upon memory for the context in which stimuli were learned at both behavioural and neural levels. Participants retrieved the association between a presented foreground object and its encoding context following a 12-h retention interval including either wake only or wake plus a night of sleep. Since sleep has been shown to selectively enhance some forms of emotional memory, we examined both neutral and emotionally valenced contexts. Behaviourally, less forgetting was observed across retention intervals containing sleep than retention intervals containing only wakefulness, and this benefit was accompanied by stronger responses in hippocampus and superior parietal cortex. This sleep-related reduction in forgetting did not differ between neutral and negative contexts, but there was a clear interaction between sleep and context valence at the functional level, with left amygdala, right parahippocampus, and other components of the episodic memory system all responding more strongly during correct memory for emotional contexts post-sleep. Connectivity between right parahippocampus and bilateral amygdala/periamygdala was also enhanced during correct post-sleep attribution of emotional contexts. Because there was no interaction between sleep and valence in terms of context memory performance these functional results may be associated with memory for details about the emotional encoding context rather than for the link between that context and the foreground object. Overall, our data show that while context memory decays less across sleep than across an equivalent period of wake, the sleep-related protection of such associations is not influenced by context emotionality in the same way as direct recollection of emotional information.
21613466	Traditionally, the medial temporal lobe (MTL) is thought to be dedicated to declarative memory. Recent evidence challenges this view, suggesting that perirhinal cortex (PrC), which interfaces the MTL with the ventral visual pathway, supports highly integrated object representations in recognition memory and perceptual discrimination. Even with comparable representational demands, perceptual and memory tasks differ in numerous task demands and the subjective experience they evoke. Here, we tested whether such differences are reflected in distinct patterns of connectivity between PrC and other cortical regions, including differential involvement of prefrontal control processes. We examined functional magnetic resonance imaging data for closely matched perceptual and recognition memory tasks for faces that engaged right PrC equivalently. Multivariate seed analyses revealed distinct patterns of interactions: Right ventrolateral prefrontal and posterior cingulate cortices exhibited stronger functional connectivity with PrC in recognition memory; fusiform regions were part of the pattern that displayed stronger functional connectivity with PrC in perceptual discrimination. Structural equation modeling revealed distinct patterns of effective connectivity that allowed us to constrain interpretation of these findings. Overall, they demonstrate that, even when MTL structures show similar involvement in recognition memory and perceptual discrimination, differential neural mechanisms are reflected in the interplay between the MTL and other cortical regions.
21591906	The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.
21589884	Electrophysiological studies in animals have shown coordinated reactivation of neuronal ensembles during a restricted time period of behavioral inactivity that immediately followed active encoding. In the present study we directly investigated off-line processing of associative memory formation in the human brain. Subjects' regional cerebral blood flow (rCBF) as a surrogate marker of neural activity during rest was measured by MR-based perfusion imaging in a sample of 14 healthy male subjects prior to (Pre2) and after (Post) extensive learning of 24 face-name associations within a selective reminding task (SR). Results demonstrated significant Post-Pre2 rCBF increases in hippocampal and temporal lobe regions, while in a control comparison of two perfusion scans with no learning task in-between (Pre2-Pre1) no differences in rCBF emerged. Post perfusion scanning was followed by a surprise cued associative recall task from which two types of correctly retrieved names were obtained: older names already correctly retrieved at least once during one of the SR blocks, and recent names acquired during the last SR block immediately prior to the Post scan. In the anterior hippocampus individual perfusion increases were correlated with both correct retrievals of older and recent names. By contrast, older but not recently learned names showed a significant correlation with perfusion increases in the left lateral temporal cortex known to be associated with long-term memory. Recent, but not older names were correlated with dopaminergic midbrain structures reported to contribute to the persistence of memory traces for novel information. Although the direct investigation of off-line memory processing did not permit concomitant experimental control, neither intentional rehearsal, nor substantial variations in subjects' states of alertness appear to contribute to present results. We suggest that the observed rCBF increases might reflect processes that possibly contribute to the long-term persistence of memory traces.
21575014	Binge drinking (BD), which is characterized by sporadic consumption of large quantities of alcohol in short periods, is prevalent among university students. Animal studies have shown that BD is associated with damage to the hippocampus, a region of the brain that plays a key role in learning and memory. The temporal cortex undergoes structural and functional changes during adolescence. The aim of the present study was to examine the association between BD and declarative memory in male and female university students.The participants were 122 students (between 18 and 20 years of age): 62 BD (30 women) and 60 non-BD (29 women). The neuropsychological assessment included the Rey Auditory Verbal Learning Test (RAVLT) and Weschler Memory Scale-3rd ed. (WMS-III) Logical Memory subtest, to evaluate verbal declarative memory, and the WMS-III Family Pictures subtest, to measure visual declarative memory.	The BD students remembered fewer words in the interference list and displayed greater proactive interference in the RAVLT; they performed worse in the Logical Memory subtest, both on immediate and delayed recall. There were no differences between the groups in performance of the Family Pictures subtest. No significant interactions were observed between BD and sex.	Binge drinking is associated with poorer verbal declarative memory, regardless of sex. The findings are consistent with the vulnerability of the adolescent hippocampus to the neurotoxic effects of alcohol. Longitudinal studies will help determine the nature of this relationship, the neurodevelopmental trajectories for each sex, and the repercussions on academic performance.	
21574717	This study explored verbal semantic and episodic memory in children with unilateral temporal lobe epilepsy to determine whether they had impairments in both or only 1 aspect of memory, and to examine relations between performance in the 2 domains.Sixty-six children and adolescents (37 with seizures of left temporal lobe onset, 29 with right-sided onset) were given 4 tasks assessing different aspects of semantic memory (picture naming, fluency, knowledge of facts, knowledge of word meanings) and 2 episodic memory tasks (story recall, word list recall).	High rates of impairments were observed across tasks, and no differences were found related to the laterality of the seizures. Individual patient analyses showed that there was a double dissociation between the 2 aspects of memory in that some children were impaired on episodic but not semantic memory, whereas others showed intact episodic but impaired semantic memory.	This double dissociation suggests that these 2 memory systems may develop independently in the context of temporal lobe pathology, perhaps related to differential effects of dysfunction in the lateral and mesial temporal lobe structures.	
21552364	Computational models of semantic memory exploit information about cooccurrences of words in naturally-occurring text to extract information about the meaning of the words that are present in the language. Such models implicitly specify a representation of temporal context. Depending on the model, words are said to have occurred in the same context if they are presented within a moving window, within the same sentence or within the same document. The temporal context model (TCM), a specific quantitative specification of temporal context has proved useful in the study of episodic memory. The predictive temporal context model (pTCM) uses the same definition of temporal context to generate semantic memory representations. Taken together pTCM and TCM may prove to be part of a general model of declarative memory.
21543596	Under the assumption that dream recall is a peculiar form of declarative memory, we have hypothesized that (1) the encoding of dream contents during sleep should share some electrophysiological mechanisms with the encoding of episodic memories of the awake brain and (2) recalling a dream(s) after awakening from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep should be associated with different brain oscillations. Here, we report that cortical brain oscillations of human sleep are predictive of successful dream recall. In particular, after morning awakening from REM sleep, a higher frontal 5-7 Hz (theta) activity was associated with successful dream recall. This finding mirrors the increase in frontal theta activity during successful encoding of episodic memories in wakefulness. Moreover, in keeping with the different EEG background, a different predictive relationship was found after awakening from stage 2 NREM sleep. Specifically, a lower 8-12 Hz (alpha) oscillatory activity of the right temporal area was associated with a successful dream recall. These findings provide the first evidence of univocal cortical electroencephalographic correlates of dream recall, suggesting that the neurophysiological mechanisms underlying the encoding and recall of episodic memories may remain the same across different states of consciousness.
21541757	Over the past two decades, research has accumulated compelling evidence that sleep supports the formation of long-term memory. The standard two-stage memory model that has been originally elaborated for declarative memory assumes that new memories are transiently encoded into a temporary store (represented by the hippocampus in the declarative memory system) before they are gradually transferred into a long-term store (mainly represented by the neocortex), or are forgotten. Based on this model, we propose that sleep, as an offline mode of brain processing, serves the 'active system consolidation' of memory, i.e. the process in which newly encoded memory representations become redistributed to other neuron networks serving as long-term store. System consolidation takes place during slow-wave sleep (SWS) rather than rapid eye movement (REM) sleep. The concept of active system consolidation during sleep implicates that (a) memories are reactivated during sleep to be consolidated, (b) the consolidation process during sleep is selective inasmuch as it does not enhance every memory, and (c) memories, when transferred to the long-term store undergo qualitative changes. Experimental evidence for these three central implications is provided: It has been shown that reactivation of memories during SWS plays a causal role for consolidation, that sleep and specifically SWS consolidates preferentially memories with relevance for future plans, and that sleep produces qualitative changes in memory representations such that the extraction of explicit and conscious knowledge from implicitly learned materials is facilitated.
21535999	Major depressive disorder (MDD) has been associated with hypercortisolism, reduced glucocorticoid feedback sensitivity, and impaired memory function. In healthy subjects, administration of hydrocortisone impairs declarative memory. The aim of this study was to examine the effects of acute hydrocortisone administration on memory retrieval in MDD patients and healthy controls. We further tested whether the enhancing or impairing effects of hydrocortisone would prevail when it was given after encoding and when delayed retrieval was tested at a time point when glucocorticoid levels were still elevated.In a placebo-controlled, double-blind crossover study, 44 patients with DSM-IV MDD and 51 healthy control participants received either placebo or 10 mg of hydrocortisone orally before memory testing. A word list paradigm and the Logical Memory Test from the Wechsler Memory Scale were applied. The study was conducted from April 2008 until April 2010 at sites in Bielefeld and Hamburg, Germany.	In both memory tests, patients with MDD performed worse than controls. Healthy controls showed impaired memory performance after hydrocortisone administration compared to placebo. In contrast, hydrocortisone had no effects on memory in MDD patients. Furthermore, in healthy controls we found that administration of hydrocortisone immediately after learning did not lead to an enhanced free recall during increased cortisol levels.	It appears that the impairing effects of hydrocortisone on memory performance are missing in patients with MDD. This might be interpreted in the context of reduced central glucocorticoid receptor functioning.	
21527348	Cognitive deficits are among the most important factors leading to poor functional outcomes in schizophrenia, with deficits in declarative memory among the largest and most robust of these. Thus far, attempts to enhance cognition in schizophrenia have shown only modest success, which underlies increasing efforts to develop effective treatment strategies. This review is divided into three main parts. The first section delineates the nature and extent of the deficits in both patients with schizophrenia and in their adult, non-psychotic relatives. The second part focuses on structural and functional abnormalities in the hippocampus, both in people with schizophrenia and in animal studies that model relevant features of the illness. The third section views problems in declarative memory and hippocampal function from the perspective of elevated rates of common medical disorders in schizophrenia, with a focus on insulin insensitivity/diabetes. The likelihood that poor glucose regulation/availability contribute to declarative memory deficits and hippocampal abnormalities is considered, along with the possibility that schizophrenia and poor glucose regulation share common etiologic elements, and with clinical implications of this perspective for enhancing declarative memory.
21517143	Several studies in nonhuman primates have shown that neurons in the dorsolateral prefrontal cortex have activity that persists throughout the delay period in delayed matching to sample tasks, and age-related changes in the microcolumnar organization of the prefrontal cortex are significantly correlated with age-related declines in cognition. Activity that persists beyond the presentation of a stimulus could mediate working memory processes, and disruption of those processes could account for memory deficits that often accompany the aging process. These potential memory and aging mechanisms are being systematically examined with eyeblink conditioning paradigms in nonprimate mammalian animal models including the rabbit. The trace version of the conditioning paradigm is a particularly good system to explore declarative memory since humans do not acquire trace conditioning if they are unable to become cognitively aware of the association between a conditioning tone and an airpuff to the eye. This conditioning paradigm has been used to show that the hippocampus and cerebellum interact functionally since both conditioned responses and conditioned hippocampal pyramidal neuron activity are abolished following lesions of the cerebellar nuclei and since hippocampal lesions prevent or abolish trace conditioned blinks. However, because there are no direct connections between the hippocampal formation and the cerebellum, and because the hippocampus is not necessary for trace conditioning after a period of consolidation has elapsed, we and others have been examining the prefrontal cortex for its role in forebrain-dependent trace eyeblink conditioning. This review examines some of the literature which suggests that the prefrontal cortex serves to orchestrate a neuronal network that interacts with the cerebellum to mediate adaptively timed conditioned responses.
21514391	The consolidation of declarative memories benefits from sleep. The neural mechanisms involved in sleep-dependent consolidation, however, are largely unknown. Here, we used a combination of functional magnetic resonance imaging, polysomnography and a face-location associative memory task to target neural connectivity of a face sensitive area during an afternoon nap. Fusiform connectivity was substantially greater during sleep stage 1 than in wake in a network extending from early visual areas bilaterally to the fusiform gyrus, ventrally and into the posterior parietal cortices, dorsally. In sleep stage 2, fusiform connectivity was found to be larger in the precuneus, bilateral middle temporal gyrus and medial prefrontal cortex. Specific functional connectivity increases observed during light sleep were positively correlated with memory performance for face-location associations. A distinction could be made between fusiform-medial prefrontal connectivity during sleep stage 1 and 2 that was positively correlated with retention of associations learned prior to sleep and fusiform-hippocampal connectivity during sleep stage 1 that was correlated with better acquisition of new associations learned after sleep. Our results suggest that fusiform-medial prefrontal connectivity during sleep has a stabilizing effect on recently learned associative memories, possibly due to the existence of a task-related schema that allows rapid consolidation of related information. Our data further indicate that sleep-dependent connectivity between the fusiform gyrus and hippocampus correlated with new learning after sleep. Thus, our study provides correlational evidence for the behavioral relevance of specific medial prefrontal and hippocampal interactions with the fusiform gyrus during light sleep.
21514368	The reconsolidation hypothesis proposes that a previously consolidated memory recalled by a reminder enters an unstable state (memory labilization) during which it is transiently sensitive to disruption. Although this process has been shown in very diverse species and types of memories, including human declarative memory, elucidating the role of this process is still an open challenge. The hypothesis that reconsolidation allows the incorporation of new information has recently been demonstrated in humans. However, the findings show that, during the reconsolidation phase, memory retention can be increased by pharmacological modulation or real life events in animals have not been found in humans yet. In order to evaluate this, we used a paradigm of human declarative memory whose reminder structure allows us to differentiate between a retrieved labile memory state and a retrieved but non-labile state. Volunteers learned an association between five cue-syllables and their respective response-syllables. 6 days later, the paired-associate memory was reactivated by exposing the subjects to the reminder, and then they received a mild stressor, cold pressor stress (CPS). Poor memory performance was found at both the time of memory reactivation (day 6 after training) and at testing of all groups that were designed as controls (day 7). Conversely, robust memory performance was shown at testing when the CPS administration was concurrent with the retrieved-labile memory state. Results from the present study reveal that a naturalistic mild stressor can enhance reconsolidation, improving the long-term expression of this declarative memory. This finding might have significant implications for the comprehension of memory persistence and memory expression, and add new evidence in order to understand the adaptive meaning of the reconsolidation process.
21509624	Elderly persons frequently complain about problems with speech understanding especially in complex acoustic situations. Besides hearing impairment the decline of cognitive functions might explain these problems.In 12 normal hearing young subjects and 14 elderly listeners with extraordinarily good hearing speech perception was measured in a broad range of different acoustic situations. Cognitive functioning was evaluated with different neuropsychological tests.	Despite comparable pure tone thresholds the elderly listeners revealed worse speech discrimination than the young subjects in almost all test situations. Largest differences were found in situations with fluctuating maskers and competing talkers. Most of the speech perception results revealed significant correlations with the outcome from a neuropsychological test addressing declarative verbal memory.	In complex listening situations elderly persons reveal worse speech understanding than younger subjects. Differences in speech perception can partly be attributed to cognitive abilities. In particular, working memory seems to be an important factor.	
21501632	Electrical high frequency stimulation (HFS) has been used to treat various neurological and psychiatric diseases. The striatal area contributes to response learning and procedural memory. Therefore, we investigated the effect of striatal HFS application on procedural/declarative-like memory in rats. All rats were trained in a flooded Double-H maze for three days (4 trials/day) to swim to an escape platform hidden at a constant location. The starting place was the same for all trials. After each training session, HFS of the left dorsal striatum was performed over 4h in alternating 20 min periods (during rest time, 10a.m. to 3p.m.). Nineteen hours after the last HFS and right after a probe trial assessing the rats' strategy (procedural vs. declarative-like memory-based choice), animals were sacrificed and the dorsal striatum was quickly removed. Neurotransmitter levels were measured by HPLC. Stimulated rats did not differ from sham-operated and control rats in acquisition performance, but exhibited altered behavior during the probe trial (procedural memory responses being less frequent than in controls). In stimulated rats, GABA levels were significantly increased in the dorsal striatum on both sides. We suggest that HFS of the dorsal striatum does not alter learning behavior in rats but influences the strategy by which the rats solve the task. Given that the HFS-induced increase of GABA levels was found 19 h after stimulation, it can be assumed that HFS has consequences lasting for several hours and which are functionally significant at a behavioral level, at least under our stimulation (frequency, timing, location, side and strength of stimulation) and testing conditions.
21489700	Healthy sleep facilitates the consolidation of newly acquired memories. Although patients with posttraumatic stress disorder (PTSD) often complain of sleep disturbances and memory deficits, the interrelatedness of these symptoms is not well understood. Sleep may be disturbed in PTSD by increased awakenings during sleep, which has been associated with decreased growth hormone (GH) secretion. We conducted a controlled study in which we assessed sleep fragmentation, nocturnal secretion of GH, and memory consolidation in patients with PTSD.While sleep EEG was being monitored, 13 veterans with PTSD, 15 trauma controls (TC) and 15 healthy controls (HC) slept with an iv catheter, through which blood was collected every 20 min from 23:00 h to 08:00 h. Declarative memory encoding was assessed with the 15 word task before sleep, and consolidation was assessed the next morning by a free recall.	Sleep was more fragmented in patients with PTSD, with more awakenings in the first half of the night (p<0.05). Plasma levels of GH during the night were significantly decreased in PTSD compared with HC (p<0.05). Furthermore, GH secretion and awakenings were independent predictors for delayed recall, which was lower in PTSD compared to HC (p<0.05).	These data show that PTSD is associated with increased awakenings during sleep and decreased nocturnal GH secretion. Furthermore, decreased GH secretion may be related to sleep fragmentation and both variables may exert a negative effect on sleep dependent memory consolidation.	
21489585	Pure progressive amnesia is a rare and unusual syndrome involving long preservation of autonomy and absence of progression in other cognitive domains.We report a case which remained quiescent for 16 years characterized by severe isolated episodic amnesia and preservation of spatial, semantic and implicit memory and autonomy. MRI revealed bilateral focal atrophy of the hippocampus.	This specific pattern of impairment differs from other types of amnesic syndromes. It is important to identify this kind of amnesia because of its specific course. Studying the topography of the brain lesions may contribute to a better understanding of the neural systems involved in declarative memory.	
21484237	Several studies have shown that glucocorticoids can impair declarative memory retrieval and working memory (WM) performance. The aim of the present study was to investigate the impact of a high dose of hydrocortisone on WM, as well as to examine the effects of cortisol suppression via treatment with a high dose of dexamethasone (DEX). We hypothesized that hydrocortisone treatment results in an impaired cognitive function compared with placebo. We further expected that dexamethasone treatment is also followed by cognitive impairment, due to the hypothesis that very low levels of cortisol are also associated with alterations in memory performance.In a placebo-controlled study with a within-subject design, 16 healthy volunteers received placebo or 120 mg of hydrocortisone (two boluses of 60 mg) directly before neuropsychological testing or 4 mg of DEX the day before testing.	We did not find any effect of hydrocortisone on WM and cognitive flexibility, even though cortisol levels were high at the time of testing. Furthermore, we did not find any effect of DEX treatment on WM and reaction time in a cognitive flexibility test. However, cognitive flexibility was negatively correlated with adrenocorticotropin (ACTH) in the DEX condition.	Our results found no clear effect of hydrocortisone and dexamethasone treatment on WM. These results emphasize the need for further research on the association between hypothalamic-pituitary-adrenal axis activity and cognition. These studies should investigate the hypotheses of dose-dependent associations in more detail and should also include analyses on ACTH and cognition.	
21481945	The Wisconsin Card Sorting Test (WCST) is a set-switching task used extensively to study impaired executive functioning in schizophrenia. Declarative memory deficits have also been associated with schizophrenia and may affect WCST performance because continued correct responding depends on remembering the outcome of previous responses. This study examined whether performance in visual and verbal declarative memory tasks were associated with WCST performance. Subjects comprised 30 patients with schizophrenia or schizoaffective disorder (SCZ) and 30 demographically matched healthy controls (CON) who were tested on the WCST, the Benton Visual Retention Test (BVRT), the California Verbal Learning Test (CVLT), and the Continuous Performance Test (CPT). SCZ subjects showed significant correlations between visual and verbal declarative memory and performance on the WCST-64 that were in the hypothesized direction such that worse memory performance was associated with worse performance on the WCST. CON subjects did not show a significant relationship between visual or verbal memory and WCST-64 performance. Fisher's r to z transformations indicated that the associations between declarative memory and WCST-64 performance in the SCZ subjects differed significantly from those of CON subjects. The findings suggest that interpretations of WCST-64 scores for subjects with schizophrenia should be considered in light of their declarative memory functioning.
21474841	Language function in patients with impaired declarative memory presents a compelling opportunity to investigate the inter-dependence of memory and language in referential communication. We examined amnesic patients' use of definite references during a referential communication task. Discursively, definite references can be used to mark a referent as situationally unique (e.g., "the game," as in the case of a recently publicized game) or as shared information (e.g., "the game," as in one discussed previously). We found that despite showing normal collaborative learning after repeated referring-as indexed by consistent and increasingly efficient descriptive labels for previously unfamiliar tangram figures-amnesic patients did not consistently use definite references in referring to those figures. The use of definite references seems to be critically dependent on declarative memory, and the engagement of such memory is signaled by language.
21471400	A large number of studies have demonstrated that structures within the medial temporal lobe, such as the hippocampus, are intimately involved in declarative memory for objects and people. Although these items are abstractions of the visual scene, specific visual details can change the speed and accuracy of their recall. By recording from 415 neurons in the hippocampus and amygdala of human epilepsy patients as they viewed images drawn from 10 image categories, we showed that the firing rates of 8% of these neurons encode image illuminance and contrast, low-level properties not directly pertinent to task performance, whereas in 7% of the neurons, firing rates encode the category of the item depicted in the image, a high-level property pertinent to the task. This simultaneous representation of high- and low-level image properties within the same brain areas may serve to bind separate aspects of visual objects into a coherent percept and allow episodic details of objects to influence mnemonic performance.
21455727	Retinal vascular calibre changes may reflect early subclinical microvascular disease in diabetes. Because of the considerable homology between retinal and cerebral microcirculation, we examined whether retinal vascular calibre, as a proxy of cerebral microvascular disease, was associated with cognitive function in older people with type 2 diabetes.A cross-sectional analysis of 954 people aged 60-75 years with type 2 diabetes from the population-based Edinburgh Type 2 Diabetes Study was performed. Participants underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. The Mill Hill Vocabulary Scale was used to estimate pre-morbid cognitive ability. Retinal vascular calibre was measured from an image field with the optic disc in the centre using a validated computer-based program.	After age and sex adjustment, larger retinal arteriolar and venular calibres were significantly associated with lower scores for the Wechsler Logical Memory test, with standardised regression coefficients -0.119 and -0.084, respectively (p < 0.01), but not with other cognitive tests. There was a significant interaction between sex and retinal vascular calibre for logical memory. In male participants, the association of increased retinal arteriolar calibre with logical memory persisted (p < 0.05) when further adjusted for vocabulary, venular calibre, depression, cardiovascular risk factors and macrovascular disease. In female participants, this association was weaker and not significant.	Retinal arteriolar dilatation was associated with poorer memory, independent of estimated prior cognitive ability in older men with type 2 diabetes. The sex interaction with stronger findings in men requires confirmation. Nevertheless, these data suggest that impaired cerebral arteriolar autoregulation in smooth muscle cells, leading to arteriolar dilatation, may be a possible pathogenic mechanism in verbal declarative memory decrements in people with diabetes.	
21453016	Bilinguals must focus their attention to control competing languages. In bilingual aphasia, damage to the fronto-subcortical loop may lead to pathological language switching and mixing and the attrition of the more automatic language (usually L1). We present the case of JZ, a bilingual Basque-Spanish 53-year-old man who, after haematoma in the left basal ganglia, presented with executive deficits and aphasia, characterised by more impaired language processing in Basque, his L1. Assessment with the Bilingual Aphasia Test revealed impaired spontaneous and automatic speech production and speech rate in L1, as well as impaired L2-to-L1 sentence translation. Later observation led to the assessment of verbal and non-verbal executive control, which allowed JZ's impaired performance on language tasks to be related to executive dysfunction. In line with previous research, we report the significant attrition of L1 following damage to the left basal ganglia, reported for the first time in a Basque-Spanish bilingual. Implications for models of declarative and procedural memory are discussed.
21452088	Stressful life events can result into declined memory performance at later age. One hypothesis suggests that stress affects the hippocampus, a brain area important for memory functioning. This study explored a potential relationship between the number of negative stressful life events and hippocampus-dependent declarative but not hippocampus-independent procedural memory performance in a community sample of 255 children, aged 6-12 years. The findings revealed that negative stressful life events were negatively related to verbal declarative memory, but not to nonverbal declarative and procedural memory. The memory impairments could not be accounted for by attention and sleep disturbances, and parenting characteristics as perceived by the child did not influence the vulnerability for the stress-related memory impairments. These findings provide further insight into the deleterious effects of negative stressful life events on learning in school-aged children.
21443892	Posttraumatic stress disorder (PTSD) is defined by one's response to an environmental event. However, genetic factors are important in determining people's response to that event, and even their likelihood of being exposed to particular traumatic events in the first place. Classical twin designs can decompose genetic and environmental sources of variance. Such studies are reviewed extensively elsewhere, and we cover them only briefly in this review. Instead, we focus primarily on the identical co-twin control design. This design makes it possible to resolve the "chicken-egg" dilemma inherent in standard case-control designs, namely, distinguishing risk from sequelae. Abnormalities that are present in both the twin with PTSD and the unaffected co-twin suggest pre-existing vulnerability indicators. These include smaller hippocampal volume, large cavum septum pellucidum, more neurological soft signs, lower general intellectual ability, and poorer performance in the specific cognitive abilities of executive function, attention, declarative memory, and processing of contextual cues. In contrast, abnormalities in a twin with PTSD that are not present in the identical co-twin suggest consequences of PTSD or trauma exposure. These include psychophysiological responding, higher resting anterior cingulate metabolism, event-related potential abnormalities associated with attentional processes, recall intrusions, and possibly some types of chronic pain. Most co-twin control studies of PTSD have been small and come from the same twin registry of middle-aged male veterans. Consequently, there is a great need for replication and extension of the findings, particularly in women and younger individuals. The creation of new twin registries would do much toward accomplishing this goal. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
21415172	Many people spend an increasing amount of time in front of computer screens equipped with light-emitting diodes (LED) with a short wavelength (blue range). Thus we investigated the repercussions on melatonin (a marker of the circadian clock), alertness, and cognitive performance levels in 13 young male volunteers under controlled laboratory conditions in a balanced crossover design. A 5-h evening exposure to a white LED-backlit screen with more than twice as much 464 nm light emission {irradiance of 0,241 Watt/(steradian × m(2)) [W/(sr × m(2))], 2.1 × 10(13) photons/(cm(2) × s), in the wavelength range of 454 and 474 nm} than a white non-LED-backlit screen [irradiance of 0,099 W/(sr × m(2)), 0.7 × 10(13) photons/(cm(2) × s), in the wavelength range of 454 and 474 nm] elicited a significant suppression of the evening rise in endogenous melatonin and subjective as well as objective sleepiness, as indexed by a reduced incidence of slow eye movements and EEG low-frequency activity (1-7 Hz) in frontal brain regions. Concomitantly, sustained attention, as determined by the GO/NOGO task; working memory/attention, as assessed by "explicit timing"; and declarative memory performance in a word-learning paradigm were significantly enhanced in the LED-backlit screen compared with the non-LED condition. Screen quality and visual comfort were rated the same in both screen conditions, whereas the non-LED screen tended to be considered brighter. Our data indicate that the spectral profile of light emitted by computer screens impacts on circadian physiology, alertness, and cognitive performance levels. The challenge will be to design a computer screen with a spectral profile that can be individually programmed to add timed, essential light information to the circadian system in humans.
21402164	Although D-cycloserine (DCS), a partial agonist of the N-methyl-d-aspartate (NMDA) receptor, and valproic acid (VPA), a histone deacetylase inhibitor, have been investigated for their roles in the facilitation of emotional learning, the effects on non-emotional declarative and procedural learning have not been clarified. We performed a randomized, blind, placebo-controlled, 4-arm clinical trial to determine the effects of DCS and VPA on the overnight properties of declarative and procedural learning in 60 healthy adults. Subjects were orally administrated a placebo, 100 mg DCS, 400 mg VPA, or a combination of 100 mg DCS and 400 mg VPA before they performed declarative and procedural learning tasks. Subjects then had their performance retested the following day. We observed that DCS facilitated procedural but not declarative learning and that VPA did not contribute to learning. Surprisingly, however, VPA attenuated the enhancement effect of DCS when coadministered with it. These results suggest that DCS acts as an enhancer of hippocampus-independent learning and that VPA may have an extinguishing pharmacological effect on excitatory post-synaptic action potentials that NMDA receptors regulate within procedural learning.
21391764	There has been general consensus that initial word learning during early infancy is a slow and time-consuming process that requires very frequent exposure, whereas later in development, infants are able to quickly learn a novel word for a novel meaning. From the perspective of memory maturation, this shift in behavioral development might represent a shift from slow procedural to fast declarative memory formation. Alternatively, it might be caused by the maturation of specific brain structures within the declarative memory system that may support lexical mapping from the very first. Here, we used the neurophysiological method of ERPs to watch the brain activity of 6-month-old infants, when repeatedly presented with object-word pairs in a cross-modal learning paradigm. We report first evidence that infants as young as 6 months are able to associate objects and words after only very few exposures. A memory test 1 day later showed that infants did not fully forget this newly acquired knowledge, although the ERP effects indicated it to be less stable than immediately after encoding. The combined results suggest that already at 6 months the encoding process of word learning is based on fast declarative memory formation, but limitations in the consolidation of declarative memory diminish the long lasting effect in lexical-semantic memory at that age.
21391761	Recent studies indicate that medial-temporal lobe (MTL) damage, either from focal lesions or neurodegenerative disease (e.g., semantic dementia), impairs perception as well as long-term declarative memory. Notably, however, these two patient groups show different performance for meaningful versus unfamiliar stimuli. In amnesics with nonprogressive MTL lesions, the use of meaningful stimuli, compared with unfamiliar items, boosted discrimination performance. In semantic dementia, a condition characterized by progressive deterioration of conceptual knowledge in the context of anterolateral temporal lobe damage, performance for meaningful stimuli was equivalent to that for unfamiliar items. To further investigate these findings, we scanned healthy volunteers while they performed odd-one-out discriminations involving familiar (i.e., meaningful/famous) and unfamiliar (i.e., novel) objects and faces and a baseline task of size oddity. Outside the scanner, volunteers' recognition memory was assessed. We found above baseline activity in the perirhinal cortex and hippocampus for all object and face discriminations and above baseline activity in the temporal pole for all face discriminations. The comparison of meaningful, relative to novel, faces and objects, revealed increased activity in the perirhinal cortex and hippocampus. In the temporal pole, we also found activity related to meaningfulness for faces but not for objects. Importantly, these meaningfulness effects were evident even for discriminations that were not subsequently well remembered, suggesting that the difference between meaningful and novel stimuli reflects perceptual or conceptual processes rather than solely incidental encoding into long-term memory. The results provide further evidence that the MTL is recruited during complex perceptual discrimination and additionally suggest that these structures are recruited in semantic processing of objects and faces.
21354976	Several experiments carried out with a subset of patients with temporal lobe epilepsy have demonstrated normal memory performance at standard delays of recall (i.e. minutes to hours) but impaired performance over longer delays (i.e. days or weeks), suggesting altered long-term consolidation mechanisms. These mechanisms were specifically investigated in a group of five adult-onset pharmaco-sensitive patients with temporal lobe epilepsy, exhibiting severe episodic memory complaints despite normal performance at standardized memory assessment. In a first experiment, the magnitude of autobiographical memory loss was evaluated using retrograde personal memory tasks based on verbal and visual cues. In both conditions, results showed an unusual U-shaped pattern of personal memory impairment, encompassing most of the patients' life, sparing however, periods of the childhood, early adulthood and past several weeks. This profile was suggestive of a long-term consolidation impairment of personal episodes, adequately consolidated over 'short-term' delays but gradually forgotten thereafter. Therefore, in a subsequent experiment, patients were submitted to a protocol specifically devised to investigate short and long-term consolidation of contextually-bound experiences (episodic memory) and context-free information (semantic knowledge and single-items). In the short term (1 h), performance at both contextually-free and contextually-bound memory tasks was intact. After a 6-week delay, however, contextually-bound memory performance was impaired while contextually-free memory performance remained preserved. This effect was independent of task difficulty and the modality of retrieval (recall and recognition). Neuroimaging studies revealed the presence of mild metabolic changes within medial temporal lobe structures. Taken together, these results show the existence of different consolidation systems within declarative memory. They suggest that mild medial temporal lobe dysfunction can impede the building and stabilization of episodic memories but leaves long-term semantic and single-items mnemonic traces intact.
21354714	Temporomandibular disorder (TMD) is a somatic manifestation of stress. Previous researches suggested hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in TMD, through which TMD patients exhibited abnormalities of the stress response hormone - causing additional cortisol release. Increased cortisol, the principal circulating glucocorticoid in humans, would impair memory retrieval of declarative material. This effect on memory retrieval may in particular be due to glucocorticoid receptors (GR) in the hippocampus. The hypothesis we proposed is that TMD might result in declarative memory impairment by increasing the cortisol.
21352389	It has been hypothesized that non-rapid eye movement (NREM) sleep facilitates declarative memory consolidation, and rapid eye movement (REM) sleep is particularly important in promoting procedural learning. The aim of this study was to examine the effects of pharmacological REM sleep suppression on performance in different neuropsychological tasks. For our baseline, we chose 41 moderately depressed patients (age range 19-44 years), who were not taking antidepressants. In the morning after polysomnography, we tested memory recall and cognitive flexibility by assessment of verbal and figural fluency, a shift of attention task and the Trail Making Test B. After recording baseline values, patients were assigned randomly to one of three treatment groups: medication with citalopram; medication with reboxetine; or exclusive treatment with psychotherapy. Retesting took place 1 week after onset of treatment. The main results were: (1) an association of slow-wave sleep with verbal memory performance at baseline; (2) a suppression of REM sleep in patients taking citalopram and reboxetine; (3) no differences regarding neuropsychological performance within the treatment groups; and (4) no association of REM sleep diminution with decreases in memory performance or cognitive flexibility in patients treated with citalopram or reboxetine. In line with other studies, our results suggest that there are no negative effects of a decrease in REM sleep on memory performance in patients taking antidepressants.
21345223	Memory is one of the most impaired functions after traumatic brain injury (TBI). We used diffusion tensor imaging (DTI) to determine the structural basis of memory deficit. We correlated fractional anisotropy (FA) of the fasciculi connecting the main cerebral regions that are involved in declarative and working memory functions.Fifteen patients with severe and diffuse TBI and sixteen healthy controls matched by age and years of education were scanned. The neuropsychological assessment included: Letter-number sequencing test (LNS), 2-back task, digit span (forwards and backwards) and the Rivermead profilet. DTI was analyzed by a tract-based spatial statics (TBSS) approach.	Whole brain DTI analysis showed a global decrease in FA values that correlated with the 2-back d-prime index, but not with the Rivermead profile. ROI analysis revealed positive correlations between working memory performance assessed by 2-back d-prime and superior longitudinal fasciculi, corpus callosum, arcuate fasciculi and fornix. Declarative memory assessed by the Rivermead profile scores correlated with the fornix and the corpus callosum.	Diffuse TBI is associated with a general decrease of white matter integrity. Nevertheless deficits in specific memory domains are related to different patterns of white matter damage.	
21340034	Previously the application of a weak electric anodal current oscillating with a frequency of the sleep slow oscillation (∼0.75 Hz) during non-rapid eye movement sleep (NonREM) sleep boosted endogenous slow oscillation activity and enhanced sleep-associated memory consolidation. The slow oscillations occurring during NonREM sleep and theta oscillations present during REM sleep have been considered of critical relevance for memory formation. Here transcranial direct current stimulation (tDCS) oscillating at 5 Hz, i.e., within the theta frequency range (theta-tDCS) is applied during NonREM and REM sleep. Theta-tDCS during NonREM sleep produced a global decrease in slow oscillatory activity conjoint with a local reduction of frontal slow EEG spindle power (8-12 Hz) and a decrement in consolidation of declarative memory, underlining the relevance of these cortical oscillations for sleep-dependent memory consolidation. In contrast, during REM sleep theta-tDCS appears to increase global gamma (25-45 Hz) activity, indicating a clear brain state-dependency of theta-tDCS. More generally, results demonstrate the suitability of oscillating-tDCS as a tool to analyze functions of endogenous EEG rhythms and underlying endogenous electric fields as well as the interactions between EEG rhythms of different frequencies.
21335834	We used a cognitive architecture (ACT-R) to explore the procedural learning of surgical tasks and then to understand the process of perceptual motor learning and skill decay in surgical skill performance. The ACT-R cognitive model simulates declarative memory processes during motor learning. In this ongoing study, four surgical tasks (bimanual carrying, peg transfer, needle passing, and suture tying) were performed using the da Vinci<sup>©</sup> surgical system. Preliminary results revealed that an ACT-R model produced similar learning effects. Cognitive simulation can be used to demonstrate and optimize the perceptual motor learning and skill decay in surgical skill training.
21295050	Foxy or Methoxy Foxy (5-methoxy-N,N-di(iso)propyltryptamine hydrochloride; 5-MeO-DIPT) is rapidly gaining popularity among recreational users as a hallucinogenic "designer drug." Unfortunately, much remain unknown about the consequences of its use on neuropsychological development or behavior. During one of two adolescent periods, the rats were given repeated injections of 5 mg/kg or 20 mg/kg of 5-MeO-DIPT or a corresponding volume of isotonic saline. After the animals reached adulthood, they were trained and tested on a number of tasks designed to assess the impact of 5-MeO-DIPT, if any, on spatial memory, presumably involving declarative memory systems as well as a nonspatial task that is considered sensitive to disruptions in nondeclarative memory. Both the 5-MeO-DIPT- and saline-treated rats were able to master spatial navigation tests where the task included a single goal location and all groups performed comparably on these phases of training and testing. Regardless of exposure level during adolescence, the performance of the drug-treated rats was markedly inferior to that of the control animals on a task where the goal was moved to a new location and on a response learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. Detected reductions in serotonin activity in the forebrain similar to the effects of extensively investigated compounds such as methylenedioxymethamphetamine (MDMA), suggest that 5-MeO-DIPT may produce its adverse effects by compromising serotonergic systems in the brain.
21293788	We propose and evaluate a memory-based model of Hick's law, the approximately linear increase in choice reaction time with the logarithm of set size (the number of stimulus-response alternatives). According to the model, Hick's law reflects a combination of associative interference during retrieval from declarative memory and occasional savings for stimulus-response repetitions due to non-retrieval. Fits to existing data sets show that the model accounts for the basic set-size effect, changes in the set-size effect with practice, and stimulus-response repetition effects that challenge the information-theoretic view of Hick's law. We derive the model's prediction of an interaction between set size, stimulus fan (the number of responses associated with a particular stimulus), and stimulus-response transition, which is subsequently tested and confirmed in two experiments. Collectively, the results support the core structure of the model and its explanation of Hick's law in terms of basic memory effects.
21289163	The brain encodes huge amounts of information, but only a small fraction is stored for a longer time. There is now compelling evidence that the long-term storage of memories preferentially occurs during sleep. However, the factors mediating the selectivity of sleep-associated memory consolidation are poorly understood. Here, we show that the mere expectancy that a memory will be used in a future test determines whether or not sleep significantly benefits consolidation of this memory. Human subjects learned declarative memories (word paired associates) before retention periods of sleep or wakefulness. Postlearning sleep compared with wakefulness produced a strong improvement at delayed retrieval only if the subjects had been informed about the retrieval test after the learning period. If they had not been informed, retrieval after retention sleep did not differ from that after the wake retention interval. Retention during the wake intervals was not affected by retrieval expectancy. Retrieval expectancy also enhanced sleep-associated consolidation of visuospatial (two-dimensional object location task) and procedural motor memories (finger sequence tapping). Subjects expecting the retrieval displayed a robust increase in slow oscillation activity and sleep spindle count during postlearning slow-wave sleep (SWS). Sleep-associated consolidation of declarative memory was strongly correlated to slow oscillation activity and spindle count, but only if the subjects expected the retrieval test. In conclusion, our work shows that sleep preferentially benefits consolidation of memories that are relevant for future behavior, presumably through a SWS-dependent reprocessing of these memories.
21288694	Genetic studies of schizophrenia focus increasingly on putative endophenotypes because their genetic etiology may be simpler than clinical diagnosis. The Consortium on the Genetics of Schizophrenia (COGS), a multisite family study, aims to identify the genetic basis of several endophenotypes including verbal declarative memory (VDM), a neurocognitive function that shows robust impairment in schizophrenia. We present data on one type of measure of VDM, the California Verbal Learning Test, Second Edition (CVLT-II), in schizophrenia probands (n=305), their full biological siblings (n=449) and parents (n=232), and in community comparison subjects (CCS; n=509) across seven sites. Probands performed more poorly on each of five CVLT-II measures compared to related sibling and parent groups and CCS. Siblings and parents performed significantly worse than CCS on one measure (Discriminability), but with smaller effect sizes and less impairment than observed previously. The results raise questions about the homogeneity of VDM as an endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia.
21285855	This study examined the cortisol secretion pattern and declarative memory performance of dementia caregivers. An illustrated story paradigm memory task was used to evaluate the effects of emotional arousal on memory and assess the caregivers' cognitive compensation capacity. Younger (n=19) and elderly (n=24) noncaregivers and elderly caregivers (n=14) took part in 2 experiments to elucidate the effects of aging (experiment 1) and chronic stress (experiment 2) on memory performance and cortisol levels. Each group was divided in 2 subgroups: one that was exposed to an emotionally neutral story, and one that was exposed to a similar, but emotionally arousing story. Participants completed a multiple-choice questionnaire in the test session. Salivary cortisol samples were collected at 8:00 AM, 4:00 PM, and 10:00 PM, 1 day after memory testing. Experiment 1 showed that, despite an age-related memory deficit, arousal manipulation produced a similar effect in both age groups. Experiment 2 showed that, in addition to the characteristic memory decline of aging, elderly caregivers did not benefit from emotionally arousing material as their noncaregiver counterparts did. This impairment correlated with elevated nighttime cortisol levels, indicating a potential worsening impact of caregiver burden on age-related cognitive decline.
21264597	The human response to uncertainty has been well studied in tasks requiring attention and declarative memory systems. However, uncertainty monitoring and control have not been studied in multi-dimensional, information-integration categorization tasks that rely on non-declarative procedural memory. Three experiments are described that investigated the human uncertainty response in such tasks. Experiment 1 showed that following standard categorization training, uncertainty responding was similar in information-integration tasks and rule-based tasks requiring declarative memory. In Experiment 2, however, uncertainty responding in untrained information-integration tasks impaired the ability of many participants to master those tasks. Finally, Experiment 3 showed that the deficit observed in Experiment 2 was not because of the uncertainty response option per se, but rather because the uncertainty response provided participants a mechanism via which to eliminate stimuli that were inconsistent with a simple declarative response strategy. These results are considered in the light of recent models of category learning and metacognition.
21256802	There is broad evidence that sleep as opposed to waking facilitates the consolidation of both declarative and procedural memory. The current study addressed the question whether different extents of sleep restriction after learning would impair long-term memory consolidation in adolescents.Eighty-eight healthy adolescents were randomized to five different sleep protocols with 9, 8, 7, 6 or 5 h of time in bed for four consecutive nights under controlled conditions that excluded daytime sleep. Declarative (word-pair task) and procedural memory (mirror tracing task) encoding was assessed prior to the sleep restriction protocol. Recall was assessed after two recovery nights following the sleep protocol and 4 weeks later.	Sleep diaries and actigraphy data demonstrated that the participants closely followed the sleep protocols. There were no differences in demographic parameters or memory encoding at baseline. In contrast to the initial prediction, restriction of nocturnal sleep over four consecutive nights had no significant impact on declarative or procedural memory consolidation. Polysomnographic monitoring after sleep restriction demonstrated a high preservation of the amount of slow wave sleep in the restricted conditions.	The results suggest that adolescents show a high resilience of memory consolidation to substantial sleep curtailment across four nights that might be promoted by increased sleep intensity under conditions of sleep restriction.	
21256437	A new study shows that the 'fast' component of motor adaptation is distinct from its 'slow' counterpart and shares critical resources with declarative memory.
21255590	In humans lacunar infarcts in the mesial and anterior regions of the thalami are frequently associated with amnesic syndromes. In this review paper, we scrutinized 41 papers published between 1983 and 2009 that provided data on a total of 83 patients with the critical ischemic lesions (i.e. 17 patients with right-sided lesions, 25 with left-sided lesions and 41 with bilateral lesions). We aimed to find answers to the following questions concerning the vascular thalamic amnesia syndrome: (i) Which qualitative pattern of memory impairment (and associated cognitive and behavioral deficits) do these patients present? (ii) Which lesioned intrathalamic structures are primarily responsible for the amnesic syndrome? (iii) Are the recollection and familiarity components of declarative memory underlain by the same or by different thalamic structures? Results of the review indicate that, similar to patients with amnesic syndromes due to mesio-temporal lobe damage, patients with vascular thalamic amnesia display a prevalent deficit of declarative anterograde long-term memory, a less consistent deficit of declarative retrograde long-term memory and substantially spared short-term and implicit memory. Unlike mesio-temporal lobe patients, however, vascular thalamic amnesics often present dysexecutive and behavioral deficits similar to those observed in patients with frontal damage. The presence of an amnesic syndrome in patients with thalamic lacunar infarcts is strongly predicted by involvement of the mammillo-thalamic tract, which connects the anterior nuclei complex to the hippocampus proper via the fornix and the mammillary bodies. Finally, data reported in a few single cases provide support for the hypothesis that thalamic regions connected to distinct areas of the mesio-temporal lobe play differential roles in recollection and familiarity processes. The mammillo-thalamic tract/anterior nuclei axis seems primarily implicated in recollective processes, whereas the ventroamygdalofugal pathway/medio-dorsal axis primarily underlies familiarity processes.
21228604	Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients.The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT).	Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning.	VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment.	
21219089	The current study looked for a differential response to memory rehabilitation, testing the hypotheses that outcome would vary significantly as a function of patient diagnosis and severity of memory impairment.Unblinded, open-label, pre/post-treatment comparison of memory rehabilitation in patients stratified by diagnosis (brain injury, n = 15; stroke, n = 12; other neurological condition, n = 6) and memory impairment severity.	Patients underwent an ecologically-oriented, strategy-based intervention for memory impairment and were evaluated pre- and post-treatment on seven simulations (four with alternate forms, randomized to the pre- or post-test) of everyday declarative or prospective memory tasks.	Patients at all levels of severity and in all three diagnostic groups showed equivalent, statistically significant improvement in memory performance. Neither practice effects from repeat test administration nor spontaneous recovery accounted for the improvement in memory performance.	The current study provided evidence of improved performance in everyday memory content domains with compensatory-based cognitive rehabilitation. Comparable improvement was seen across diagnostic groups and severity ranges. Additional case series and randomized clinical trials are needed to evaluate further the efficacy of compensation-based approaches to cognitive rehabilitation.	
21212840	During times of emotional stress, individuals often engage in emotion regulation to reduce the experiential and physiological impact of negative emotions. Interestingly, emotion regulation strategies also influence memory encoding of the event. Cognitive reappraisal is associated with enhanced memory while expressive suppression is associated with impaired explicit memory of the emotional event. However, the mechanism by which these emotion regulation strategies affect memory is unclear. We used event-related fMRI to investigate the neural mechanisms that give rise to memory formation during emotion regulation. Twenty-five participants viewed negative pictures while alternately engaging in cognitive reappraisal, expressive suppression, or passive viewing. As part of the subsequent memory design, participants returned to the laboratory two weeks later for a surprise memory test. Behavioral results showed a reduction in negative affect and a retention advantage for reappraised stimuli relative to the other conditions. Imaging results showed that successful encoding during reappraisal was uniquely associated with greater co-activation of the left inferior frontal gyrus, amygdala, and hippocampus, suggesting a possible role for elaborative encoding of negative memories. This study provides neurobehavioral evidence that engaging in cognitive reappraisal is advantageous to both affective and mnemonic processes.

21207809	To summarize, all children interacted with the experimenter and actively participated in the imitation task. There was evidence of improvement in performance from baseline to recall as would be expected with attention to, and memory for, the actions that were modeled by the experimenter. All participants evidenced a decrease in performance as the difficulty of the task increased, as would be expected. When the maltreated children were compared to the nonmaltreated children in a 2-group design, there was no statistically significant difference in performance. However, when the maltreated group was divided into two subtypes of either neglected or abused, and performance was compared in a 3-group design, it was revealed that the neglected children experienced deficits in performance relative to abused children. For production of target actions, the neglected children's performance trended toward significance when compared to the nonmaltreated children's performance. However, there was no significant difference between the performance of the abused children and the nonmaltreated children for either production of target actions or productions of ordered pairs. The children in this longitudinal study were assessed previously at 12 months of age in a mother-child play situation (Valentino et al., 2006). Interactions during structured play between mother and child were evaluated for maternal directives and child responses. Interestingly, the difference in social interactions that was most reliable was the finding that the abused children imitated their mothers more often than did the nonmaltreated children. There was no difference between the imitative behaviors of the neglected children and the abused or nonmaltreated children. The researchers note that by imitating their mothers, the abused children might be attempting to prevent further abusive incidents. Limit setting behaviors of the mothers in response to child initiations were positively related to the children's imitative behaviors. Thus, it would appear that maternal negative feedback to child-initiated behaviors is related to an increase in imitative behaviors that are most likely met with positive reinforcement. The continued pursuit of this positivity may impede the development of self-initiated behaviors; delayed development of self-initiated behavior has been linked to disorders of social competence (Landry, Smith, Miller-Loncar, & Swank, 1998). However, imitation has long been known to be a mechanism of learning (Piaget, 1962) and has become an accepted tool for assessment of declarative memory (Bauer, 2004). Whereas the adaptation to abuse posited by Valentino et al. (2006) may be detrimental to social development, our data for this same sample indicate that the reliance on imitative behavior exhibited by the abused children may afford them an advantage at 21 months of age in imitation paradigms. The neglected children are thus at a disadvantage relative to the abused children in the study reported here in that they were not reinforced by mothers for imitative behavior. It is important to note that all children in this sample were from low-income homes. Scores on these events for both target actions and ordered pairs are higher in samples of higher SES children (e.g., Bauer et al., 2000). Thus, the low SES of the families affected performance across the groups. It is possible that the factor responsible for the difference between the abused group and the neglected group is resilience in the face of poverty. Resilience is the ability to recover following a traumatic event or adversity (Masten, 2001), and has been related to child characteristics, such as general intelligence (Masten et al., 1988). It has been proposed that neural plasticity may be responsible for this recovery (Cicchetti & Curtis, 2006). Alternatively, as has been detailed earlier in this chapter, the advantage afforded abused children could arise from the strengthening of neural pathways. It would be adaptive to develop exceptional event memory so as to avoid the events that lead to abuse. Mechanisms of plasticity are responsible for the laying down of memories (Aimone, Wiles, & Gage, 2006). Thus, the higher performance seen in the abused group could be related to a preservation of brain plasticity that facilitates resilience in the face of poverty, stress, and/or trauma. Plasticity in the brains of the neglected children may be lost due to the lack of stimulation, leaving them more vulnerable to the stress of poverty and neglect. In conclusion, maltreated children have often been studied as a single group. However, it is becoming clear from research conducted by our group and others that the subtypes of maltreatment may have different developmental sequelae. It is important that we understand the differential pathways involved in the development of abused versus neglected children. As discussed in other chapters of this volume, the imitation paradigm has emerged as a valuable tool in the identification of at-risk infants and toddlers. With the data reported here, it is evident that data from the elicited imitation procedure utilized herein differentiates between the subtypes of maltreatment. Research must be conducted to further elucidate the correlates of resilience in toddlers who have been abused. A longitudinal investigation would enable investigation of the questions of continuity of the observed increase in imitative behavior and whether increased imitation has a detrimental social effect while exerting a bolstering cognitive effect.






21204362	Various species of macaques, particularly Macaca mulatta (rhesus), have played an important role in our current understanding of the anatomical sites and in the behavioral and molecular mechanisms involved in cognition and memory. These versatile animals have been taught to perform a broad landscape of behavioral paradigms, many of which are relevant to human learning and memory. The rhesus monkey shares 92 to 95% genetic homology with the human species, and these animals enjoy a cognitive domain that allows for evaluation of higher-order cognitive and executive function. Nonverbal human cognitive tasks have been adapted for nonhuman primates, and vice versa, without reservation that a form of declarative memory is readily accessible in these animals. Numerous operant paradigms have been designed to evaluate aspects of reference memory, attention, and working memory (both short term and long term). Despite the various macaque species employed, and the variety of testing modalities applied, the largely consistent finding is that, with age, there is a decrement in memory-related task performance [1–4]. Without doubt there are macaques (and other nonhuman primate families) within the aging population that do not appear to exhibit age-dependent decrements in memory-related task performance. The potential for successful cognitive aging in these animals obviously has a human counterpart. The ability to study the differences at anatomical, cellular, neurochemical, and functional levels between animals that are successful vs. nonsuccessful with regard to cognitive aging has largely been the domain of rodent studies. Very few labs have used this approach with regard to nonhuman primates [e.g., 5, 6]. Part of the difficulty resides in the relatively long lifespan of macaques. Most often it is not possible to know whether an aged subject that displays cognitive impairment is that way because of true age-related impairment, or because the animal was below the range of normal intelligence for these animals from early on.
21204342	It is now well known that one generally experiences relatively mild changes in cognitive abilities with age, particularly with abilities such as short-term memory, executive functions, and confrontation naming [1]. However, a select group of these “successfully” aged individuals evidence virtually no change in their cognitive abilities with age, even into the eleventh decade of life [2]. Such individuals have often been referred to as examples of “pristine” successful aging. At the other end of the continuum, a large percentage of people are known to develop marked cognitive decline with age, characterized by a dementia state, with a majority of those developing Alzheimer’s disease (AD). These individuals fall into the category of “unsuccessful” aging. In recent years, however, clinical researchers have characterized a group as individuals who, with advancing age, show a moderate impairment in one or more cognitive domains that affects the ability to carry out activities of daily living but does not reach the threshold of a dementia state. This category, classified by many as “mild cognitive impairment” (MCI), reasonably can be regarded as a second general category of “unsuccessful” aging. Although many consider MCI as the earliest stage of Alzheimer’s disease, evidence suggests that MCI represents a separate static and chronic state of normal aging. The etiology of MCI is unknown, but stroke and heart disease risk factors, genetics, and education have all been raised as possible contributors. While nongenetically altered laboratory animals do not evidence the brain changes seen in AD [3], they have reliably demonstrated age-related changes in cognitive function. Evidence from a wide range of studies in rodents, dogs, and non-human primates have shown as a group that aged subjects are significantly impaired relative to young controls on cognitive tasks that assess functions such as working memory, declarative memory, and executive function: the same functions that evidence impairment in human aging [4–16]. However, on close inspection of the data, the degree of impairment within the aged group is anything but uniform and, in fact, is often dichotomous. While the overall group effect yields an impairment in the given function, it is clear that individuals within the aged group evidence only mild or, in some cases, no impairment on the task while others demonstrate severe impairment. The finding of individual differences, emphasized in the rodent literature (see [17]), has not been addressed previously in studies of nonhuman primates. This is due in part to the small number of studies in aging primates as well as the relatively small sample sizes of aged groups available within studies. This chapter presents data that we have collected over the past 15 years as part of an ongoing study using the rhesus monkey as a model of normal human aging. During this period, more than 125 rhesus monkeys ranging in age from 5 to 31 years of age have been assessed on multiple tests of recognition memory and executive function. In this chapter we present the data from these animals and discuss their varying levels of impairments and how this relates to clinical findings in human studies.
21204334	Accepted taxonomies of memory typically distinguish among different kinds of remembering depending upon the information that must be remembered. A basic dichotomy distinguishes between the retention of factual or experiential information on the one hand, and the retention of habits and motor skills on the other. Factual memory can be further differentiated into working and reference memory. As first described by Werner Honig’s group [1], working memory is required when “different stimuli govern the criterion response on different trials, so that the cue that the animal must remember varies from trial to trial.” Thus, working memory is required for remembering information that varies unpredictably in time and/or in content: it is this type of memory that is decimated in Alzheimer’s disease and other dementias [2]. In contrast, reference memory is used to retain information that remains constant over time (e.g., removing the cup from a baited well provides access to food). The study of working memory processes is generally accomplished using delayed response (DR) tasks and, within the confines of even relatively short test sessions, one can readily assess processes associated with short-term memory using these procedures. In such tasks, one presents a bit of information (a sample) to a subject, withdraws that information, waits for a period of time (recall delay), then presents that same bit of information along with a comparison bit and asks the subject to identify (choose) which bit of information was presented previously. This process is then repeated across a number of trials. DR tasks using nonhuman primates as surrogates are used primarily to determine the biological underpinnings of human learning and memory processes and their associated mechanisms. The complex brain functions associated with the performance of these tasks can be assessed using a variety of approaches, and the careful monitoring of behavioral outputs provides important experimental advantages. Many of the different types of assessments of memory processes have evolved from studies ranging from those employing neuroanatomical lesions to electrophysiological recordings and, more recently, neuroimaging techniques. Goldman-Rakic et al. have shown the importance of the prefrontal cortex in the performance of DR tasks in nonhuman primates by employing lesions and electrophysiological and neuroimaging techniques [3–6]. Brain lesion experiments in monkeys have also demonstrated the importance of the hippocampus and its relevance to performance in DR tasks [7]. Through the use of lesions, Zola et al. (2000) and Squire (2004) have also demonstrated the importance of the medial temporal lobe in performance of these types of tasks in monkeys [8,9]. Taken together these and other studies have elucidated the importance of the prefrontal cortex in visual-spatial functions, inhibition of behavior (temporal mechanisms), decision making, working memory, problem solving, planning, and organizing. Likewise, the findings that the hippocampal formation (medial temporal lobe) is important in memory consolidation, associative memory formation, declarative memory, and recognition memory stem from these and similar studies. The prefrontal cortex and the hippocampal formation are two brain areas intricately involved in the performance of DR tasks. The understanding of short-term memory and, more specifically, working memory has benefited greatly from this work.
21199935	Anterograde amnesia following hippocampal damage involves the loss of the capacity to form new declarative memories but leaves nondeclarative memory processes intact. Current theories of declarative memory suggest the existence of two complementary memory systems: a hippocampal-based system that specializes in rapid acquisition of specific events and a neocortical system that slowly learns through environmental statistical regularities and requires the initial support of the hippocampal system. Contrary to this notion, we demonstrate a neurocognitive mechanism that enables rapid acquisition of novel arbitrary associations independently of the hippocampus. This mechanism has been dubbed "fast mapping" (FM) and is believed to support the rapid acquisition of vocabulary in children as young as 16 mo of age. We used FM to teach novel word-picture associations to four profoundly amnesic patients with hippocampal system damage. Patients were able to acquire arbitrary associations through FM normally, despite profound impairment on a matched standard associative memory task. Most importantly, they retained what they learned through FM after a week's delay, when they were around chance level on the standard task. By contrast, two patients with unilateral damage to the left polar temporal neocortex were impaired on FM, suggesting that this cortical region is critical for associative learning through FM. Left perirhinal and entorhinal cortices might also play a role in learning through FM. Contrary to current theories, these findings indicate that rapid acquisition of declarative-like (relational) memory can be accomplished independently of the hippocampus and that neocortical plasticity can be induced rapidly to support novel arbitrary associations.
23136461	Discourse cohesion and coherence gives our communication continuity. Deficits in cohesion and coherence have been reported in patients with cognitive-communication disorders (e.g., TBI, dementia). However, the diffuse nature of pathology and widespread cognitive deficits of these disorders have made identification of specific neural substrates and cognitive systems critical for cohesion and coherence challenging.Taking advantage of a rare patient group with selective and severe declarative memory impairments, the current study attempts to isolate the contribution of declarative memory to the successful use of cohesion and coherence in discourse. METHODS #ENTITYSTARTX00026; PROCEDURES: Cohesion and coherence were examined in the discourse of six participants with hippocampal amnesia and six demographically matched comparison participants. Specifically, this study (1) documents the frequency, type, and completeness of cohesive ties; (2) evaluates discourse for local and global coherence; and (3) compares use of cohesive ties and coherence ratings in amnesia and healthy participants. OUTCOMES #ENTITYSTARTX00026; RESULTS: Overall, amnesia participants produced fewer cohesive ties per T-unit, the adequacy of their ties were more often judged to be incomplete, and the ratings of their local coherence were consistently lower than comparison participants.	These findings suggest that declarative memory may contribute to the discursive use of cohesion and coherence. Broader notions of cohesion, or interactional cohesion, i.e., cohesion across speakers (two or more people), time (days, weeks), and communicative resources (gesture), warrant further study as the experimental tasks used in the literature, and here, may actually underestimate or overestimate the extent of impairment.	
21191439	Reconsolidation postulates that reactivation of a memory trace renders it susceptible to disruption by treatments similar to those that impair initial memory consolidation. Despite evidence that implicit, or non-declarative, human memories can be disrupted at retrieval, a convincing demonstration of selective impairment in retrieval of target episodic memories following reactivation is lacking. In human subjects, we demonstrate that if reactivation of a verbal memory, through successful retrieval, is immediately followed by an emotionally aversive stimulus, a significant impairment is evident in its later recall. This effect is time-dependent and persists for at least 6 days. Thus, in line with a reconsolidation hypothesis, established human episodic memories can be selectively impaired following their retrieval.
21185883	Associations between cognitive performance and cortisol have variously been reported for measures of both cortisol level and change, and for some domains of cognitive functioning more than others. In this study, associations between cortisol secretion measures and cognitive performance were examined in 50 healthy older people (mean age 74 years; 34 F /16 M). Participants provided 16 accurately timed saliva samples over 2 consecutive days to determine diurnal profiles of cortisol secretion. Overall cognitive performance (OCP) was measured as the principal component of a comprehensive battery of cognitive tests. Across a 30 year age range, there was a strong inverse correlation between age and OCP. Age and poorer OCP were also associated with an attenuated cortisol awakening response (CAR), defined as the rise from 0-30 min after awakening, and a subsequent less steep fall in cortisol level over the rest of the day. Partialling analyses, suggested that the correlation between fall in cortisol over the day and OCP was independent of age. Both older age and less cortisol change were particularly related to poorer performance on tests of declarative memory and executive functioning. Our conclusions are that during the short post-awakening period, an exception exists to the generally pertaining association between higher levels of cortisol and poorer cognitive performance. Consequentially dynamic measures reflecting the rise (CAR) and fall from the post-awakening peak may be particularly salient in helping to explain links between cortisol and cognitive performance. Finally our pattern of results across different cognitive tests suggests an association between cortisol and those domains of cognitive functioning which depend crucially on the integrity of the hippocampus and pre-frontal cortex.
21181130	Glucocorticoids have been shown to affect declarative memory, an explicit form of memory for facts and events operated by medial temporal lobe structures. Recent neuroimaging data suggest that the medial temporal lobe (including the hippocampus) is also active in implicit sequence learning.The aim of the present study was to investigate whether implicit sequence learning may also be affected by glucocorticoid administration.	Oral cortisol (30 mg) was given to 29 healthy subjects whereas 31 control subjects received placebo. One hour after treatment all volunteers performed five consecutive blocks of a five-choice serial reaction time task by responding to colored lights by pressing buttons of the same color. The subjects responded without knowing to a quasi-randomized stimulus sequence, including higher-order sequential regularities (a combination of two colors that predicted the following target color). The reaction speed of every button-press (100 per block) was determined and difference scores were calculated as a proof of learning.	Both groups showed significant implicit sequence learning throughout the experiment. However, we found an impaired learning performance of the cortisol group compared with the placebo group. Further analysis revealed that a delayed learning in the cortisol group occurred at the very beginning of the task.	This study is the first human investigation indicating impaired implicit memory function after exogenous administration of the stress hormone cortisol. This effect may depend on hippocampus engagement in implicit sequence learning, but the involvement of other brain structures is also discussed.	
21175014	We have previously shown that, in early stages of Parkinson's disease (PD), patients with higher reaction times are also more impaired in visual sequence learning, suggesting that movement preparation shares resources with the learning of visuospatial sequences. Here, we ascertained whether, in patients with PD, the pattern of the neural correlates of attentional processes of movement planning predict sequence learning and working memory abilities. High density Electroencephalography (EEG, 256 electrodes) was recorded in 19 patients with PD performing reaching movements in a choice reaction time paradigm. Patients were also tested with Digit Span and performed a visuomotor sequence learning task that has an important declarative learning component. We found that attenuation of alpha/beta oscillatory activity before the stimulus presentation in frontoparietal regions significantly correlated with reaction time in the choice reaction time task, similarly to what we had previously found in normal subjects. In addition, such activity significantly predicted the declarative indices of sequence learning and the scores in the Digit Span task. These findings suggest that some motor and non motor PD signs might have common neural bases, and thus, might have a similar response to the same behavioral therapy. In addition, these results might help in designing and testing the efficacy of novel rehabilitative approaches to improve specific aspects of motor performance in PD and other neurological disorders.
21173885	Cholinergic deficits are an early and functionally significant manifestation of Alzheimer's disease (AD). These deficits contribute to impairment of hippocampally mediated information processing, including declarative memory impairments and abnormal auditory sensory gating. A functional imaging technique that facilitates identification of changes in cholinergically dependent hippocampal information processing would be of considerable use in the study and clinical evaluation of persons with this condition. Techniques that interrogate hippocampal function passively, ie, in a manner requiring no cognitive effort or novel task learning during the neuroimaging procedure, would also be especially useful in this cognitively impaired population. The functional magnetic resonance imaging sensory gating paradigm developed at the University of Colorado, CO, USA, is a functional neuroimaging technique that possesses both of these characteristics. We developed a demonstration project using this paradigm in which we passively interrogated hippocampal function in two subjects with probable AD of mild severity. Imaging data were quick and easy in these subjects and served usefully as an initial demonstration of the feasibility of using this neuroimaging method in this population. Preliminary analyses of the data obtained from these subjects identified abnormal blood oxygen level-dependent responses when compared with four healthy comparators, and the pattern of these responses was consistent with impaired function of the auditory sensory gating network. The strengths and limitations of this neuroimaging paradigm and the additional issues that require investigation in order to continue its development into a research and clinical technique for use in this population are discussed.
21171907	Psychotherapy has, since the time of Freud, focused on the unconscious and dynamically repressed memory. This article explores a therapy where the focus is on what is known, on episodic memory. Episodic memory, along with semantic memory, is part of the declarative memory system. Episodic memory depends on frontal, parietal, as well as temporal lobe function. It is the system related to the encoding and recall of context-rich memory. While memory usually decays with time, powerfully encoded episodic memory may augment. This article explores the hypothesis that such augmentation is the result of conditioning and kindling. Augmented memory could lead to a powerful "top-down" focus of attention-such that one would perceive only what one had set out to perceive. The "oddball paradigm" is suggested as a route out of such a self-perpetuating system. A clinical example (a disguised composite of several clinical histories) is used to demonstrate how such an intensification of memory and attention came about as a result of the transference, and how the "oddball paradigm" was used as a way out of what had become a treatment stalemate.
21163755	Dysfunctions of auditory-verbal declarative and working memory are observed in patients with depressive disorders (DD). The authors wanted to see, whether antidepressive therapy improved the efficiency of cognitive processes among patients suffering from DD and determine possible associations between auditory-verbal declarative and working memory performance, evaluated before treatment vs. remission degree after treatment.The study was carried out in 87 subjects, patients with depressive disorders (n=30, DD) and healthy subjects (n=57, CG, control group). The AVLT (Auditory Verbal Learning Test) and the Stroop Test were used.	CG obtained higher results vs. DD-I (the evaluation started on the therapy onset) in the Stroop Test-RCNb (Reading Colour Names in Black)/time, NCWd (Naming Colour of Word - Different)/time, NCWd/errors, AVLT: the number of words after 30 minutes. CG demonstrated higher results than DD-II (following eight weeks of pharmacological treatment) in RCNb/time, NCWd/time, AVLT: the number of words in the first trial, the number of words after 30 minutes. Compared to DD-I, DD-II achieved better results in NCWd/errors. No statistically significant differences were observed in both tests between the patients with remission and without remission. Statistical analysis revealed the lack of significant dependences among HDRS after treatment and cognitive functions before treatment.	Depressive disorders are associated with deteriorated efficiency of auditory-verbal declarative and working memory. No improvement was observed in the efficiency of auditory-verbal declarative or working memory after 8-week therapy. The performance level of cognitive processes before pharmacotherapy has no effect on the intensity of depression symptoms after therapy.	
21161185	Several studies have shown that stress or the administration of glucocorticoids can impair hippocampus-based declarative memory retrieval and prefrontal dependent working memory performance in healthy subjects. Major Depressive Disorder (MDD) is often characterized by memory impairment and increased cortisol secretion. Studies indicate that the impairing effects of glucocorticoids on declarative memory performance are missing in patients with MDD. The purpose of our study was to investigate whether the finding of missing effects of acute cortisol administration on memory performance in MDD is also seen when examining prefrontal-based working memory.In a placebo-controlled study, 57 patients with MDD and 56 sex- and age-matched healthy control subjects received either placebo or 10 mg of hydrocortisone orally before memory testing. To test the verbal modality of working memory, the Word Suppression Test was applied with one negative and one neutral test part.	After hydrocortisone intake, healthy subjects showed a significantly poorer working memory performance compared to placebo treatment when negative interference words were administered. In contrast, memory performance of MDD patients was not affected by hydrocortisone treatment.	The missing effects of glucocorticoid administration on working memory in MDD might be interpreted in the context of reduced central glucocorticoid receptor function.	
21151366	Naturally occurring memory processes show features which are difficult to investigate by conventional cognitive neuroscience paradigms. Distortions of memory for problematic contents are described both by psychoanalysis (internal conflicts) and research on post-traumatic stress disorder (PTSD; external traumata). Typically, declarative memory for these contents is impaired - possibly due to repression in the case of internal conflicts or due to dissociation in the case of external traumata - but they continue to exert an unconscious pathological influence: neurotic symptoms or psychosomatic disorders after repression or flashbacks and intrusions in PTSD after dissociation. Several experimental paradigms aim at investigating repression in healthy control subjects. We argue that these paradigms do not adequately operationalize the clinical process of repression, because they rely on an intentional inhibition of random stimuli (suppression). Furthermore, these paradigms ignore that memory distortions due to repression or dissociation are most accurately characterized by a lack of self-referential processing, resulting in an impaired integration of these contents into the self. This aspect of repression and dissociation cannot be captured by the concept of memory as a storage device which is usually employed in the cognitive neurosciences. It can only be assessed within the framework of a constructivist memory concept, according to which successful memory involves a reconstruction of experiences such that they fit into a representation of the self. We suggest several experimental paradigms that allow for the investigation of the neural correlates of repressed memories and trauma-induced memory distortions based on a constructivist memory concept.
21145979	Systems consolidation involves a prolonged process of memory reorganization that appears to be distinctly related to declarative memory. Declarative memory can be sharply contrasted with simple delay eyeblink classical conditioning, a prototypical example of nondeclarative memory. Yet inserting a trace interval between the conditioned and unconditioned stimuli endows eyeblink (trace) conditioning with many features of declarative memory. Work in humans has established that trace conditioning requires declarative memory. Recently trace eyeblink conditioning in animals has become one of the most powerful methods to study systems consolidation. Thus, it is ironic that a substantially nondeclarative form of memory has been so instructive concerning the organization of declarative memory.
21142826	Children with a history of cancer are at increased risk for cognitive impairments, particularly in executive and memory domains. Traditional, in-person cognitive rehabilitation strategies may be unavailable and/or impractical for many of these children given difficulties related to resources and health status. The feasibility and efficacy of implementing a computerized, home-based cognitive rehabilitation curriculum designed to improve executive function skills was examined in these children.A one-arm open trial pilot study of an original executive function cognitive rehabilitation curriculum was conducted with 23 paediatric cancer survivors aged 7-19.	Compliance with the cognitive rehabilitation program was 83%, similar to that of many traditional programs. Following the cognitive intervention, participants showed significantly increased processing speed, cognitive flexibility, verbal and visual declarative memory scores as well as significantly increased pre-frontal cortex activation compared to baseline.	These results suggest that a program of computerized cognitive exercises can be successfully implemented at home in young children with cancer. These exercises may be effective for improving executive and memory skills in this group, with concurrent changes in neurobiologic status.	
21130809	Even though "procholinergic" drugs are almost the sole kind of treatments currently used as cognitive enhancers in patients with Alzheimer's disease, the role of acetylcholine (ACh) in learning and memory is still poorly understood. In this short review, we focus on the septo-hippocampal cholinergic system and try to demonstrate that understanding ACh-memory relationships requires taking into account two characteristics of memory function. First, this function is polymorphic and relies on multiple neural systems. It appears that hippocampal ACh may not only modulate specific computational function of the hippocampus but also contributes to the functional coordination of multiple memory systems in a task-dependent manner. Second, memorization implies different phases which are differentially regulated by ACh. Namely, several lines of evidence suggest a "biphasic" involvement with hippocampal ACh facilitating memory encoding but hampering memory consolidation and retrieval, and low hippocampal ACh promoting consolidation of declarative memory. By spotting major determinants of memory modulation by hippocampal ACh, we hope that the present non exhaustive review will help to improve our understanding of the complexity of ACh-memory relationships.
21125202	Prior studies have suggested a relationship between dehydration and poor cognitive performance. The present study examined the relationships among hydration status, declarative memory and working memory skills, and blood pressure in a sample of older community dwelling females.Data was analyzed from a larger study; relationships among hydration status, blood pressure, and cognitive measures were assessed with correlation and meditational analyses.	Laboratory.	21 postmenopausal women (mean age 60.3, SD 8.03).	Hydration status was measured using bioelectrical impedance, baseline blood pressure was assessed using a Colin Pressmate, and cognition was examined using the Auditory Verbal Learning Test and Auditory Consonant Trigrams.	Bioelectrical impedance total body water by weight was found to be related to working memory, r = .47, p = .04, and memory skills, r = .54, p = .01. Total body water by weight was also found to be related to diastolic blood pressure, r = -.56, p = .01, which in turn was related to working memory, r = -.67, p = .002, and declarative memory, r = -.57, p = .009, skills. When diastolic blood pressure was accounted for, the relationship between hydration status and cognitive skills was attenuated. A similar pattern of results was seen for systolic blood pressure, although findings did not reach statistical significance.	Results emphasize the importance of considering hydration status and blood pressure when interpreting cognitive performance in older adults.	
21120149	The idea that an already consolidated memory can become destabilized after recall and requires a process of reconsolidation to maintain it for subsequent use has gained much credence over the past decade. Experimental studies in rodents have shown pharmacological, genetic, or injurious manipulation at the time of memory reactivation can disrupt the already consolidated memory. Despite the force of experimental data showing this phenomenon, a number of questions have remained unanswered and no consensus has emerged as to the conditions under which a memory can be disrupted following reactivation. To date most rodent studies of reconsolidation are based on negatively reinforced memories, in particular fear-associated memories, while the storage and stability of forms of memory that do not rely on explicit reinforcement have been less often studied. In this review, we focus on recognition memory, a paradigm widely used in humans to probe declarative memory. We briefly outline recent advances in our understanding of the processes and brain circuits involved in recognition memory and review the evidence that recognition memory can undergo reconsolidation upon reactivation. We also review recent findings suggesting that some molecular mechanisms underlying consolidation of recognition memory are similarly recruited after recall to ensure memory stability, while others are more specifically engaged in consolidation or reconsolidation. Finally, we provide novel data on the role of Rsk2, a mental retardation gene, and of the transcription factor zif268/egr1 in reconsolidation of object-location memory, and offer suggestions as to how assessing the activation of certain molecular mechanisms following recall in recognition memory may help understand the relative importance of different aspects of remodeling or updating long-lasting memories.
21115065	To explore spatial cognition in rodents, research uses maze tasks, which differ in complexity, number of goals and pathways, behavioural flexibility, memory duration, but also in the experimenter's control over the strategy developed to reach a goal (e.g., allocentric vs. egocentric). This study aimed at validating a novel spatial memory test: the double-H maze test. The transparent device made of an alley with two opposite arms at each extremity and two in its centre is flooded. An escape platform is submerged in one arm. For experiments 1-3, rats were released in unpredictable sequences from one of both central arms to favour an allocentric approach of the task. Experiment 1 (3 trials/day over 6 days) demonstrated classical learning curves and evidence for recent and nondegraded remote memory performance. Experiment 2 (2 days, 3 trials/day) showed a dose-dependent alteration of task acquisition/consolidation by muscarinic or NMDA receptor blockade; these drug effects vanished with sustained training (experiment 3; 4 days, 3 trials/day). Experiment 4 oriented rats towards a procedural (egocentric) approach of the task. Memory was tested in a misleading probe trial. Most rats immediately switched from response learning-based to place learning-based behaviour, but only when their initial view on environmental cues markedly differed between training and probe trials. Because this simple task enables the formation of a relatively stable memory trace, it could be particularly adapted to study consolidation processes at a system level or/and the interplay between procedural and declarative-like memory systems.
21115022	The contribution of the thalamus to the functioning of prospective memory (PM) is currently unknown. Here we report an experimental investigation of the performance of two patients with bilateral infarcts in the anterior-mesial regions of the thalami on an event-based PM paradigm. One patient, G.P., had a pervasive declarative memory impairment but no significant executive deficit. The other patient, R.F., had a memory deficit limited to verbal material with associated behavioral abnormalities (inertia and apathy); she performed poorly on tests of executive functions. Although both patients performed poorly on the PM task, a qualitative analysis of performance revealed different mechanisms at the base of their impaired PM. G.P. had reduced declarative memory for target words compared with normal controls; but, unforgotten words were normally able to elicit his recall of the prospective intention. Conversely, R.F.'s declarative memory for target words was as accurate as that of normal controls, but she presented a dramatically reduced ratio between the number of target words she recalled and the number of times she activated the prospective intention on the PM task, suggesting that her deficit consisted of difficulty in activating the intention despite normal declarative memory for the target events. In conclusion, results of the present study demonstrate that thalamic structures have an important role in PM processes. They also document that damage to the anterior-mesial regions of the thalami affects PM abilities by two different mechanisms, respectively based on the relative disruption of declarative memory or executive processes functioning, which, in turn, is related to the specific intrathalamic structures involved by the lesions. Indeed, while G.P.'s pervasive declarative memory deficit was underlain by bilateral involvement of the mammillo-thalamic tract, R.F.'s executive and behavioral abnormalities were likely related to bilateral damage of the midline, intralaminar, and medio-dorsal nuclei.
21108971	Acetlylcholine (ACh) in the central nervous system is critical for a multitude of functions. Here, we concentrate on declarative memory in humans, and its equivalent episodic-like memory in rodents and highlight current understanding of cholinergic system in these processes. Spatial memory formation represents a simple form of episodic-like memory in rodents that engages the basal forebrain cholinergic system and its target structures. In these, ACh exerts numerous functions. (1) During spatial acquisition learning, ACh efflux into the extracellular space is immediate in hippocampus and cortex; during consolidation of spatial reference memory, ACh levels are low. These requirements explain why ACh receptor blockade during acquisition blocks memory formation, and it is also consonant with the notion that an unspecific enhancement of cholinergic activity during consolidation is detrimental to memory formation. (2) Working and short-term memory for spatial locations engages the nucleus basalis – prefrontal cortex ACh system. ACh activity is trial related and maintained for some time post-training. (3) Striatal cholinergic activity is increased during stimulus–response learning and behavioural flexibility (reversal learning, extinction) providing a possible switch between different behavioural strategies. (4) At present, there is no clear difference between muscarinic and nicotinergic systems with respect to spatial learning. Antagonists of the respective receptors impair memory formation, agonists can reverse these deficits or may, under specific conditions act more like a general cognitive enhancers by way of improving attention. (5) Data reviewed here do not provide conclusive evidence for muscarinic or nicotinic receptors presenting as novel therapeutic targets, and there is no clear indication for ACh derived novel biomarkers for translational medicine. Unresolved and contradictory results are highlighted and discussed.
21088685	Declarative and emotional memories are key to quality of life and day-to-day functioning. The absence of memory or the inability to recall memories properly in an emotional context leads to dysfunction but, paradoxically, memories that generate too much emotion can be equally disabling.
21075233	As critical as waking brain function is to cognition, an extensive literature now indicates that sleep supports equally important, different, yet complementary operations. This review will consider recent and emerging findings implicating sleep, and specific sleep-stage physiologies, in the modulation, regulation and even preparation of cognitive and emotional brain processes. First, evidence for the role of sleep in memory processing will be discussed, principally focusing on declarative memory. Second, at a neural level, several mechanistic models of sleep-dependent plasticity underlying these effects will be reviewed, with a synthesis of these features offered that may explain the ordered structure of sleep, and the orderly evolution of memory stages. Third, accumulating evidence for the role of sleep in associative memory processing will be discussed, suggesting that the long-term goal of sleep may not be the strengthening of individually memory items, but, instead, their abstracted assimilation into a schema of generalized knowledge. Forth, the newly emerging benefit of sleep in regulating emotional brain reactivity will be considered. Finally, and building on this latter topic, a novel hypothesis and framework of sleep-dependent affective brain processing will be proposed, culminating in testable predictions and translational implications for mood disorders.
21058846	Ample evidence suggests that emotional arousal enhances declarative/episodic memory. By contrast, there is little evidence that emotional enhancement of memory (EEM) extends to procedural skill based memory. We examined remote EEM (1.5-month delay) for cognitive skill learning using the weather prediction (WP) probabilistic classification task. Participants viewed interleaved emotionally arousing or neutral pictures during WP acquisition. Arousal retarded initial WP acquisition. While participants in the neutral condition showed substantial forgetting of WP learning across the 1.5-month delay interval, the arousal condition showed no evidence of forgetting across the same time period. Thus, arousal during encoding determined the mnemonic fate of cognitive skill learning. Emotional enhancement of WP retention was independent of verbally stated knowledge of WP learning and EEM for the picture contexts in which learning took place. These results reveal a novel demonstration of EEM for cognitive skill learning, and suggest that emotional arousal may in parallel enhance the neural systems that support procedural learning and its declarative context.
21056678	Regions within the medial temporal lobe and basal ganglia are thought to subserve distinct memory systems underlying declarative and nondeclarative processes, respectively. One question of interest is how these multiple memory systems interact during learning to contribute to goal directed behavior. While some hypotheses suggest that regions such as the striatum and the hippocampus interact in a competitive manner, alternative views posit that these structures may operate in a parallel manner to facilitate learning. In the current experiment, we probed the functional connectivity between regions in the striatum and hippocampus in the human brain during an event related probabilistic learning task that varied with respect to type of difficulty (easy or hard cues) and type of learning (via feedback or observation). We hypothesized that the hippocampus and striatum would interact in a parallel manner during learning. We identified regions of interest (ROI) in the striatum and hippocampus that showed an effect of cue difficulty during learning and found that such ROIs displayed a similar pattern of blood oxygen level dependent (BOLD) responses, irrespective of learning type, and were functionally correlated as assessed by a Granger causality analysis. Given the connectivity of both structures with dopaminergic midbrain centers, we further applied a reinforcement learning algorithm often used to highlight the role of dopamine in human reward related learning paradigms. Activity in both the striatum and hippocampus positively correlated with a prediction error signal during feedback learning. These results suggest that distinct human memory systems operate in parallel during probabilistic learning, and may act synergistically particularly when a violation of expectation occurs, to jointly contribute to learning and decision making.
21055906	Frontal-subcortical cognitive and limbic feedback loops modulate higher cognitive functioning. The final step in these feedback loops is the thalamo-cortical projection through the anterior limb of the internal capsule (AL-IC). Using diffusion tensor imaging (DTI), we evaluated abnormalities in the AL-IC fiber tract in schizophrenia. Participants comprised 16 chronic schizophrenia patients and 19 male, normal controls, who were group matched for handedness, age, and parental socioeconomic status, and underwent DTI on a 1.5 Tesla GE system. We measured the diffusion indices, fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), and manually segmented, based on FA maps, AL-IC volume, normalized for intracranial contents (ICC). The results showed a significant reduction in the ICC-corrected volume of the AL-IC in schizophrenia, but did not show diffusion measure group differences in the AL-IC in FA, MD, RD or AD. In addition, in the schizophrenia patients, AL-IC FA correlated positively with performance on measures of spatial and verbal declarative/episodic memory, and right AL-IC ICC-corrected volume correlated positively with more perseverative responses on the Wisconsin Card Sort Test (WCST). We found a reduction in AL-IC ICC-corrected volume in schizophrenia, without FA, MD, RD or AD group differences, implicating the presence of a structural abnormality in schizophrenia in this subcortical white matter region which contains important cognitive, and limbic feedback pathways that modulate prefrontal cortical function. Despite not demonstrating a group difference in FA, we found that AL-IC FA was a good predictor of spatial and verbal declarative/episodic memory performance in schizophrenia.
21050420	Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) type glutamate receptors are critical for synaptic plasticity and induction of long-term potentiation (LTP), considered as one of the synaptic mechanisms underlying learning and memory. Positive allosteric modulators of AMPA receptors could provide a therapeutic approach to the treatment of cognitive disorders resulting from aging and/or neurodegenerative diseases, such as Alzheimer disease (AD). Several AMPA potentiators have been described in the last decade, but for the moment their clinical efficacy has not been demonstrated due to the complexity of the target, AMPA receptors, and the difficulty in studying cognition in animals and humans. A better understanding of the mechanism of action of this type of drug remains an important issue, if knowledge of these compounds is to be increased and if this novel therapeutic approach is to be an interesting research area. Among the AMPA potentiators, S 18986 is emerging as a new selective positive allosteric modulator of AMPA-type glutamate receptors. S 18986, as with other positive AMPA receptor modulators, increased induction and maintenance of LTP in the hippocampus as well as the expression of brain-derived neurotrophic factor (BDNF) both in vitro and in vivo. Its cognitive-enhancing properties have been demonstrated in various behavioral models (procedural, spatial, "episodic," working, and relational/declarative memory) in young-adult and aged rodents. It is interesting to note that memory-enhancing effects appeared more robust in middle-aged animals compared with aged ones and in "episodic" and spatial memory tasks. From these results, S 18986 is expected to treat memory deficits associated with early cerebral aging and neurological diseases in elderly people.
21049185	Epileptic seizures generate cognitive and behavioral impacts in individuals who suffer from epilepsy. Declarative memory is one of the cognitive functions that can be affected by epileptic seizures. The main objective of this work was to investigate neurocognitive function, especially the emotional working memory of patients with unilateral mesial temporal lobe epilepsy, and that of patients submitted to unilateral mesial temporal lobectomy. A face recognition test that can simultaneously recruit the frontal lobe (working memory) and mesial temporal lobe (emotional memory) was used to investigate emotional working memory. Our findings showed that the epilepsy factor significantly compromised the performance in the emotional memory test. On the other hand, surgical removal of the epileptic focus promoted an improvement in the emotional working memory of these patients, in addition to the significantly decrease in the number of seizures.
21048965	A leading notion is that language skill acquisition declines between childhood and adulthood. While several lines of evidence indicate that declarative ("what", explicit) memory undergoes maturation, it is commonly assumed that procedural ("how-to", implicit) memory, in children, is well established. The language superiority of children has been ascribed to the childhood reliance on implicit learning. Here we show that when 8-year-olds, 12-year-olds and young adults were provided with an equivalent multi-session training experience in producing and judging an artificial morphological rule (AMR), adults were superior to children of both age groups and the 8-year-olds were the poorest learners in all task parameters including in those that were clearly implicit. The AMR consisted of phonological transformations of verbs expressing a semantic distinction: whether the preceding noun was animate or inanimate. No explicit instruction of the AMR was provided. The 8-year-olds, unlike most adults and 12-year-olds, failed to explicitly uncover the semantic aspect of the AMR and subsequently to generalize it accurately to novel items. However, all participants learned to apply the AMR to repeated items and to generalize its phonological patterns to novel items, attaining accurate and fluent production, and exhibiting key characteristics of procedural memory. Nevertheless, adults showed a clear advantage in learning implicit task aspects, and in their long-term retention. Thus, our findings support the notion of age-dependent maturation in the establishment of declarative but also of procedural memory in a complex language task. In line with recent reports of no childhood advantage in non-linguistic skill learning, we propose that under some learning conditions adults can effectively express their language skill acquisition potential. Altogether, the maturational effects in the acquisition of an implicit AMR do not support a simple notion of a language skill learning advantage in children.
21048140	The neural systems that support motor adaptation in humans are thought to be distinct from those that support the declarative system. Yet, during motor adaptation changes in motor commands are supported by a fast adaptive process that has important properties (rapid learning, fast decay) that are usually associated with the declarative system. The fast process can be contrasted to a slow adaptive process that also supports motor memory, but learns gradually and shows resistance to forgetting. Here we show that after people stop performing a motor task, the fast motor memory can be disrupted by a task that engages declarative memory, but the slow motor memory is immune from this interference. Furthermore, we find that the fast/declarative component plays a major role in the consolidation of the slow motor memory. Because of the competitive nature of declarative and nondeclarative memory during consolidation, impairment of the fast/declarative component leads to improvements in the slow/nondeclarative component. Therefore, the fast process that supports formation of motor memory is not only neurally distinct from the slow process, but it shares critical resources with the declarative memory system.
20981620	A deficit of declarative memory is a common sequela after a hypoxic episode. While the role of gray matter changes (i.e., atrophy of hippocampal formation) as mainly responsible for memory loss has been emphasized, the role of the white matter damage has so far been neglected. The present study was aimed at evaluating whether white matter damage, within the neural circuitry responsible for declarative memory functioning, is present in anoxic patients. We assessed, by means of voxel-based morphometry, the integrity of white matter regions in five patients with hypoxic amnesia. When anoxic patients were compared to healthy controls, significantly less white matter density was detected in the fornix, anterior portion of the cingulum bundle and uncinate fasciculus bilaterally. We conclude that cerebral hypoxia may alter, together with the hippocampi, the integrity of white matter fibers throughout the memory-limbic system.
20980591	Sleep spindle activity has been associated with improvements in procedural and declarative memory. Here, for the first time, we looked at the role of spindles in the integration of newly learned information with existing knowledge, contrasting this with explicit recall of the new information. Two groups of participants learned novel spoken words (e.g., cathedruke) that overlapped phonologically with familiar words (e.g., cathedral). The sleep group was exposed to the novel words in the evening, followed by an initial test, a polysomnographically monitored night of sleep, and a second test in the morning. The wake group was exposed and initially tested in the morning and spent a retention interval of similar duration awake. Finally, both groups were tested a week later at the same circadian time to control for possible circadian effects. In the sleep group, participants recalled more words and recognized them faster after sleep, whereas in the wake group such changes were not observed until the final test 1 week later. Following acquisition of the novel words, recognition of the familiar words was slowed in both groups, but only after the retention interval, indicating that the novel words had been integrated into the mental lexicon following consolidation. Importantly, spindle activity was associated with overnight lexical integration in the sleep group, but not with gains in recall rate or recognition speed of the novel words themselves. Spindle activity appears to be particularly important for overnight integration of new memories with existing neocortical knowledge.
20965253	The Default Mode Network (DMN) is a higher order functional neural network that displays activation during passive rest and deactivation during many types of cognitive tasks. Accordingly, the DMN is viewed to represent the neural correlate of internally-generated self-referential cognition. This hypothesis implies that the DMN requires the involvement of cognitive processes, like declarative memory. The present study thus examines the spatial and functional convergence of the DMN and the semantic memory system. Using an active block-design functional Magnetic Resonance Imaging (fMRI) paradigm and Independent Component Analysis (ICA), we trace the DMN and fMRI signal changes evoked by semantic, phonological and perceptual decision tasks upon visually-presented words. Our findings show less deactivation during semantic compared to the two non-semantic tasks for the entire DMN unit and within left-hemispheric DMN regions, i.e., the dorsal medial prefrontal cortex, the anterior cingulate cortex, the retrosplenial cortex, the angular gyrus, the middle temporal gyrus and the anterior temporal region, as well as the right cerebellum. These results demonstrate that well-known semantic regions are spatially and functionally involved in the DMN. The present study further supports the hypothesis of the DMN as an internal mentation system that involves declarative memory functions.
20962243	There is evidence that rule-based category learning is supported by a broad neural network that includes the prefrontal cortex, the anterior cingulate cortex, the head of the caudate nucleus, and medial temporal lobe structures. Although thousands of studies have examined rule-based category learning, only a few have studied the development of automaticity in rule-based tasks. Categorizing by a newly learned rule makes heavy demands on declarative memory, but after thousands of repetitions rule-based categorizations are made with no apparent effort. Thus, it seems likely that the neural systems that mediate automatic rule-based categorization are substantially different from the systems that mediate initial learning. This research aims at identifying the neural systems responsible for early and late rule-based categorization performances. Toward this end, this article reports the results of an experiment in which human participants each practiced a rule-based categorization task for >10,000 trials distributed over 20 separate sessions. Sessions 1, 4, 10, and 20 were performed inside a magnetic resonance imaging scanner. The main findings are as follows: (1) cortical activation remained approximately constant throughout training, (2) subcortical activation increased with practice (i.e., there were more activated voxels in the striatum), and (3) only cortical activation was correlated with accuracy after extensive training. The results suggest an initial subcortical neural system centered around the head of the caudate that is gradually replaced by a cortical system centered around the ventrolateral prefrontal cortex. With extensive practice, the cortical system progressively becomes more caudal and dorsal, and is eventually centered around the premotor cortex.
20955761	Functional memory disorder (FMD) is characterized by mnestic and attentional deficits without symptoms of mild cognitive impairment or dementia. FMD usually develops in subjects with high psychosocial stress level and is classified to the somatoform disorders. We assessed memory performance (procedural mirror tracing task, declarative visual and verbal memory task) and other cognitive functions before and after one night of sleep in 12 FMD patients (mean age: 51.7 yrs, 7 females) and 12 healthy subjects matched for age, gender and IQ. Memory performance and other neurocognitive tasks did not differ between the groups at baseline. After one night of sleep, FMD patients showed an impairment of declarative memory consolidation compared to healthy subjects (visual task: p=0.004; verbal task: p=0.039). Spectral analysis of sleep-EEG indicated an increased cortical excitation in FMD. We hypothesize that a hyperarousal state in FMD might contribute to sleep disturbance implicating negative effects on declarative memory consolidation.
20950558	A growing body of evidence indicates that sleep promotes memory consolidation. Although the first experimental evidence for this positive influence of sleep on memory was collected more than a century ago, the potential underlying neural mechanisms begins only to be conceptualized and experimentally characterized. A first hypothesis contrasted the influence of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep on declarative and procedural memories, respectively. As the understanding of the effects of sleep on memory consolidation during sleep progressed, the hypotheses were increasingly framed in terms of neural processes occurring with NREM and REM sleep, especially associated with phasic events such as slow waves, spindles or phasic REM sleep. This paper reviews two of these hypotheses: the synaptic downscaling and the systemic consolidation during non NREM sleep.
20943261	In this paper we examine the neurobiological correlates of syntax, the processing of structured sequences, by comparing FMRI results on artificial and natural language syntax. We discuss these and similar findings in the context of formal language and computability theory. We used a simple right-linear unification grammar in an implicit artificial grammar learning paradigm in 32 healthy Dutch university students (natural language FMRI data were already acquired for these participants). We predicted that artificial syntax processing would engage the left inferior frontal region (BA 44/45) and that this activation would overlap with syntax-related variability observed in the natural language experiment. The main findings of this study show that the left inferior frontal region centered on BA 44/45 is active during artificial syntax processing of well-formed (grammatical) sequence independent of local subsequence familiarity. The same region is engaged to a greater extent when a syntactic violation is present and structural unification becomes difficult or impossible. The effects related to artificial syntax in the left inferior frontal region (BA 44/45) were essentially identical when we masked these with activity related to natural syntax in the same subjects. Finally, the medial temporal lobe was deactivated during this operation, consistent with the view that implicit processing does not rely on declarative memory mechanisms that engage the medial temporal lobe. In the context of recent FMRI findings, we raise the question whether Broca's region (or subregions) is specifically related to syntactic movement operations or the processing of hierarchically nested non-adjacent dependencies in the discussion section. We conclude that this is not the case. Instead, we argue that the left inferior frontal region is a generic on-line sequence processor that unifies information from various sources in an incremental and recursive manner, independent of whether there are any processing requirements related to syntactic movement or hierarchically nested structures. In addition, we argue that the Chomsky hierarchy is not directly relevant for neurobiological systems.
20934312	Neuroendocrine, cognitive and hippocampal alterations have been described in Gulf War (GW) veterans, but their inter-relationships and significance for posttraumatic stress disorder (PTSD) have not been described. Hydrocortisone (Hcort) was administered to GW veterans with (PTSD+ n=12) and without (PTSD- n=8) chronic PTSD in a randomized, placebo-controlled, double-blind challenge. Changes in plasma ACTH, memory, and hippocampal [(18)F]FDG uptake on positron emission tomography were assessed. The low-dose dexamethasone suppression test was also administered. The PTSD+ group showed greater cortisol and ACTH suppression, reflecting greater peripheral glucocorticoid receptor (GR) responsiveness, and did not show an Hcort-induced decrement in delayed recall or retention. The groups had comparable relative regional hippocampal [(18)F]FDG uptake at baseline, but only the PTSD- group had an Hcort-associated decrease in hippocampal [(18)F]FDG uptake. Asymmetry in hippocampal hemispheric volumes differed between PTSD+ and PTSD- groups. This asymmetry was associated with cortisol, ACTH, retention and functional hippocampal asymmetry before, but not after, Hcort administration. Differences in brain metabolic responses between GW veterans with and without PTSD may reflect differences in peripheral and central GR responsiveness.
20884357	The degree to which the MTL system contributes to effective language skills is not well delineated. We sought to determine if the MTL plays a role in single-word decoding in healthy, normal skilled readers. The experiment follows from the implications of the dual-process model of single-word decoding, which provides distinct predictions about the nature of MTL involvement. The paradigm utilized word (regular and irregularly spelled words) and pseudoword (phonetically regular) stimuli that differed in their demand for non-lexical as opposed lexical decoding. The data clearly showed that the MTL system was not involved in single word decoding in skilled, native English readers. Neither the hippocampus nor the MTL system as a whole showed significant activation during lexical or non-lexical based decoding. The results provide evidence that lexical and non-lexical decoding are implemented by distinct but overlapping neuroanatomical networks. Non-lexical decoding appeared most uniquely associated with cuneus and fusiform gyrus activation biased toward the left hemisphere. In contrast, lexical decoding appeared associated with right middle frontal and supramarginal, and bilateral cerebellar activation. Both these decoding operations appeared in the context of a shared widespread network of activations including bilateral occipital cortex and superior frontal regions. These activations suggest that the absence of MTL involvement in either lexical or non-lexical decoding appears likely a function of the skilled reading ability of our sample such that whole-word recognition and retrieval processes do not utilize the declarative memory system, in the case of lexical decoding, and require only minimal analysis and recombination of the phonetic elements of a word, in the case of non-lexical decoding.
25164055	The study of human intelligence was once dominated by symbolic approaches, but over the last 30 years an alternative approach has arisen. Symbols and processes that operate on them are often seen today as approximate characterizations of the emergent consequences of sub- or nonsymbolic processes, and a wide range of constructs in cognitive science can be understood as emergents. These include representational constructs (units, structures, rules), architectural constructs (central executive, declarative memory), and developmental processes and outcomes (stages, sensitive periods, neurocognitive modules, developmental disorders). The greatest achievements of human cognition may be largely emergent phenomena. It remains a challenge for the future to learn more about how these greatest achievements arise and to emulate them in artificial systems.
20865730	Although it is well established that the integrity of the medial temporal lobe (MTL) is critical for declarative memory, the functional organization of the MTL remains a matter of intense debate. One issue that has received little consideration so far is whether the hippocampus can function normally in the presence of a lesion to perirhinal cortex that produces noticeable memory impairments. This question is intriguing as the MTL forms a hierarchical system, in which perirhinal cortex represents one of the critical nodes in the reciprocal projections between neocortical association areas and the hippocampus. Here, we used functional magnetic resonance imaging to examine whether NB, an individual who underwent surgical resection of the left anterior temporal lobe that included large aspects of perirhinal and entorhinal cortex but spared the hippocampus, exhibits intact hippocampal novelty responses to auditory sentences. Our results revealed such evidence in NB's left and right hippocampus. They complement previous behavioral work in NB, indicating that recollective processes considered to rely on hippocampal integrity are also preserved. Further analyses revealed intact novelty responses in structures that provide neuroanatomical input to the hippocampus, including remaining perirhinal cortex and surgically spared parahippocampal cortex. These findings point to viable neuroanatomical mechanisms as to how functional integrity in the hippocampus may be maintained in the face of widespread, but incomplete removal of its input structures.
20863515	Although much is known about the development of memory strategies and metamemory during childhood, evidence for linkages between these memory skills, either concurrently or over time, has been limited. Drawing from a longitudinal investigation of the development of memory, repeated assessments of children's (N=107) strategy use and declarative metamemory were made to examine the development of these skills and the relations between them over time. Latent curve models were used first to estimate the trajectories of children's strategy use and metamemory and then to examine predictors of children's performance in each of these domains. Children's metamemory at the beginning of Grade 1 was linked to child- and home-level factors, whereas the development of both skills was related to maternal education level. Additional modeling of the longitudinal relations between strategic sorting and metacognitive knowledge indicated that metamemory at earlier time points was predictive of subsequent strategy use.
20854522	This literature review attempts to profile specific areas of cognition that have shown unique and consistent evidence of dysfunction among people with schizophrenia. In addition, their impact on vocational functioning is illustrated, so as to highlight the importance of managing these cognitive difficulties in vocational rehabilitation.Literature search was carried out on seven key cognitive domains identified by the National Institute of Mental Health in the USA. Their impact on vocational function was also reviewed.	It is found that attention, declarative and working memory, reasoning, problem-solving and social cognition are areas of impairment that have great impact on vocational functioning. Attention and memory problems affect learning of new work tasks. Executive function is particularly crucial in determining supported and open employment outcomes, as executive dysfunction cannot be easily compensated. Lastly, social cognition plays a major role in determining the success of workplace social exchanges.	Occupational therapists need to have a good understanding of the profile of cognitive problems among people with schizophrenia, in order to tailor our intervention according to their cognitive strengths and difficulties. Several cognitive remediation strategies and programs have been designed specifically for people with mental illness. Equipping ourselves with skills in conducting such programs will augment our expertise in vocational rehabilitation.	
20850275	Galantamine, a reversible cholinesterase inhibitor with effects on nicotinic receptors, has shown mixed effects on cognitive impairments in patients with schizophrenia. Given these mixed results we examined whether galantamine compared to adjunctive placebo may improve cognitive functions in patients treated concomitantly with a long acting atypical antipsychotic.The parent study was a 52-week double-blind, randomized study of treatment with long-acting injectable risperidone 25mg or 50mg every two weeks. Adjunctive galantamine or placebo treatment was administered from Month 6 to 12. Outcome measures were neurocognitive, psychopathology, social and quality of life functions. Patients were randomized to blinded galantamine up to 24mg/day or matching placebo tablets. All patients were maintained on their randomized long-acting injectable risperidone regimen for the duration of the trial.	32 patients were included in the intent-to-treat analysis. No statistically significant differences were found for Attention Vigilance, Declarative Memory, Processing Speed, Reasoning/Problem Solving, Working Memory domains and the Neurocognitive Composite Score. Group specific analysis showed a statistically significant group interaction (p=0.043) with the Social Cognition domain showing in the galantamine group significantly lower scores at endpoint than placebo patients. The PANSS general psychopathology subscale showed significantly higher scores in the galantamine group at endpoint (p=0.05). ANCOVA model for within treatment group comparisons showed a significant increase of 7.3 points for the total PANSS score for the galantamine group.	Galantamine showed no ameliorative effects on cognitive measures in this 6month, double-blind study of patients with schizophrenia treated with an assured and stable antipsychotic medication delivery system. Galantamine may not be an appropriate augmentation agent for cognitive impairments in patients with schizophrenia at the dose used.	
20849944	The brain is a major target of circulating insulin. Enhancing central nervous insulin action has been shown to improve memory functions in animals as well as in humans, benefitting in particular hippocampus-dependent (declarative) memory. As Alzheimer's disease (AD) is associated with reduced central nervous insulin signaling and attenuated permeation of blood-borne insulin across the blood-brain-barrier, the cognitive decline in AD patients may at least in part be derived from impaired brain insulin signaling. Thus, therapeutic strategies to overcome central nervous system insulin deficiency and resistance might be an attractive option in the treatment of cognitive impairments like AD. Insulin can be effectively delivered directly to the brain via the intranasal route that enables the hormone to bypass the blood-brain barrier and modulate central nervous functions. This review summarizes a series of studies demonstrating beneficial effects of intranasal insulin on memory functions both in healthy humans and in patients with cognitive impairments such as AD. These experiments in humans consistently indicate that enhancing brain insulin signaling by intranasal administration of the hormone improves hippocampus-dependent memory in the absence of adverse side effects. Considering that insulin also acts as a neuroprotective signal, up-regulating brain insulin levels by intranasal insulin administration appears to be a promising approach in the treatment and prevention of central nervous system insulin deficiency and resistance as found in AD.
20824723	Controversy exists over the functional role of the medial temporal lobe (MTL) in episodic memory. Some have suggested that the hippocampus plays a unique and qualitatively different role than other MTL regions, whereas others suggest that the entire MTL has one functional role, which is to support the consolidation of declarative memories. Hierarchical relational binding theory (hRBT) purports that the functional role of the entire MTL is the binding of features associated with an episodic experience. As the hippocampus sits at the top of this hierarchy, binding at this level is particularly efficient in reinstating event features at the time of retrieval. Thus, this theory offers a unified account of MTL that yields outcomes similar to theories that suggest a special role of the hippocampus. In this way, hRBT captures features of both single- and dual-process models of MTL and reconciles controversies about the nature of episodic recollection.
20819324	Corticosteroids are commonly associated with changes in mood, memory, and the hippocampus. Declarative memory decline occurs rapidly after corticosteroid administration. Minimal research has focused on interventions to prevent or reverse corticosteroid effects on the human brain and associated adverse psychiatric effects. Acetaminophen has neuroprotective properties in animal models. We examined acetaminophen add-on therapy in patients prescribed corticosteroids. Thirty outpatients prescribed oral high-dose prednisone therapy for asthma (n = 28) or allergic rhinitis (n = 2) were randomized to approximately 7 days of acetaminophen (4000 mg/day) or placebo in a double-blind fashion at the same time as prednisone. Mood was assessed with the Hamilton Rating Scale for Depression, Young Mania Rating Scale, and Activation subscale of the Internal State Scale. Memory was assessed with the Rey Auditory Learning Test and asthma symptoms with the Asthma Control Questionnaire. Between-group differences were assessed using mixed ANCOVAs and within-group changes were examined with paired t-tests. Baseline mean depression scores were elevated. In the total sample, depressive and asthma symptoms improved significantly, while declarative memory worsened during prednisone therapy. No between treatment-group differences were found in mood or memory measures. Change in asthma symptoms with receiving prednisone was not related to change in mood or memory. Prednisone therapy was associated with a reduction in depressive symptom severity and decline in declarative memory that was not related to changes in asthma symptoms. This is consistent with prior research suggesting that prednisone impairs memory and may have antidepressant properties. Acetaminophen did not attenuate corticosteroid-induced mood or memory changes.
20810471	The hippocampal formation is one of the most extensively studied regions of the brain, with well-described anatomy and basic physiology; moreover, aspects of human memory mediated by the hippocampus are well characterized. In schizophrenia, alterations in hippocampal anatomy, perfusion, and activation are consistently reported; impairments in declarative memory function, especially in the flexible use of event memories (e.g., in the service of memory-based inference), are common. Postmortem molecular changes suggest a selective reduction in glutamate transmission in the dentate gyrus and in its efferent fibers, the mossy fiber pathway. A reduction in dentate gyrus glutamatergic output and in its information processing functions could generate two co-occurring outcomes in the hippocampus: 1) a change in homeostatic plasticity processes in cornu ammonis 3 (CA3), accompanied by increased activity due to reduced afferent stimulation from the dentate gyrus onto CA3 neurons, a process that could increase the pattern completion functions of CA3, and 2) the loss of mnemonic functions specific to the dentate gyrus, namely pattern separation, a change that could increase the prevalence of illusory pattern completion and reduce discrimination between present and past experiences in memory. The resulting increase in "runaway" CA3-mediated pattern completion could result in cognitive "mistakes," generating psychotic associations and resulting in memories with psychotic content. Tests of this model could result in novel approaches to the treatment of psychosis and declarative memory alterations and in novel animal preparations for basic schizophrenia research.
20808821	Learning followed by a period of sleep, even as little as a nap, promotes memory consolidation. It is now generally recognized that sleep facilitates the stabilization of information acquired prior to sleep. However, the temporal nature of the effect of sleep on retention of declarative memory is yet to be understood. We examined the impact of a delayed nap onset on the recognition of neutral pictorial stimuli with an added spatial component.Participants completed an initial study session involving 150 neutral pictures of people, places, and objects. Immediately following the picture presentation, participants were asked to make recognition judgments on a subset of "old", previously seen, pictures versus intermixed "new" pictures. Participants were then divided into one of four groups who either took a 90-minute nap immediately, 2 hours, or 4 hours after learning, or remained awake for the duration of the experiment. 6 hours after initial learning, participants were again tested on the remaining "old" pictures, with "new" pictures intermixed.	Interestingly, we found a stabilizing benefit of sleep on the memory trace reflected as a significant negative correlation between the average time elapsed before napping and decline in performance from test to retest (p = .001). We found a significant interaction between the groups and their performance from test to retest (p = .010), with the 4-hour delay group performing significantly better than both those who slept immediately and those who remained awake (p = .044, p = .010, respectively). Analysis of sleep data revealed a significant positive correlation between amount of slow wave sleep (SWS) achieved and length of the delay before sleep onset (p = .048). The findings add to the understanding of memory processing in humans, suggesting that factors such as waking processing and homeostatic increases in need for sleep over time modulate the importance of sleep to consolidation of neutral declarative memories.	
20796031	Tuberoinfundibular peptide of 39 residues (TIP39) is a neuropeptide localized to neural circuits subserving emotional processing. Recent work showed that mice with null mutation for the gene coding TIP39 (TIP39-KO mice) display increased susceptibility to environmental provocation. Based on this stressor-dependent phenotype, the neuroanatomical distribution of TIP39, and knowledge that novelty-induced arousal modulates memory functions via noradrenergic activation, we hypothesized that exposure to a novel environment differently affects memory performance of mice with or without TIP39 signaling, potentially by differences in sensitivity of the noradrenergic system. We tested TIP39-KO mice and mice with null mutation of its receptor, the parathyroid hormone 2 receptor (PTH2-R), in tasks of short-term declarative and social memory (object recognition and social recognition tests, respectively), and of working memory (Y-maze test) under conditions of novelty-induced arousal or acclimation to the test conditions. Mice lacking TIP39 signaling showed memory impairment selectively under conditions of novelty-induced arousal. Acute administration of a PTH2-R antagonist in wild-type mice had a similar effect. The restoration of memory functions in TIP39-KO mice after injection of a β-adrenoreceptor-blocker, propranolol, suggested involvement of the noradrenergic system. Collectively, these results suggest that the TIP39/PTH2-R system modulates the effects of novelty exposure on memory performance, potentially by acting on noradrenergic signaling.
20738888	Neuroimaging studies which investigate brain activity underlying declarative memory processes typically use artificial, unimodal laboratory stimuli. In contrast, we developed a paradigm which much more closely approximates real-life situations of information encoding.In this study, we tested whether ecologically valid stimuli--clips of a TV news show--are apt to assess memory-related fMRI activation in healthy participants across a wide age range (22-70 years). We contrasted brain responses during natural stimulation (TV news video clips) with a control condition (scrambled versions of the same clips with reversed audio tracks). After scanning, free recall performance was assessed.	The memory task evoked robust activation of a left-lateralized network, including primarily lateral temporal cortex, frontal cortex, as well as the left hippocampus. Further analyses revealed that--when controlling for performance effects--older age was associated with greater activation of left temporal and right frontal cortex.	We demonstrate the feasibility of assessing brain activity underlying declarative memory using a natural stimulation paradigm with high ecological validity. The preliminary result of greater brain activation with increasing age might reflect an attempt to compensate for decreasing episodic memory capacity associated with aging.	
20719879	The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical en bloc hippocampus resections. After proliferation of the progenitor cell pool in vitro we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 ± 13% of in vitro cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 ± 2%). This was reflected by reduced numbers of proliferating cells in vivo as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient's regenerative capacity in vitro (r = 0.813; P < 0.001; linear regression: R²(adjusted) = 0.635), as well as the same patient's ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R²(adjusted) = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain.
20712740	The medial temporal lobes (MTL) support declarative memory and mature structurally and functionally during the postnatal years in humans. Although recent work has addressed the development of declarative memory in early childhood, less is known about continued development beyond this period of time. The purpose of this investigation was to explore MTL-dependent memory across middle childhood. Children (6 -10 years old) and adults completed two computerized tasks, place learning (PL) and transitive inference (TI), that each examined relational memory, as well as the flexible use of relational learning. Findings suggest that the development of relational memory precedes the development of the ability to use relational knowledge flexibly in novel situations. Implications for the development of underlying brain areas and ideas for future neuroimaging investigations are discussed.
20702070	Declarative memory disturbances, known to substantially contribute to cognitive impairment in schizophrenia, have previously been attributed to prefrontal as well as hippocampal dysfunction.To characterize the role of prefrontal and mesolimbic/hippocampal dysfunction during memory encoding in schizophrenia.	Neuronal activation in schizophrenia patients and controls was assessed using functional magnetic resonance imaging (fMRI) during encoding of words in a deep (semantic judgement) and shallow (case judgment) task. A free recall (no delay) and a recognition task (24h delay) were performed.	Free recall, but not recognition performance was reduced in patients. Reduced performance was correlated with positive symptoms which in turn were related to increased left hippocampal activity during successful encoding. Furthermore, schizophrenia patients displayed a hippocampal hyperactivity during deep encoding irrespective of encoding success along with a reduced anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (DMPFC) activity in successful encoding but an intact left inferior frontal cortex (LIFC) activity.	This study provides the first evidence directly linking positive symptoms and memory deficits to dysfunctional hippocampal hyperactivity. It thereby underscores the pivotal pathophysiological role of a hyperdopaminergic mesolimbic state in schizophrenia.	
20700470	The successful development of neural prostheses requires an understanding of the neurobiological bases of cognitive processes, i.e., how the collective activity of populations of neurons results in a higher level process not predictable based on knowledge of the individual neurons and/or synapses alone. We have been studying and applying novel methods for representing nonlinear transformations of multiple spike train inputs (multiple time series of pulse train inputs) produced by synaptic and field interactions among multiple subclasses of neurons arrayed in multiple layers of incompletely connected units. We have been applying our methods to study of the hippocampus, a cortical brain structure that has been demonstrated, in humans and in animals, to perform the cognitive function of encoding new long-term (declarative) memories. Without their hippocampi, animals and humans retain a short-term memory (memory lasting approximately 1 min), and long-term memory for information learned prior to loss of hippocampal function. Results of more than 20 years of studies have demonstrated that both individual hippocampal neurons, and populations of hippocampal cells, e.g., the neurons comprising one of the three principal subsystems of the hippocampus, induce strong, higher order, nonlinear transformations of hippocampal inputs into hippocampal outputs. For one synaptic input or for a population of synchronously active synaptic inputs, such a transformation is represented by a sequence of action potential inputs being changed into a different sequence of action potential outputs. In other words, an incoming temporal pattern is transformed into a different, outgoing temporal pattern. For multiple, asynchronous synaptic inputs, such a transformation is represented by a spatiotemporal pattern of action potential inputs being changed into a different spatiotemporal pattern of action potential outputs. Our primary thesis is that the encoding of short-term memories into new, long-term memories represents the collective set of nonlinearities induced by the three or four principal subsystems of the hippocampus, i.e., entorhinal cortex-to-dentate gyrus, dentate gyrus-to-CA3 pyramidal cell region, CA3-to-CA1 pyramidal cell region, and CA1-to-subicular cortex. This hypothesis will be supported by studies using in vivo hippocampal multineuron recordings from animals performing memory tasks that require hippocampal function. The implications for this hypothesis will be discussed in the context of "cognitive prostheses"-neural prostheses for cortical brain regions believed to support cognitive functions, and that often are subject to damage due to stroke, epilepsy, dementia, and closed head trauma.
20673291	It has been suggested that healthy sleep facilitates the consolidation of newly acquired memories and underlying brain plasticity. The authors tested the hypothesis that patients with primary insomnia (PI) would show deficits in sleep-related memory consolidation compared to good sleeper controls (GSC). The study used a four-group parallel design (n=86) to investigate the effects of 12 h of night-time, including polysomnographically monitored sleep ('sleep condition' in PI and GSC), versus 12 h of daytime wakefulness ('wake condition' in PI and GSC) on procedural (mirror tracing task) and declarative memory consolidation (visual and verbal learning task). Demographic characteristics and memory encoding did not differ between the groups at baseline. Polysomnography revealed a significantly disturbed sleep profile in PI compared to GSC in the sleep condition. Night-time periods including sleep in GSC were associated with (i) a significantly enhanced procedural and declarative verbal memory consolidation compared to equal periods of daytime wakefulness in GSC and (ii) a significantly enhanced procedural memory consolidation compared to equal periods of daytime wakefulness and night-time sleep in PI. Across retention intervals of daytime wakefulness, no differences between the experimental groups were observed. This pattern of results suggests that healthy sleep fosters the consolidation of new memories, and that this process is impaired for procedural memories in patients with PI. Future work is needed to investigate the impact of treatment on improving sleep and memory.
25414548	Schizophrenia is associated with changes in the structure and functioning of a number of key brain systems, including prefrontal and medial temporal lobe regions involved in working memory and declarative memory, respectively. Imaging techniques provide an unparalleled window into these changes, allowing repeated assessments across pre- and post-onset stages of the disorder and in relation to critical periods of brain development. Here we review recent directions in structural and functional neuroimaging research on schizophrenia. The view emerging from this work is that schizophrenia is fundamentally a disorder of disrupted neural connectivity, the sources of which appear to be genetic and environmental risk factors influencing brain development both prenatally and during adolescence.
22396855	A possible link between a deficient neurogenesis at the dentate gyrus, and the loss of memory found in Alzheimer's disease patients is discussed. First is indicated that Alzheimer disease is a memory disorder. Since adult neurogenesis at the dentate gyrus plays a role in declarative memory, a brief comment on the structure and function of dentate gyrus has been included. At molecular level, we have discussed the function of the enzyme GSK3 on the development of neurogenesis at the subgranular zone of the dentate gyrus. Finally, we have indicated that in Alzheimer disease there is an increase in GSK3 activity. This increase could impair the neurogenesis process and it could result in the memory deficit found in Alzheimer patients.
20666600	The solution of a problem left unresolved in the evening can sometimes pop into mind as a sudden insight after a night of sleep in the following morning. Although favorable effects of sleep on insightful behavior have been experimentally confirmed, the neural mechanisms determining this delayed insight remain unknown. Here, using fMRI, we characterize the neural precursors of delayed insight in the number reduction task (NRT), in which a hidden task structure can be learned implicitly, but can also be recognized explicitly in an insightful process, allowing immediate qualitative improvement in task performance. Normal volunteers practiced the NRT during two fMRI sessions (training and retest), taking place 12 hours apart after a night of sleep. After this delay, half of the subjects gained insight into the hidden task structure ("solvers," S), whereas the other half did not ("nonsolvers," NS). Already at training, solvers and nonsolvers differed in their cerebral responses associated with implicit learning. In future solvers, responses were observed in the superior frontal sulcus, posterior parietal cortex, and the insula, three areas mediating controlled processes and supporting early learning and novice performance. In contrast, implicit learning was related to significant responses in the hippocampus in nonsolvers. Moreover, the hippocampus was functionally coupled with the basal ganglia in nonsolvers and with the superior frontal sulcus in solvers, thus potentially biasing participants' strategy towards implicit or controlled processes of memory encoding, respectively. Furthermore, in solvers but not in nonsolvers, response patterns were further transformed overnight, with enhanced responses in ventral medial prefrontal cortex, an area previously implicated in the consolidation of declarative memory. During retest in solvers, before they gain insight into the hidden rule, significant responses were observed in the same medial prefrontal area. After insight, a distributed set of parietal and frontal areas is recruited among which information concerning the hidden rule can be shared in a so-called global workspace.
20655508	The neuroplasticity hypothesis of depression proposes that a dysfunction of neural plasticity-the basic ability of living organisms to adapt their neural function and structure to external and internal cues-might represent a final common pathway underlying the biological and clinical characteristics of the disorder. This study examined learning and memory as correlates of long-term synaptic plasticity in humans to further test the neuroplasticity hypothesis of depression.Learning in three tasks, for which memory consolidation has been shown to depend on local synaptic refinement in areas of interest (hippocampus-dependent declarative word-pair learning, amygdala-dependent fear conditioning, and primary-cortex-dependent visual texture discrimination), was assessed in 23 inpatients who met International Classification of Disease, 10th Revision, criteria for severe unipolar depression and 35 nondepressed comparison subjects.	Depressed subjects showed a significant deficit in declarative memory consolidation and enhanced fear acquisition as indicated by skin conductance responses to conditioned stimuli, in comparison with nondepressed subjects. Depressed subjects demonstrated impaired visual discrimination at baseline, not allowing for valid group comparisons of gradual improvement, the plasticity-dependent phase of the task.	The results of the study are consistent with the neuroplasticity hypothesis of depression, showing decreased synaptic plasticity in a dorsal executive network that comprises the hippocampus and elevated synaptic plasticity in a ventral emotional network that includes the amygdala in depression. Evaluation of further techniques aimed at modulating synaptic plasticity might prove useful for developing novel treatments for major depressive disorder.	
20645078	Declarative memory deficits are common in untreated adults with attention-deficit hyperactivity disorder (ADHD), but limited evidence exists to support improvement after treatment with methylphenidate. The objective of this study was to examine the effects of methylphenidate on memory functioning of adults with ADHD.Eighteen adults with ADHD who were clinical responders to methylphenidate participated in this randomized crossover trial. After 3 days of no treatment, patients received in random order either their usual methylphenidate dose (mean: 14.7 mg; range: 10-30 mg) or placebo, separated by a 6-7-day washout period. Patients performed an immediate word recall test 1 h after treatment administration. Three hours after intake, patients performed the second part of the memory test (delayed word recall and a recognition test).	Delayed recognition and immediate recall was similar on treatment and on placebo. Delayed word recall was significantly better in the methylphenidate than in the placebo condition (F (1, 17) = 7.0, p <  0.017). A significant correlation was found between prestudy CES-D depression scores and difference scores on delayed recall (r = 0.602, p <  0.008).	Methylphenidate improves declarative memory functioning in patients with ADHD. New studies should further examine whether subclinical depressive symptoms mediate the effect of methylphenidate on declarative memory.	
20629484	Memory deficits are among the most frequently reported sequelae of mild traumatic brain injury (MTBI), especially early after injury. To date, these cognitive deficits remain poorly understood, as in most patients the brain is macroscopically intact. To identify the mechanism by which MTBI causes declarative memory impairments, we probed the functionality of the medial temporal lobe (MTL) and the prefrontal cortex (PFC), within 6 weeks after injury in 43 patients from a consecutive cohort, and matched healthy controls. In addition to neuropsychological measures of declarative memory and other cognitive domains, all subjects underwent functional magnetic resonance imaging (fMRI). Behavioral results showed poorer declarative memory performance in patients than controls, and decreasing performance with increasing duration of post-traumatic amnesia (a measure of injury severity). Task performance in the scanner was, as intended by the task and design, similar in patients and controls, and did not relate to injury severity. The task used reliably activated the MTL and PFC. Although we did not find significant differences in brain activity when comparing patients and controls, we revealed, in agreement with our neuropsychological findings, an inverse correlation between MTL activity and injury severity. In contrast, no difference in prefrontal activation was found between patients and controls, nor was there a relation with injury severity. On a behavioral level, injury severity was inversely related to declarative memory performance. In all, these findings suggest that reduced medial temporal functionality may contribute to poorer declarative memory performance in the post-acute stage of MTBI, especially in patients with longer post-traumatic amnesia.
20625093	Administration of cognitive test batteries by telephone has been shown to be a valid and cost-effective means of assessing cognition, but it remains relatively uncommon in epidemiological research.To develop composite cognitive measures and assess how much of the variability in their scores is associated with mode of test administration (ie, in person or by telephone).	Cross-sectional cohort study.	Late-Onset Alzheimer's Disease Family Study conducted at 18 centers across the United States.	A total of 1584 persons, 368 with dementia, from 646 families.	Scores on composite measures of memory and cognitive function derived from a battery of 7 performance tests administered in person (69%) or by telephone (31%) by examiners who underwent a structured performance-based training program with annual recertification.	Based in part on the results of a factor analysis of the 7 tests, we developed summary measures of working memory, declarative memory, episodic memory, semantic memory, and global cognition. In linear regression analyses, mode of test administration accounted for less than 2% of the variance in the measures. In mixed-effects models, variability in cognitive scores due to center was small relative to variability due to differences between individuals and families.	In epidemiologic research on aging and Alzheimer disease, assessment of cognition by telephone has little effect on performance and provides operational flexibility and a means of reducing both costs and missing data.	
20620156	Transient Epileptic Amnesia (TEA) is a form of temporal lobe epilepsy associated with ictal and interictal memory disturbance. Some patients with TEA exhibit Accelerated Long-term Forgetting (ALF), in which memory for verbal and non-verbal material is retained normally over short delays but fades at an unusually rapid rate over days to weeks. This study addresses three questions about ALF in TEA: (i) whether real-life events undergo ALF in a similar fashion to laboratory-based stimuli; (ii) whether ALF can be detected within 24h; (iii) whether procedural memories are susceptible to ALF. Eleven patients with TEA and eleven matched healthy controls wore a novel, automatic camera, SenseCam, while visiting a local attraction. Memory for images of events was assessed on the same day and after delays of one day, one week, and three weeks. Forgetting of real-life events was compared with forgetting of a word list and with performance on a procedural memory task. On the day of their excursion, patients and controls recalled similar numbers of primary events, associated secondary details (contiguous events, thoughts and sensory information) and items from the word list. In contrast, patients showed ALF for primary events over three weeks, with ALF for contiguous events, thoughts and words over the first day. Retention on the procedural memory task was normal over three weeks. The results indicate that accelerated forgetting in TEA: (i) affects memory for real-life events as well as laboratory stimuli; (ii) is maximal over the first day; and (iii) is specific to declarative memories.
20615932	Ecstasy/MDMA use has been associated with various memory deficits. This study assessed declarative and procedural memory in ecstasy/MDMA users. Participants were tested in two sessions, 24 h apart, so that the memory consolidation function of sleep on both types of memory could also be assessed. Groups were: drug-naive controls (n = 24); recent ecstasy/MDMA users, who had taken ecstasy/MDMA 2-3 days before the first testing session (n = 25), and abstinent users, who had not taken ecstasy/MDMA for at least 8 days before testing (n = 17). Procedural memory did not differ between groups, but greater lifetime consumption of ecstasy was associated with poorer procedural memory. Recent ecstasy/MDMA users who had taken other drugs (mainly cannabis) 48-24 h before testing exhibited poorer declarative memory than controls, but recent users who had not taken other drugs in this 48-24-h period did not differ from controls. Greater lifetime consumption of ecstasy, and of cocaine, were associated with greater deficits in declarative memory. These results suggest that procedural, as well as declarative, memory deficits are associated with the extent of past ecstasy use. However, ecstasy/MDMA did not affect the memory consolidation function of sleep for either the declarative or the procedural memory task.
20600352	Episodic memory refers to the ability to remember specific personal events from the past. Ever since Tulving first made the distinction between episodic memory and other forms of declarative memory in 1972, most cognitive psychologists and neuroscientists have assumed that episodic recall is unique to humans. The seminal paper on episodic-like memory in Western scrub-jays (Aphelocoma californica) by Clayton and Dickinson [4] has inspired a number of studies and in a wide range of species over the past 10 years. Here we shall first review the avian studies of what-where-when memory, namely in the Western scrub-jays, magpies, black-capped chickadees and pigeons; we shall then present an alternative approach to studying episodic-like memory also tested in pigeons. In the second and third section we want to draw attention to topics where we believe the bird model could prove highly valuable, namely studying development of episodic-memory in pre-verbal children, and the evolution and ontogeny of brain areas subserving episodic(-like) memory.
20600195	Previous research has suggested that different components of complex tool knowledge (e.g., attributes of a tool, how it is grasped, how it is used) may be mediated by different memory systems. For instance, while tool attributes may be represented in the declarative memory system, motor skill acquisition has been shown to be represented in the procedural memory system. Still other aspects of tool knowledge such as grasping for use and skilled tool use may rely on an integration of both declarative and procedural memory processes. However, the specific memory representations of different aspects of complex tool knowledge are still unclear. In the current study, D.A., an individual with amnesia, and a sample of matched controls were trained to use a set of novel complex tools. Subsequently, memory for different aspects of tool knowledge including motor skill acquisition, tool attributes, tool grasping, and skilled tool use was tested. Results showed that, in comparison to controls, D.A. was unimpaired in motor skill acquisition. In contrast, D.A. was severely impaired in recall of tool attributes, tool grasping, and skilled tool use, suggesting that these components of tool knowledge, at least in part, rely on declarative memory. Results also showed that providing contextual cues during tests of skilled tool use led to remarkable improvement in D.A.'s demonstration of tool use as well as his subsequent recall of tool functional knowledge. Implications of these findings and future directions are discussed.
20592579	Sleep is important for declarative memory consolidation in healthy adults. Sleep disruptions are typical in Alzheimer disease, but whether they contribute to memory impairment is unknown. Sleep has not been formally examined in amnestic mild cognitive impairment (aMCI), which is characterized by declarative-memory deficits without dementia and can signify prodromal Alzheimer disease. We studied 10 aMCI patients and 10 controls over 2 weeks using daily sleep surveys, wrist-worn activity sensors, and daily recognition tests. Recognition was impaired and more variable in aMCI patients, whereas sleep was similar across groups. However, lower recognition of items learned the previous day was associated with lower subjective sleep quality in aMCI patients. This correlation was not present for information learned the same day and thus did not reflect nonspecific effects of poor sleep on memory. These results indicate that inadequate memory consolidation in aMCI patients is related to declines in subjective sleep indices. Furthermore, participants with greater across-night sleep variability exhibited lower scores on a standardized recall test taken prior to the 2-week protocol, suggesting that consistent sleep across nights also contributes to successful memory. Physiological analyses are needed to further specify which aspects of sleep in neurological disorders impact memory function and consolidation. 
26271496	Sleep is a complex physiologic state, the importance of which has long been recognized. Lack of sleep is detrimental to humans and animals. Over the past decade, an important link between sleep and cognitive processing has been established. Sleep plays an important role in consolidation of different types of memory and contributes to insightful, inferential thinking. While the mechanism by which memories are processed in sleep remains unknown, several experimental models have been proposed. This article explores the link between sleep and cognition by reviewing (1) the effects of sleep deprivation on cognition, (2) the influence of sleep on consolidation of declarative and non-declarative memory, and (3) some proposed models of how sleep facilitates memory consolidation in sleep. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website. 
26271495	The idea that there are multiple memory systems can be traced to early philosophical considerations and introspection. However, the early experimental work considered memory a unitary phenomenon and focused on finding the mechanism upon which memory is based. A full reconciliation of debates about that mechanism, and a coincidental rediscovery of the idea of multiple memory systems, emerged from studies in the cognitive neuroscience of memory. This research has identified three major forms of memory that have distinct operating principles and are supported by different brain systems. These include: (1) a cortical-hippocampal circuit that mediates declarative memory, our capacity to recollect facts and events; (2) procedural memory subsystems involving a cortical-striatal circuit that mediates habit formation and a brainstem-cerebellar circuit that mediates sensorimotor adaptations; and (3) a circuit involving subcortical and cortical pathways through the amygdala that mediates the attachment of affective status and emotional responses to previously neutral stimuli. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website. 
20577636	The neocortex plays a critical role in the gradual formation and storage of remote declarative memories. Because the circuitry mechanisms of systems-level consolidation are not well understood, the precise cortical sites for memory storage and the nature of enduring memory correlates (mnemonic plasticity) are largely unknown. Detailed maps of neuronal activity underlying recent and remote memory recall highlight brain regions that participate in systems consolidation and constitute putative storage sites, and thus may facilitate detection of mnemonic plasticity. To localize cortical regions involved in the recall of a spatial memory task, we trained rats in a water-maze and then mapped mRNA expression patterns of a neuronal activity marker Arc/Arg3.1 (Arc) upon recall of recent (24 h after training) or remote (1 month after training) memories and compared them with swimming and naive controls. Arc gene expression was significantly more robust 24 h after training compared to 1 month after training. Arc expression diminished in the parietal, cingulate and visual areas, but select segments in the prefrontal, retrosplenial, somatosensory and motor cortical showed similar robust increases in the Arc expression. When Arc expression was compared across select segments of sensory, motor and associative regions within recent and remote memory groups, the overall magnitude and cortical laminar patterns of task-specific Arc expression were similar (stereotypical). Arc mRNA fractions expressed in the upper cortical layers (2/3, 4) increased after both recent and remote recall, while layer 6 fractions decreased only after the recent recall. The data suggest that robust recall of remote memory requires an overall smaller increase in neuronal activity within fewer cortical segments. This activity trend highlights the difficulty in detecting the storage sites and plasticity underlying remote memory. Application of the Arc maps may ameliorate this difficulty.
20568090	To determine whether the process involved in movement preparation of patients in the early stages of Parkinson's disease (PD) shares attentional resources with visual learning, we tested 23 patients with PD and 13 healthy controls with two different tasks. The first was a motor task where subjects were required to move as soon as possible to randomly presented targets by minimizing reaction time. The second was a visual learning task where targets were presented in a preset order and subjects were asked to learn the sequence order by attending to the display without moving. Patients with PD showed higher reaction and movement times, while visual learning was reduced compared with controls. For patients with PD, reaction times, but not movement times, displayed an inverse significant correlation with the scores of visual learning. We conclude that visual declarative learning and movement preparation might share similar attentional and working memory resources. (c) 2010 Movement Disorder Society.
20566303	According to a widespread opinion the vast majority of infant febrile seizures (IFS) are harmless. However, IFS are often associated with hippocampal sclerosis, which should lead to deficient episodic memory with spared context-free semantic memories. Although IFS represent the most common convulsive disorder in children, these consequences are rarely examined.We measured the hippocampal volume of 17 IFS children (7-9 years old) and an age-matched control group on the basis of MR images. Furthermore, we examined episodic and semantic memory performance with standardized neuropsychological tests. Two processes underlying recognition memory, namely familiarity and recollection, were assessed by means of event-related potentials (ERP).	The IFS children did not show a decreased hippocampus volume. Intelligence, working memory, semantic and episodic memory were intact. However, ERP indices of recognition memory subprocesses revealed deficits in recollection-based remembering that presumably relies on the integrity of the hippocampus, whereas familiarity-based remembering seemed to be intact.	Although hippocampus volume remains unaffected, IFS seems to induce functional changes in the MTL memory network, characterized by a compensation of recollection by familiarity-based remembering.	This study significantly adds to the debate on the consequences of IFS by differentiating the impact on memory processing.	
20559786	Cerebellar contribution to non-motor functions has been supported by several animal, human and functional neuroimaging studies. Which cognitive skills and to what extent the cerebrocerebellar loops contribute remain unclear, however. Among other reasons, this may be explained by the fact that authors have studied patients with extracerebellar lesions. The goal of this study was to explore the role of the cerebellum in cognition and affect in patients with autosomal recessive cerebellar ataxia type 1 (ARCA-1), a newly described inherited cerebellar disease characterised by middle-age onset of ataxia as well as pure, severe and diffuse cerebellar atrophy. To this end, the performance of 21 ARCA-1 patients was compared to that of 21 normal controls paired for age and education on a 3-h battery of attention, executive, visuospatial and memory skills. Results indicated similar IQ, naming and declarative memory abilities between groups. ARCA-1 patients showed significant deficits in attention (attention span, speed of information processing, sustained attention), verbal working memory and visuospatial/visuoconstructional skills (3-D drawings, copy of a complex figure). Functional brain imaging in a subset of patients showed diffuse severe cerebellar hypometabolism associated with a small area of right parietal hypometabolism. None of the patients presented a significant affective syndrome. Correlational analyses suggested that cognitive deficits could not be explained by the severity of motor deficits, duration of disease or mood. Altogether, this study confirms that pure cerebellar damage as seen in ARCA-1 is associated with significant cognitive impairments but not with psychiatric comorbidity. These deficits are correlated with an overall moderate impact on patient's autonomy. Our data favour an indirect participation of the dorsolateral prefrontal and posterior parietal cortical areas to the cerebrocerebellar circuit.
20559553	Sensorimotor cortex has a role in procedural learning. Previous studies suggested that this learning is subserved by long-term potentiation (LTP), which is in turn maintained by the persistently active kinase, protein kinase Mzeta (PKMzeta). Whereas the role of PKMzeta in animal models of declarative knowledge is established, its effect on procedural knowledge is not well understood. Here we show that PKMzeta inhibition, via injection of zeta inhibitory peptide (ZIP) into the rat sensorimotor cortex, disrupts sensorimotor memories for a skilled reaching task even after several weeks of training. The rate of relearning the task after the memory disruption by ZIP was indistinguishable from the rate of initial learning, suggesting no significant savings after the memory loss. These results indicate a shared molecular mechanism of storage for declarative and procedural forms of memory.
20552047	This brief review will focus on a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be "plastic". The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic "marks" drive aging-related cognitive dysfunction. Here we focus on this theme, reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging. Finally, several open questions will be discussed that we believe will fuel experimental discovery.
20541660	Life expectancies have increased substantially in the last century, dramatically amplifying the proportion of individuals who will reach old age. As individuals age, cognitive ability declines, although the rate of decline differs amongst the forms of memory domains and for different individuals. Memory domains especially impacted by aging are declarative and spatial memories. The hippocampus facilitates the formation of declarative and spatial memories. Notably, the hippocampus is particularly vulnerable to aging. Genetic predisposition and lifetime experiences and exposures contribute to the aging process, brain changes and subsequent cognitive outcomes. In this review, two factors to which an individual is exposed, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, will be considered regarding the impact of age on hippocampal-dependent function. Spatial memory can be affected by cumulative exposure to chronic stress via glucocorticoids, released from the HPA axis, and from gonadal steroids (estrogens, progesterone and androgens) and gonadotrophins, released from the HPG axis. Additionally, this review will discuss how these hormones impact age-related hippocampal function. We hypothesize that lifetime experiences and exposure to these hormones contribute to the cognitive makeup of the aged individual, and contribute to the heterogeneous aged population that includes individuals with cognitive abilities as astute as their younger counterparts, as well as individuals with severe cognitive decline or neurodegenerative disease.
20536334	While running a selection procedure, 27 male Belgian Special Forces candidates, with a mean age of 27.4 years (SD = 5.1), were randomly assigned to a no-stress control (n = 14) or a high-intensity stress group (n = 13). Participants in the latter group were exposed to an extremely strenuous mock prisoner of war (POW) exercise. Immediately after stress or control treatment, working memory and visuo-spatial declarative memory performances were measured by the digit span (DS) test and the Rey-Osterrieth complex figure (ROCF), respectively. Concurrently, stress levels were assessed by obtaining salivary cortisol measurements and subjectively by the NASA Task Load Index (TLX). As expected, exposure to high-intensity stress led to both robust cortisol increases and significant differences in TLX scores. Stress induction also significantly impaired DS and ROCF performances. Moreover, delta cortisol increases and ROCF performance in the POW stress group showed a significant negative correlation, while DS performances followed the same tendency. Summarizing, the current findings complement and extend previous work on hormonal stress effects, and the subsequent performance deterioration on two memory tests in a unique high-intensity stress environment.
20531422	Prominent models of human long-term memory distinguish between memory systems on the basis of whether learning and retrieval occur consciously or unconsciously. Episodic memory formation requires the rapid encoding of associations between different aspects of an event which, according to these models, depends on the hippocampus and on consciousness. However, recent evidence indicates that the hippocampus mediates rapid associative learning with and without consciousness in humans and animals, for long-term and short-term retention. Consciousness seems to be a poor criterion for differentiating between declarative (or explicit) and non declarative (or implicit) types of memory. A new model is therefore required in which memory systems are distinguished based on the processing operations involved rather than by consciousness.
20524222	To determine whether the cognitive impairments observed in adults with type 2 diabetes mellitus (T2DM) exist in preclinical disease, we compared 38 adult participants with evidence of insulin resistance (IR) to 54 age-, gender-, and education-matched control participants on a battery of neuropsychological tests. We found that participants with IR had performance reductions in declarative memory and executive functioning. When we examined IR simultaneously with other biomedical indicators with which it co-occurs, only IR itself was associated with declarative memory, and hemoglobin A1c (HbA1c) was associated with executive functioning and working memory. We conclude that individuals with insulin resistance already demonstrate similar reductions in cognitive performance as those described in T2DM.
20523971	Previous research has suggested that long-term verbal declarative memory is particularly sensitive to enhancement by glucose loading; however, investigation of glucose effects on certain memory domains has hitherto been neglected. Therefore, domain specificity of glucose effects merits further elucidation.The aim of the present research was to provide a more comprehensive investigation of the possible effects of glucose administration on different aspects of memory by 1) contrasting the effect of glucose administration on different memory domains (implicit/explicit memory; verbal/non-verbal memory, and recognition/familiarity processes), 2) investigating whether potential effects on memory domains differ depending on the dose of glucose administered (25 g versus 60 g), 3) exploring the duration of the glucose facilitation effect (assessment of memory performance 35 min and 1 week after encoding).	A double-blind between-subjects design was used to test the effects of administration of 25 and 60 g glucose on memory performance.	Implicit memory was improved following administration of 60 g of glucose. Glucose supplementation failed to improve face recognition performance but significantly improved performance of word recall and recognition following administration of 60 g of glucose. However, effects were not maintained 1 week following encoding.	Improved implicit memory performance following glucose administration has not been reported before. Furthermore, the current data tentatively suggest that level of processing may determine the required glucose dosage to demonstrate memory improvement and that higher dosages may be able to exert effects on memory pertaining to both hippocampal and non-hippocampal brain regions.	
20509828	Slow-wave sleep (SWS) has been shown to play an important role in the reinforcement of declarative memory. A dialogue between the neocortex and hippocampus is important during this consolidation and appears to be largely regulated by <1 Hz electroencephalographic (EEG) slow oscillations. Events experienced during wakefulness are encoded in the neocortex but, simultaneously they are encoded even more strongly in the hippocampus. Slow oscillations that characterize SWS originate in the neocortex and their amplitude increases with increased amounts of information encoded during prior waking. Neuronal activity is temporarily grouped by these slow oscillations into up-states of enhanced neuronal activity and down-states of neuronal silence. Grouping is not only induced in the neocortex but also in other relevant structures, such as the thalamus and the hippocampus, generating spindle activity and sharp-wave ripples, respectively. Sharp-wave ripples are known to accompany a memory replay of encoded information in the hippocampus during SWS which stimulates the transfer of this memory-related information to the neocortex. The slow oscillations synchronize this transfer with the thalamocortical spindles arriving at the neocortex at the same time as the hippocampal memory information. This synchronization is thought to be critical to the long-term storage of respective memories within neocortical networks.
20508750	To investigate the neural systems that contribute to the formation of complex, self-relevant emotional memories, dedicated fans of rival college basketball teams watched a competitive game while undergoing functional magnetic resonance imaging (fMRI). During a subsequent recognition memory task, participants were shown video clips depicting plays of the game, stemming either from previously-viewed game segments (targets) or from non-viewed portions of the same game (foils). After an old-new judgment, participants provided emotional valence and intensity ratings of the clips. A data driven approach was first used to decompose the fMRI signal acquired during free viewing of the game into spatially independent components. Correlations were then calculated between the identified components and post-scanning emotion ratings for successfully encoded targets. Two components were correlated with intensity ratings, including temporal lobe regions implicated in memory and emotional functions, such as the hippocampus and amygdala, as well as a midline fronto-cingulo-parietal network implicated in social cognition and self-relevant processing. These data were supported by a general linear model analysis, which revealed additional valence effects in fronto-striatal-insular regions when plays were divided into positive and negative events according to the fan's perspective. Overall, these findings contribute to our understanding of how emotional factors impact distributed neural systems to successfully encode dynamic, personally-relevant event sequences.
20501508	Autobiographical memories enable us to mentally reconstruct and relive past events, which is essential for one's personal identity. Unfortunately, this complex memory system is susceptible to age-related deterioration, possibly changing the way episodic information is being processed in older adults. The aim of this study was to investigate whether age influences the neural activity associated with content (episodic versus semantic) and remoteness (recent versus remote) of memories. Using functional magnetic resonance imaging in healthy older and young adults, we found significant age-dependent differences in the neural networks underlying memory content but not remoteness. Our data suggest an age-associated functional reorganization in the neural networks underlying long-term declarative memory. Relative increase in activity of posterior brain regions could reflect changes in visuospatial processing during episodic memory retrieval in older adults.
20470807	The goal of the present study was to demonstrate that declarative and non-declarative knowledge acquired in an incidental sequence learning task contributes differentially to memory retrieval and leads to dissociable ERP signatures in a recognition memory task. For this purpose, participants performed a sequence learning task and were classified as verbalizers, partial verbalizers, or nonverbalizers according to their ability to verbally report the systematic response sequence. Thereafter, ERPs were recorded in a recognition memory task time-locked to sequence triplets that were either part of the previously learned sequence or not. Although all three groups executed old sequence triplets faster than new triplets in the recognition memory task, qualitatively distinct ERP patterns were found for participants with and without reportable knowledge. Verbalizers and, to a lesser extent, partial verbalizers showed an ERP correlate of recollection for parts of the incidentally learned sequence. In contrast, nonverbalizers showed a different ERP effect with a reverse polarity that might reflect priming. This indicates that an ensemble of qualitatively different processes is at work when declarative and non-declarative sequence knowledge is retrieved. By this, our findings favor a multiple-systems view postulating that explicit and implicit learning are supported by different and functionally independent systems.
20466009	Research has firmly established that the integrity of the medial temporal lobe (MTL) is critical for recognition memory. This ability is supported by recollection, which involves recovery of contextual details of a past stimulus encounter, and familiarity assessment, which leads to awareness of prior occurrence without such recovery. Dual-process models of MTL organization posit that recollection and familiarity are supported by the hippocampus and perirhinal cortex, respectively. Alternatively, it has been argued that both structures support these recognition processes similarly as part of a more integrated declarative memory system; from this perspective, reported selective recollection impairments with circumscribed hippocampal lesions may reflect differential sensitivity to overall memory strength, rather than a deficit in a distinct recognition process. Findings from past neuropsychological research remain inconsistent and controversial, in part due to biases in patient selection, variability in clinical etiology, and limited lesion documentation. Here, we administered a verbal recognition-memory task in combination with remember-know judgements to 10 individuals who had undergone left- or right-sided stereotactic amygdalo-hippocampotomy as a surgical treatment for intractable temporal-lobe epilepsy. Comparisons with healthy control participants revealed isolated impairments in recollection with preserved familiarity, regardless of hemispheric site of lesion. In addition, we show that this impairment can be observed at a comparable level of memory strength (i.e., overall recognition performance) as the selective familiarity impairment we previously described in N.B.--an individual who underwent a tailored surgical resection of the left anterior temporal lobe with hippocampal sparing for treatment of temporal-lobe epilepsy. By revealing a double dissociation concerning temporal-lobe mechanisms for recollection and familiarity, this evidence argues against a unitary, strength-based account of MTL organization.
20465021	The aim of this study was to investigate the effects of obstructive sleep apnea (OSA) on procedural and declarative memory encoding in the evening prior to sleep, on memory consolidation during subsequent sleep, and on retrieval in the morning after sleep.Memory performance (procedural mirror-tracing task, declarative visual and verbal memory task) and general neuropsychological performance were assessed before and after one night of polysomnographic monitoring in 15 patients with moderate OSA and 20 age-, sex-, and IQ-matched healthy subjects.	Encoding levels prior to sleep were similar across groups for all tasks. Conventional analyses of averaged mirror tracing performance suggested a significantly reduced overnight improvement in OSA patients. Single trial analyses, however, revealed that this effect was due to significantly flattened learning curves in the evening and morning session in OSA patients. OSA patients showed a significantly lower verbal retention rate and a non-significantly reduced visual retention rate after sleep compared to healthy subjects. Polysomnography revealed a significantly reduced REM density, increased frequency of micro-arousals, elevated apnea-hypopnea index, and subjectively disturbed sleep quality in OSA patients compared to healthy subjects.	The results suggest that moderate OSA is associated with a significant impairment of procedural and verbal declarative memory. Future work is needed to further determine the contribution of structural or functional alterations in brain circuits relevant for memory, and to test whether OSA treatment improves or normalizes the observed deficits in learning.	
20452887	Several studies have shown persistent neurocognitive impairment in patients with a bipolar affective disorder (BD) even in euthymia as well as in patients with a schizoaffective disorder (SAD). The aim of our study was to compare the neuropsychological performance between these two groups. Confounding variables were controlled to enhance our understanding of cognitive dysfunction in both BD and SAD.Several domains of neurocognitive function, executive function, memory, attention, concentration and perceptuomotor function were examined in 28 euthymic SAD patients and 32 BD patients by using a neuropsychological test battery. The Hamilton Depression Rating Scale (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) were used to evaluate the patients' clinical status. Data analysis was performed by using a multivariate analysis of covariance (ANCOVA/MANCOVA).	Euthymic SAD patients showed greater cognitive impairment than euthymic BD patients in the tested domains including declarative memory and attention. Putative significant group differences concerning cognitive flexibility vanished when controlled for demographic and clinical variables. Age and medication were robust predictors to cognitive performance of both SAD and BD patients.	Our results point out the worse cognitive outcome of SAD compared to BD patients in remission. Remarkably, the variance is higher for some of the test results between the groups than within each group, this being discussed in light of the contradictive concept of SAD.	
20446168	Declarative memory is a long-term store for facts, concepts and words. Procedural memory subserves the learning and control of sensorimotor and cognitive skills, including the mental grammar. In this study, we report a single-case study of a mild aphasic patient who showed procedural deficits in the presence of preserved declarative memory abilities. We administered several experiments to explore rule application in morphology, syntax and number processing. Results partly support the differentiation between declarative and procedural memory. Moreover, the patient's performance varied according to the domain in which rules were to be applied, which underlines the need for more fine-grained distinctions in cognition between procedural rules.
20446142	The study's aim was to assess a broad range of declarative and nondeclarative memory functions in schizophrenia to identify areas of impairment versus relative preservation. Participants included 40 schizophrenia outpatients and 30 demographically comparable community residents. All participants were administered a battery assessing declarative memory (verbal learning, working memory, semantic memory, remote memory, verbal retention) and nondeclarative memory (procedural learning, priming). To control for order effects, the battery was divided into three parts of approximately equal length with order of administration counterbalanced across study participants. The results showed persons with schizophrenia to be significantly impaired relative to community residents in verbal learning, working memory, semantic memory, remote memory, and priming. In contrast, the two groups were comparable in verbal retention and procedural learning. In the schizophrenia group, priming ability best discriminated past year's vocational status. In sum, the findings indicate a specific pattern of impairment and preservation of memory functioning in schizophrenia. Skill (procedural) learning and retention of learned, declarative verbal information across a delay appear intact, while all other areas measured appear impaired.
20435102	We assessed major cognitive domains in symptom-free children of patients with schizophrenia compared to the healthy children of parents with no psychopathology using neurocognitive tests. We hypothesized that, offspring at high-risk for schizophrenia would have significant impairment in major domains: attention, memory, verbal-linguistic ability and executive functions. Thirty symptom-free children (17-males, 13-females; intelligence quotient=99.6+/-13.6; age=12.69+/-2.32 and education=5.8+/-2.3 years) having a parent diagnosed with schizophrenia and 37 healthy children matched for gender (19-males, 18-females), IQ (106.05+/-14.70), age (12.48+/-2.58) and years of education (6.0+/-2.5) were evaluated. The study group showed significant poor performance in cognitive domains, such as working memory (assessed with Auditory consonant trigram test), focused attention (Stroop test), attention speed (Trail making test), divided attention (Auditory consonant trigram test), executive functions (Wisconsin card sorting test), verbal fluency (Controlled word association test) and declarative memory (Rey verbal learning and Short-term memory test). However, no group differences were detected either on verbal attention (Digit span forward test) or sustained attention (TOVA, a continuous performance task); the latter as consistently reported to be a predictor of schizophrenia. In order to determine the cognitive endophenotype of schizophrenia, it seems more rational to conduct comprehensive evaluation of neurocognitive domains in well-matched groups via using sufficiently challenging tests to detect slight deficits. In addition, longitudinal studies with a larger sample size evaluating neurocognitive functions combined with genetic analysis may provide clues about explaining the genetic background of the disorder within the endophenocognitype concept and serve as new targets for early interventions.
20430044	Historically, the hippocampus has been viewed as a temporary memory structure. Consistent with the central premise of standard consolidation theory (SCT), a memory is initially hippocampus-dependent but, over time, it undergoes a consolidation process and eventually becoming represented in a distributed cortical network independent of the hippocampus. In this paper, we review evidence that is incompatible with each of the following essential features of SCT that are derived from its central premise: (1) Hippocampal damage reliably produces temporally graded retrograde amnesia, (2) all declarative explicit memories are equivalent with respect to consolidation, (3) consolidation entails a process of duplication in which a particular cortically based memory is identical to the hippocampus-dependent memory from which it derived, (4) consolidated memories are permanent and immutable. We propose an alternative hypothesis that assumes a transformation process and changes in the memory over time. Building on multiple trace theory (Nadel & Moscovitch, 1997), the transformation hypothesis contains three key elements that differentiate it from SCT: (1) An initially formed memory, which is assumed to be episodic and context-bound, remains dependent on the hippocampus for as long as it is available, (2) with time and experience, a hippocampal memory supports the development, in neocortex, of a less integrated, schematic version, which retains the gist of the original memory, but few of its contextual details, (3) there is a dynamic interplay between the two types of memory such that one or another may be dominant, depending on the circumstances at retrieval. Evidence is provided in support of the transformation hypothesis, which is advanced as a framework for unifying the seemingly disparate results of studies of anterograde and retrograde memory in the animal and human literatures.
20410144	Fragile X-associated tremor/ataxia syndrome, a neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the FMR1 gene, affects many carriers in late-life. Patients with fragile X-associated tremor/ataxia syndrome typically have cerebellar ataxia, intranuclear inclusions in neurons and astrocytes, as well as cognitive impairment. Dementia can also be present with cognitive deficits that are as severe as in Alzheimer's disease, however frontosubcortical type impairment is more pronounced in fragile X-associated tremor/ataxia syndrome. We sought to characterize the P600 and N400 word repetition effects in patients with fragile X-associated tremor/ataxia syndrome, using an event-related potential word repetition paradigm with demonstrated sensitivity to very early Alzheimer's disease. We hypothesized that the fragile X-associated tremor/ataxia syndrome-affected participants with poor declarative verbal memory would have pronounced abnormalities in the P600 repetition effect. In the event-related potential experiment, subjects performed a category decision task whilst an electroencephalogram was recorded. Auditory category statements were each followed by an associated visual target word (50% 'congruous' category exemplars, 50% 'incongruous' nouns). Two-thirds of the stimuli (category statement-target word pairs) were repeated, either at short-lag (approximately 10-40 s) or long-lag (approximately 100-140 s). The N400 and P600 amplitude data were submitted to split-plot analyses of variance. These analyses of variance showed a highly significant reduction of the N400 repetition effect (F = 22.5, P < 0.001), but not of the P600 repetition effect, in mild fragile X-associated tremor/ataxia syndrome (n = 32, mean age = 68.7, mean Mini-Mental State Examination score = 26.8). Patients with fragile X-associated tremor/ataxia syndrome had significantly smaller late positive amplitude (550-800 ms post-stimulus onset) to congruous words (P = 0.04 for group effect). Reduced P600 repetition effect amplitude was associated with poorer recall within fragile X-associated tremor/ataxia syndrome patients (r = 0.66) and across all subjects (r = 0.52). Larger P600 amplitude to new congruous words also correlated significantly with higher free recall scores (r = 0.37, P < 0.01) across all subjects. We found a correlation between the amplitude of late positivity and CGG repeat length in those with fragile X-associated tremor/ataxia syndrome (r = 0.47, P = 0.006). Higher levels of FMR1 mRNA were associated with smaller N400s to incongruous words and larger positive amplitudes (between 300 and 500 ms) to congruous words. In conclusion, event-related potential word repetition effects appear sensitive to the cognitive dysfunction present in patients with mild fragile X-associated tremor/ataxia syndrome. Their more severe reduction in N400 repetition effect, than P600, is in contrast to the reverse pattern reported in amnestic mild cognitive impairment and incipient Alzheimer's disease (Olichney et al., 2008).
20381628	In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid replication. Moreover, given the constructive nature of memories, the intact recollection of the fear association could eventually 'rebuild' the fear memory, resulting in the spontaneous recovery of the fear response. Yet, perseverance of the amnesic effects would have substantial clinical implications, as even the most effective treatments for psychiatric disorders display high percentages of relapse. Using a differential fear conditioning procedure in humans, we replicated our previous findings by showing that administering propranolol (40mg) prior to memory reactivation eliminated the startle fear response 24h later. But most importantly, this effect persisted at one month follow-up. Notably, the propranolol manipulation not only left the declarative memory for the acquired contingency untouched, but also skin conductance discrimination. In addition, a close association between declarative knowledge and skin conductance responses was found. These findings are in line with the supposed double dissociation of fear conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. They support the view that skin conductance conditioning primarily reflects contingency learning, whereas the startle response is a rather specific measure of fear. Furthermore, the results indicate the absence of a causal link between the actual knowledge of a fear association and its fear response, even though they often operate in parallel. Interventions targeting the amygdalar fear memory may be essential in specifically and persistently dampening the emotional impact of fear. From a clinical and ethical perspective, disrupting reconsolidation points to promising interventions persistently erasing fear responses from trauma memory without affecting the actual recollection.
20364888	Several studies have reported that stress impairs memory retrieval, even though findings are not unequivocal. Moreover, memory for socially relevant information was not previously investigated. The present study aimed to test the effects of stress on the retrieval of social memory (e.g., memory concerning names, birthdays, or biographies). In a randomized cross-over experiment, the cognitive performance of 29 subjects (15 women) was tested twice. Social memory was tested in a stress session, in which participants were exposed to a brief standardized psychosocial laboratory stressor between encoding and retrieval. Performance was compared with a stress-free control session. Stress exposure caused an increase in cortisol concentrations and changes in several mood measures. Social memory retrieval was reduced in the stress compared with the control session. An association between the cortisol stress response and poorer retrieval was significant in responders, that is, those participants displaying a cortisol rise after stress onset. Thus, similar to other forms of declarative memory, the retrieval of declarative memory for socially relevant information learned from biographical notes is impaired after acute stress exposure. This effect is linked to the stress-induced cortisol increase.
25163790	Learning in educational settings emphasizes declarative and procedural knowledge. Studies of expertise, however, point to other crucial components of learning, especially improvements produced by experience in the extraction of information: perceptual learning (PL). We suggest that such improvements characterize both simple sensory and complex cognitive, even symbolic, tasks through common processes of discovery and selection. We apply these ideas in the form of perceptual learning modules (PLMs) to mathematics learning. We tested three PLMs, each emphasizing different aspects of complex task performance, in middle and high school mathematics. In the MultiRep PLM, practice in matching function information across multiple representations improved students' abilities to generate correct graphs and equations from word problems. In the Algebraic Transformations PLM, practice in seeing equation structure across transformations (but not solving equations) led to dramatic improvements in the speed of equation solving. In the Linear Measurement PLM, interactive trials involving extraction of information about units and lengths produced successful transfer to novel measurement problems and fraction problem solving. Taken together, these results suggest (a) that PL techniques have the potential to address crucial, neglected dimensions of learning, including discovery and fluent processing of relations; (b) PL effects apply even to complex tasks that involve symbolic processing; and (c) appropriately designed PL technology can produce rapid and enduring advances in learning. 
20304078	Two experiments tested whether declarative and procedural memory systems operate independently or inhibit each other during perceptual categorization. Both experiments used a hybrid category-learning task in which perfect accuracy could be achieved if a declarative strategy is used on some trials and a procedural strategy is used on others. In the two experiments, only 2 of 53 participants learned a strategy of this type. In Experiment 1, most participants appeared to use simple explicit rules, even though control participants reliably learned the procedural component of the hybrid task. In Experiment 2, participants pre-trained either with the declarative or procedural component and then transferred to the hybrid categories. Despite this extra training, no participants in either group learned to categorize the hybrid stimuli with a strategy of the optimal type. These results are inconsistent with the most prominent single- and multiple-system accounts of category learning. They also cannot be explained by knowledge partitioning, or by the hypothesis that the failure to learn was due to high switch costs. Instead, these results support the hypothesis that declarative and procedural memory systems interact during category learning.
20303474	The N-methyl-D-aspartate receptor (NMDAR) is critical for learning-related synaptic plasticity in amygdala and hippocampus. As a consequence, there is considerable interest in drugs targeting this receptor to help enhance amygdala- and hippocampus-dependent learning. A promising candidate in this respect is the NMDAR glycine-binding site partial agonist D-cycloserine (DCS). Accumulating clinical evidence indicates the efficacy of DCS in the facilitation of amygdala-dependent fear extinction learning in patients with phobic, social anxiety, panic, and obsessive-compulsive disorder. An important unresolved question though is whether the use of DCS can also facilitate hippocampus-dependent declarative learning in healthy people as opposed to being restricted to the fear memory domain.In the present study, we investigated whether or not DCS can facilitate hippocampus-dependent declarative learning. We have therefore combined functional magnetic resonance imaging with two different declarative learning tasks and cytoarchitectonic probabilistic mapping of the hippocampus and its major subdivisions in 40 healthy volunteers administered either a 250 mg single oral dose of DCS or a placebo.	We found that DCS facilitates declarative learning as well as blood-oxygen level dependent activity levels in the probabilistically defined cornu ammonis region of the hippocampus. The absence of activity changes in visual control areas underscores the specific action of DCS in the hippocampal cornu ammonis region.	Our findings highlight NMDAR glycine-binding site partial agonism as a promising pharmacological mechanism for facilitating declarative learning in healthy people.	
20298641	We sought to elucidate the existence of neuropsychological subtypes in Complex Regional Pain Syndrome (CRPS). One hundred thirty seven patients with CRPS were administered tests that assess executive control, naming/lexical retrieval, and declarative memory. A 2-step cluster analysis that does not require any a priori specification regarding the number of clusters, classified patients into three groups. Group 1 obtained scores that were in the average range on all tests (n = 48; normal CRSP group). Group 2 (n = 58; dysexecutive CRSP group) presented with mild impairment or statistically low average test performance on working memory/verbal fluency tests. Group 3 (n = 31; global CRSP group) produced scores in the statistically low average/borderline range on all tests with particularly reduced scores on naming/declarative memory tests. Between-group analyses found that the CRPS group 1 obtained higher scores than CRPS groups 2 and 3 on all tests. However, groups 2 and 3 were equally impaired on executive tests. CRPS group 3 was impaired on tests of naming/memory tests compared to the other groups. Significant neuropsychological deficits are present in 65% of patients, with many patients presenting with elements of a dysexecutive syndrome and some patients presenting with global cognitive impairment.
20237266	Memory enhancement for emotional events is dependent on amygdala activation and noradrenergic modulation during learning. A potential role for noradrenaline (NE) during retrieval of emotional memory is less well understood. Here, we report that administration of the beta-adrenergic receptor antagonist propranolol at retrieval abolishes a declarative memory enhancement for emotional items. Critically, this effect persists at a subsequent 24 h memory test, in the absence of propranolol. Thus, these findings extend our current understanding of the role of NE in emotional memory to encompass effects at retrieval, and provide face validity to clinical interventions using beta-adrenergic antagonists in conjunction with reactivation of unwanted memories in anxiety-related disorders.
20230140	In the present study, we investigated which cognitive functions in older adults at Time A are predictive of conversion to dementia of the Alzheimer's type (DAT) at Time B. Forty-seven healthy individuals were initially tested in 1992-1994 on a trial-by-trial computerized Stroop task along with a battery of psychometric measures that tap general knowledge, declarative memory, visual-spatial processing, and processing speed. Twelve of these individuals subsequently developed DAT. The errors on the color incongruent trials (along with the difference between congruent and incongruent trials) and changes in the reaction time distributions were the strongest predictors of conversion to DAT, consistent with recent arguments regarding the sensitivity of these measures. Notably in the psychometric measures, there was little evidence of a difference in declarative memory between converters and nonconverters, but there was some evidence of changes in visual-spatial processing. Discussion focuses on the accumulating evidence suggesting a role of attentional control mechanisms as an early marker for the transition from healthy cognitive aging to DAT.
20229922	The Knowledge Map is considered an external representation of an individual's ideational (commonly called declarative or conceptual) knowledge stored in ideational (or propositional) memory. The Knowledge Map contains 4 graphic components: concepts, concept clusters, multicomponent links, and texts. The graphic components are mutually related by their inclusion and connectedness, and their analysis yields numerous visible and abstract unitary dimensions which have local, intermediate, and global values described by a 3-level framework and correspond to the elements of the ideational memory. That correspondence and the nature of these dimensions imply the Bigness of Change and Interminate Changes principles: all changes in the Knowledge Map and ideational memory are expansive, and in ideational memory they are expansive and never-ending.
20227327	An active debate in the learning and memory literature centers on the question of whether the perirhinal cortex, part of the medial temporal lobe (MTL), plays its major role in declarative/relational learning and memory or if it also makes an important contribution to high- level perception, similar to the functions of the adjacent visual area TE. Here I consider evidence from neuroanatomical and neurophysiological studies and argue that the perirhinal cortex has distinct and dissociable structure and function from area TE, making its major contribution to declarative/relational learning and memory. I propose additional neurophysiological studies that could help differentiate between these two debated roles of the perirhinal cortex: memory alone or memory plus high- level perception.
20224820	Regions in the medial temporal lobe (MTL) and prefrontal cortex (PFC) are involved in memory formation for scenes in both children and adults. The development in children and adolescents of successful memory encoding for scenes has been associated with increased activation in PFC, but not MTL, regions. However, evidence suggests that a functional subregion of the MTL that supports scene perception, located in the parahippocampal gyrus (PHG), goes through a prolonged maturation process. Here we tested the hypothesis that maturation of scene perception supports the development of memory for complex scenes. Scenes were characterized by their levels of complexity defined by the number of unique object categories depicted in the scene. Recognition memory improved with age, in participants ages 8-24, for high-, but not low-, complexity scenes. High-complexity compared to low-complexity scenes activated a network of regions including the posterior PHG. The difference in activations for high- versus low-complexity scenes increased with age in the right posterior PHG. Finally, activations in right posterior PHG were associated with age-related increases in successful memory formation for high-, but not low-, complexity scenes. These results suggest that functional maturation of the right posterior PHG plays a critical role in the development of enduring long-term recollection for high-complexity scenes.
20215998	Neuropsychological impairment represents a core characteristic of schizophrenia, but its underlying components have yet to be clearly established. Using a comprehensive battery of standardized measures of intelligence, declarative episodic memory, and executive function, we hypothesized that the variance in neuropsychological performance in schizophrenia may reflect at least 2 distinct sources related to failures of (a) the central executive division of working memory and (b) social comprehension. In comparison to age-matched controls, patients with schizophrenia showed not only overall reduced scores on Wechsler intelligence and memory scales and Wisconsin Card Sorting Test (WCST) of executive function, but they also demonstrated different patterns of performance for each of these tests. Hierarchical regression revealed executive attentional control, measured by Trails B performance speed, and social comprehension, measured by Wechsler IQ Comprehension and Picture Arrangement subtests, each accounted for a unique and specific proportion of variance in test scores for the patient group, even when controlling for general intelligence. Failures in social comprehension and executive attentional control may account for distinct sources of variance in the neuropsychological impairment of schizophrenia.
20211193	As we learn new information about the social and moral behaviors of other people, we form and update character judgments of them, and this can profoundly influence how we regard and act towards others. In the study reported here, we capitalized on two interesting neurological patient populations where this process of complex "moral updating" may go awry: patients with bilateral damage to ventromedial prefrontal cortex (vmPFC) and patients with bilateral damage to hippocampus (HC). We predicted that vmPFC patients, who have impaired emotion processing, would exhibit reduced moral updating, and we also investigated how moral updating might be affected by severe declarative memory impairment in HC patients. The vmPFC, HC, and brain-damaged comparison (BDC) participants made moral judgments about unfamiliar persons before and after exposure to social scenarios depicting the persons engaged in morally good, bad, or neutral behaviors. In line with our prediction, the vmPFC group showed the least amount of change in moral judgments, and interestingly, the HC group showed the most amount of change. These results suggest that the vmPFC and hippocampus play critical but complementary roles in updating moral character judgments about others: the vmPFC may attribute emotional salience to moral information, whereas the hippocampus may provide necessary contextual information from which to make appropriate character judgments.
20176120	Sleep facilitates declarative memory processing. However, we know little about whether sleep plays a role in the processing of a fundamental feature of declarative memory, relational memory - the flexible representation of items not directly learned prior to sleep. Thirty-one healthy participants first learned at 12 pm two sets of face-object photograph pairs (direct associative memory), in which the objects in each pair were common to both lists, but paired with two different faces. Participants either were given approximately 90 min to have a NREM-only daytime nap (n=14) or an equivalent waking period (n=17). At 4:30 pm, participants who napped demonstrated significantly better retention of direct associative memory, as well as better performance on a surprise task assessing their relational memory, in which participants had to associate the two faces previously paired with the same object during learning. Particularly noteworthy, relational memory performance was correlated with the amount of NREM sleep during the nap, with only slow-wave sleep predicting relational memory performance. Sleep stage data did not correlate with direct associative memory retention. These results suggest an active role for sleep in facilitating multiple processes that are not limited to the mere strengthening of rote memories, but also the binding of items that were not directly learned together, reorganizing them for flexible use at a later time.
20167376	The present three-wave longitudinal study analyzed the development of declarative memory in N=92 infants (12-, 18- and 24-month-olds) using a deferred imitation task. As expected, overall memory performance improved throughout the second year. Previous research is also replicated insofar as stability of inter-individual differences was low to moderate within this age range. In addition, cluster analyses identified two developmental groups showing different growth and different stability patterns. Multivariate analyses revealed specificities in language and self-development in these two developmental groups having different developmental trajectories.
20161995	THE STUDY OF SOCIOECONOMIC STATUS (SES) AND THE BRAIN FINDS ITSELF IN A CIRCUMSTANCE UNUSUAL FOR COGNITIVE NEUROSCIENCE: large numbers of questions with both practical and scientific importance exist, but they are currently under-researched and ripe for investigation. This review aims to highlight these questions, to outline their potential significance, and to suggest routes by which they might be approached. Although remarkably few neural studies have been carried out so far, there exists a large literature of previous behavioural work. This behavioural research provides an invaluable guide for future neuroimaging work, but also poses an important challenge for it: how can we ensure that the neural data contributes predictive or diagnostic power over and above what can be derived from behaviour alone? We discuss some of the open mechanistic questions which Cognitive Neuroscience may have the power to illuminate, spanning areas including language, numerical cognition, stress, memory, and social influences on learning. These questions have obvious practical and societal significance, but they also bear directly on a set of longstanding questions in basic science: what are the environmental and neural factors which affect the acquisition and retention of declarative and nondeclarative skills? Perhaps the best opportunity for practical and theoretical interests to converge is in the study of interventions. Many interventions aimed at improving the cognitive development of low SES children are currently underway, but almost all are operating without either input from, or study by, the Cognitive Neuroscience community. Given that longitudinal intervention studies are very hard to set up, but can, with proper designs, be ideal tests of causal mechanisms, this area promises exciting opportunities for future research.
20146605	Memory is constructive in nature so that it may sometimes lead to the retrieval of distorted or illusory information. Sleep facilitates accurate declarative memory consolidation but might also promote such memory distortions. We examined the influence of sleep and lack of sleep on the cerebral correlates of accurate and false recollections using fMRI. After encoding lists of semantically related word associates, half of the participants were allowed to sleep, whereas the others were totally sleep deprived on the first postencoding night. During a subsequent retest fMRI session taking place 3 days later, participants made recognition memory judgments about the previously studied associates, critical theme words (which had not been previously presented during encoding), and new words unrelated to the studied items. Sleep, relative to sleep deprivation, enhanced accurate and false recollections. No significant difference was observed in brain responses to false or illusory recollection between sleep and sleep deprivation conditions. However, after sleep but not after sleep deprivation (exclusive masking), accurate and illusory recollections were both associated with responses in the hippocampus and retrosplenial cortex. The data suggest that sleep does not selectively enhance illusory memories but rather tends to promote systems-level consolidation in hippocampo-neocortical circuits of memories subsequently associated with both accurate and illusory recollections. We further observed that during encoding, hippocampal responses were selectively larger for items subsequently accurately retrieved than for material leading to illusory memories. The data indicate that the early organization of memory during encoding is a major factor influencing subsequent production of accurate or false memories.
20144894	The medial temporal lobe includes a system of anatomically connected structures that are essential for declarative memory (conscious memory for facts and events). A prominent form of declarative memory is recognition memory (the ability to identify a recently encountered item as familiar). Recognition memory has been frequently assessed in humans and in the experimental animal. This article traces the successful development of an animal model of human medial temporal lobe amnesia, which eventually identified the structures in the medial temporal lobe important for memory. Attention is given to two prominent behavioral paradigms (delayed nonmatching to sample and tests of spontaneous novelty preference).
20138151	We combined a feedback-based learning task with a recognition memory paradigm to investigate how reward-based learning affects the event-related potential (ERP) correlates of recognition memory in younger and older adults. We found that positive, but not negative learning improves memory and results in an increased early ERP old-new effect, which is typically associated with familiarity-based memory. This indicates that reward-based learning supports a fast and relatively automatic memory retrieval process. Furthermore, we found age-related impairments in reward-based learning, whereas memory for the learned information was intact in the elderly, suggesting that declarative memory might be less affected by aging.
20133798	Long-term potentiation (LTP) phenomenon is widely accepted as a cellular model of memory consolidation. Object recognition (OR) is a particularly useful way of studying declarative memory in rodents because it makes use of their innate preference for novel over familiar objects. In this study, mice had electrodes implanted in the hippocampal Schaffer collaterals-pyramidal CA1 pathway and were trained for OR. Field EPSPs evoked at the CA3-CA1 synapse were recorded at the moment of training and at different times thereafter. LTP-like synaptic enhancement was found 6 h posttraining. A testing session was conducted 24 h after training, in the presence of one familiar and one novel object. Hippocampal synaptic facilitation was observed during exploration of familiar and novel objects. A short depotentiation period was observed early after the test and was followed by a later phase of synaptic efficacy enhancement. Here, we show that OR memory consolidation is accompanied by transient potentiation in the hippocampal CA3-CA1 synapses, while reconsolidation of this memory requires a short-lasting phase of depotentiation that could account for its well described vulnerability. The late synaptic enhancement phase, on the other hand, would be a consequence of memory restabilization.
20133017	Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Aβ) Aβ42/Aβ40, t-tau/Aβ42 and p-tau(231)/Aβ42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Aβ42/Aβ40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage.
20132832	Damage to structures in the human medial temporal lobe causes severe memory impairment. Animal object recognition tests gained prominence from attempts to model 'global' human medial temporal lobe amnesia, such as that observed in patient HM. These tasks, such as delayed nonmatching-to-sample and spontaneous object recognition, for assessing object memory in non-human primates and rodents have proved invaluable as animal models of specific aspects of human declarative memory processes. This paper reviews research in non-human primates and rats using object recognition memory tasks to assess the neurobiological bases of amnesia. A survey of this research reveals several important implications for our understanding of the anatomical basis of memory and the medial temporal lobe amnesic syndrome. First, research with monkeys and rats reveals that the contributions of medial temporal lobe structures such as the hippocampus and perirhinal cortex to memory processes are dissociable, with particular structures contributing to specific tasks on the basis of the specific type of information that a structure is optimized to process. Second, the literature suggests that cognitive tasks requiring integration of different types of information, such as in the case of complex, multimodal declarative memory, will recruit structures of the medial temporal lobe in an interactive manner. The heterogeneity of function within the medial temporal lobe, as well as the multimodal and complex nature of human declarative memory, implies that animal tests of object recognition memory, once believed to be comprehensive models for the study of human global amnesia, model just one important facet of human declarative memory. Finally, in light of the research reviewed here, it is apparent that the specific nature of amnesia observed in an individual with medial temporal lobe damage will depend on the particular medial temporal lobe regions affected and their specific representational capacities.
20127868	Acute psychosocial stress in humans triggers the release of glucocorticoids (GCs) and influences performance in declarative and working memory (WM) tasks. These memory systems rely on the hippocampus and prefrontal cortex (PFC), where GC-binding receptors are present. Previous studies revealed contradictory results regarding effects of acute stress on WM-related brain activity. We combined functional magnetic resonance imaging with a standardized psychosocial stress protocol to investigate the effects of acute mental stress on brain activity during encoding, maintenance, and retrieval of WM. Participants (41 healthy young men) underwent either a stress or a control procedure before performing a WM task. Stress increased salivary cortisol levels and tended to increase WM accuracy. Neurally, stress-induced increases in cortical activity were evident in PFC and posterior parietal cortex (PPC) during WM maintenance. Furthermore, hippocampal activity was modulated by stress during encoding and retrieval with increases in the right anterior hippocampus during WM encoding and decreases in the left posterior hippocampus during retrieval. Our study demonstrates that stress increases activity in PFC and PPC specifically during maintenance of items in WM, whereas effects on hippocampal activity are restricted to encoding and retrieval. The finding that psychosocial stress can increase and decrease activity in two different hippocampal areas may be relevant for understanding the often-reported phase-dependent opposing behavioral effects of stress on long-term memory.
20124116	Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes.To adjudicate neurocognitive endophenotypes for bipolar disorder.	All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status.	Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas.	Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia.	Neurocognitive test performance.	Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory.	This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.	
20117810	Patient H.M.'s recent death provides the opportunity to highlight the importance of his contribution to a better understanding of the anterograde amnesic syndrome. The thorough study of this patient over five decades largely contributed to shape the unitary model of declarative memory. This model holds that declarative memory is a single system that cannot be fractionated into subcomponents. As a system, it depends mainly on medial temporal lobes structures. The objective of this review is to present the main characteristics of different modular models that have been proposed as alternatives to the unitary model. It is also an opportunity to present different patients, who, although less famous than H.M., helped make signification contribution to the field of memory.The characteristics of the five main modular models are presented, including the most recent one (the perceptual-mnemonic model). The differences as well as how these models converge are highlighted.	Different possibilities that could help reconcile unitary and modular approaches are considered.	Although modular models differ significantly in many aspects, all converge to the notion that memory for single items and semantic memory could be dissociated from memory for complex material and context-rich episodes. In addition, these models converge concerning the involvement of critical brain structures for these stages: Item and semantic memory, as well as familiarity, are thought to largely depend on anterior subhippocampal areas, while relational, context-rich memory and recollective experiences are thought to largely depend on the hippocampal formation.	
20097662	vascular risk factors and diseases can negatively impact cognitive function. Determinants of blood flow are implicated in thrombogenesis and ischaemic events, yet little is known about their relationship with cognition.blood rheology data were collected in 1987/88, and cognitive testing was performed in 1998/99 when the mean (+ or - standard deviation) age of the study sample was 73.1 years (+ or - 5.0). Follow-up assessment was performed 4 years later. Information was collected on verbal declarative memory, non-verbal reasoning, verbal fluency, information processing speed and a general cognitive factor representing the variance common to the individual test scores.	after controlling for age, sex and cognitive performance in 1998/99, blood viscosity (BV) (P < 0.05) and fibrinogen (P < 0.05) predicted decline in non-verbal reasoning over 4 years. When estimated from pre-morbid level, decline in general cognition (P < 0.05), non-verbal reasoning (P < 0.05) and information processing speed (P < 0.01) was associated with BV levels. Haematocrit (HCT) had similar effects (P < 0.01 to P < 0.001). All associations persisted after control for multiple confounders. When examined together, HCT but not BV independently predicted cognitive decline.	blood rheology is independently related to cognitive decline in older people. The value of strategies aimed at preserving cognition through influencing blood rheology needs investigation.	
20093096	Memory for public events (PEs) was assessed as a marker of remote declarative memory in 36 patients with temporal lobe epilepsy (TLE) and compared with that of 19 patients with extra-TLE (ETLE), 17 patients with idiopathic generalized epilepsy (IGE), and 23 healthy volunteers. Verbal IQ, inventory-based evidence of depression, handedness, onset of illness, disease duration, and medication were obtained. Memory for PEs was reduced in all patient groups (TLE, P<0.0001; ETLE, P=0.009; IGE, P=0.008). The TLE group showed reduced memory for PEs compared with the other patients with epilepsy (P=0.001). A time gradient was observed, with worse memory for PEs of the 1990 s and for PEs that occurred after onset of illness. Our data support the key role of the temporal lobe in remote declarative memory. With patients with TLE remembering fewer PEs from the period after onset of epilepsy, the deficits can be partly attributed to unsuccessful consolidation rather than retrieval difficulties alone.
20091793	Declarative memory is remarkably adaptive in the way it maintains sensitivity to relative novelty in both unknown and highly familiar environments. However, the neural mechanisms underlying this contextual adaptation are poorly understood. On the basis of emerging links between novelty processing and reinforcement learning mechanisms, we hypothesized that responses to novelty will be adaptively scaled according to expected contextual probabilities of new and familiar events, in the same way that responses to prediction errors for rewards are scaled according to their expected range. Using functional magnetic resonance imaging in humans, we show that the influence of novelty and reward on memory formation in an incidental memory task is adaptively scaled and furthermore that the BOLD signal in orbital prefrontal and medial temporal cortices exhibits concomitant scaled adaptive coding. These findings demonstrate a new mechanism for adjusting gain and sensitivity in declarative memory in accordance with contextual probabilities and expectancies of future events.
20091339	We hypothesise that of the two processes underlying declarative memory, recollection is impaired in high-functioning autism (HFA) whereas recollection and familiarity are impaired in low-functioning autism (LFA). Testing these hypotheses necessitates assessing recollection and familiarity separately. However, this is difficult, because both processes contribute to performance on standard memory tests. Moreover, tests must be suitable for use with young or intellectually disabled participants. This study aimed to develop tests of recollection and familiarity separately, and to make preliminary tests of our hypotheses. We developed a temporal source memory task to assess recollection in LFA, and a shape recognition task to assess familiarity and an action recall task assessing recollection in HFA. The methods and implications of the results are discussed.
20089946	Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.
20079765	Research indicates that habitual short sleepers show more rapid accumulation of slow-wave sleep at the beginning of the night. Enhancement in performance on declarative memory tasks has been associated with early NonREM sleep, consisting of the highest percentage of slow-wave sleep. Twenty-four subjects (eight short sleepers <or=7h, nine average >7 but <9h, seven long >or=9h) were tested. Subjects were presented with unfamiliar face stimuli and asked to memorize them for a subsequent test. Following sleep, the subjects were presented with the 40 "old/studied" items intermixed with 40 new and asked to indicate the previously presented stimuli. Event-related potentials (ERPs) were analyzed to verify the existence of the "Old/New" effect, i.e. amplitude difference [in ERPs] between the old and new stimuli. ANOVA on the scores revealed a significant interaction between the stimuli and group. Post-hoc test on the studied items revealed more accurate responses in the short sleepers compared to the average and long sleepers. Strikingly, the long sleepers failed to show significant retention of the old/studied items, with their recognition of old faces not different from chance. Reaction time (RT) responses were faster for the old vs. the new items. Pearson correlation revealed a significant negative correlation between accuracy and sleep duration in the short sleepers. However, long and average sleepers showed a positive correlation between the two variables. ANOVA performed on the ERPs revealed main effects of stimuli and site, and no interactions involving the group factor. In conclusion, our data show that individual differences in recognition memory performance may be associated with differences in habitual sleep duration.
20071524	Memory consolidation is widely believed to benefit from sleep. Sleep-dependent memory consolidation has been established broadly in humans, appearing in declarative and procedural tasks. Animal studies have indicated a variety of mechanisms that could potentially serve as the neural basis of sleep-dependent consolidation, such as the offline replay of waking neural activity and the modulation of specific sleep parameters or synaptic strength during sleep. Memory consolidation, however, cannot be inferred from neuronal events alone, and the behavioral demonstration of sleep-dependent consolidation has been limited in animals. Here we investigated whether adult animals undergo sleep-dependent memory consolidation comparable to that of humans. European starlings (Sturnus vulgaris) were trained to discriminate between segments of novel starling song and retested after retention periods that included a regular night of sleep or consisted only of wakefulness. Auditory discrimination performance improved significantly after retention periods that included sleep but not after time spent awake, and the performance changes following sleep were significantly greater than after comparable periods of wakefulness. Thus, sleep produces a pattern of memory benefits in adult starlings that is fundamentally similar to the patterns of sleep-dependent consolidation observed in humans, suggesting a common sleep-dependent mechanism works across many vertebrate species to consolidate memories and establishing a robust animal model for this phenomenon.
20069588	To examine the frequency of Mild Cognitive Impairment (MCI) in African American older adults. The study also plans to explore the specific cognitive domains of impairment as well as whether there are differences in demographics, health, and cognitive performance between MCI and normal participants.Cross-sectional.	Independent-living sample of urban dwelling elders in Baltimore, Maryland.	The sample consisted of 554 subjects ranging in age from 50 to 95 (Mean = 68.79 +/- 9.60).	Socio-demographics and health were assessed. Several cognitive measures were administered to assess inductive reasoning, declarative memory, perceptual speed, working memory, executive functioning, language and global cognitive functioning.	Approximately 22% of participants were considered MCI (i.e. 18% non-amnestic vs. 4% amnestic). A majority of the non-amnestic MCI participants had impairment in one cognitive domain, particularly language and executive function. Individuals classified as non-amnestic MCI were significantly older and had more years of education than normal individuals. The MCI groups were not significantly different than cognitively normal individuals on health factors. Individuals classified as MCI performed significantly worse on global cognitive measures as well as across specific cognitive domains than cognitively normal individuals.	This study demonstrates that impairment in a non-memory domain may be an early indicator of cognitive impairment, particularly among African Americans.	
20063304	Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face-name paired associate task, which allows for the dissociation of encoding and recall-related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task-related brain regions during encoding. During recognition, bipolar patients under-activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo-activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition-related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over-engaged dorsolateral prefrontal regions when learning face-name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long-term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms.
20060911	Memory dysfunction is a prominent feature in schizophrenia. Impairments of declarative memory have been consistently linked to alterations especially within hippocampal-prefrontal regions. Due to the high heritability of schizophrenia, susceptibility genes and their modulatory impact on the neural correlates on memory are of major relevance. In the present study the influence of the COMT val(158)met status on the neural correlates of declarative memory was investigated in healthy subjects.From an initial behavioural sample of 522 healthy individuals (Sheldrick et al., 2008), 84 subjects underwent fMRI scanning while performing a memory encoding and a retrieval task. The COMT val(158)met status was determined for the whole sample and correlated with cortical activation within the group of n=84 individuals.	There were no effects of COMT status on behavioural performance. For declarative memory processing the number of met alleles predicted circumscribed bilateral insula and anterior hippocampus activations during memory encoding as well as less deactivations within the bilateral posterior parahippocampal gyri during memory retrieval.	Although declarative memory performance was unaffected, the neural correlates within hippocampal-prefrontal regions demonstrate a link between COMT val(158)met carrier status and brain areas associated with declarative memory processing. The study contributes to a better understanding of the role that susceptibility genes might play in the aetiology of schizophrenia.	
20054010	The relationship between age-related memory decline and hippocampal anatomic changes is a matter of debate.To investigate the relationship between age-related memory decline and MRI hippocampal anatomic changes in a cohort of healthy individuals.	In this cross-sectional study, 76 healthy individuals (44 male and 32 female), ranging in age from 20 to 80 years, were recruited from universities, community recreational centers, hospital personnel, and patients' relatives from 2005 to 2008. These individuals were submitted to a 3-T MRI protocol with a whole-brain T1-weighted and diffusion-weighted scanning and a neuropsychological assessment. For each subject, we calculated the volumes of the total brain (gray + white matter) and hippocampi. The segmented hippocampi defined the binary masks where mean values of mean diffusivity (MD) and fractional anisotropy (FA) were calculated. Neuropsychological evaluation included tests of verbal memory (15 minutes delayed recall of a 15-word list) and visuospatial memory (20 minutes delayed reproduction of Rey complex figure).	Hippocampal MD, but not hippocampal FA, hippocampal volume, or total brain volume, predicted performance of individuals beyond their 50s on tests of verbal and visuospatial memory.	High mean diffusivity values in the hippocampal formation of healthy elderly individuals predict memory decline, as reflected by performance on tests of declarative verbal and visual-spatial memory.	
20028356	Excessive alcohol use is associated with damage to the structure and function of the brain and impairment of cognition and behavior. Traditional test batteries used to assess cognitive performance in alcoholics are extensive and costly, limiting their use across various clinical and research settings. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a relatively new instrument that attempts to overcome some of these limitations. As yet the individual effect of moderate to heavy alcohol consumption on RBANS performance has not been examined. The primary aim of this study was to explore and quantify differences in performance between controls and drinkers on the RBANS and to examine the influence of age, gender, and alcohol use patterns on test performance.Data from a subset of "Using Our Brains" (UoB) donors (n = 28) still actively drinking and meeting criteria for moderate to heavy alcohol use (30 to 80 g of ethanol per day) (Harper, 1988) and 28 matched controls (age, education, and premorbid Intelligence Quotient) were compared.	Participants in the alcohol group performed below the healthy control group on the visuospatial and immediate memory index, and also on the RBANS total score p < 0.001 and showed a greater decline in RBANS scores from estimated cross-sectional premorbid levels. There was a positive association between alcohol ingestion in the preceding 12 months and the language index p < 0.03 and the semantic fluency subtest (p < 0.03). Age was negatively associated with story memory (p < 0.02), coding (p < 0.001), list recognition (p < 0.01), story recall (p < 0.03), and figure recall (p < 0.02).	Our results suggest that the RBANS is able to detect and characterize differences in verbal fluency, visuospatial skills, components of declarative memory, and psychomotor speed between healthy controls and moderate to heavy active alcohol users. Executive functions, commonly affected by alcoholism and not included in the RBANS, require assessment with additional measures.	
20020356	A model is described in which the hippocampal system functions as resource manager for the neocortex. This model is developed from an architectural concept for the brain as a whole within which the receptive fields of neocortical columns can gradually expand but with some limited exceptions tend not to contract. The definition process for receptive fields is constrained so that they overlap as little as possible, and change as little as possible, but at least a minimum number of columns detect their fields within every sensory input state. Below this minimum, the receptive fields of some columns are expanded slightly until the minimum level is reached. The columns in which this expansion occurs are selected by a competitive process in the hippocampal system that identifies those in which only a relatively small expansion is required, and sends signals to those columns that trigger the expansion. These expansions in receptive fields are the information record that forms the declarative memory of the input state. Episodic memory activates a set of columns in which receptive fields expanded simultaneously at some point in the past, and the hippocampal system is therefore the appropriate source for information guiding access to such memories. Semantic memory associates columns that are often active (with or without expansions in receptive fields) simultaneously. Initially, the hippocampus can guide access to such memories on the basis of initial information recording, but to avoid corruption of the information needed for ongoing resource management, access control shifts to other parts of the neocortex. The roles of the mammillary bodies, amygdala and anterior thalamic nucleus can be understood as modulating information recording in accordance with various behavioral priorities. During sleep, provisional physical connectivity is created that supports receptive field expansions in the subsequent wake period, but previously created memories are not affected. This model matches a wide range of neuropsychological observation better than alternative hippocampal models. The information mechanisms required by the model are consistent with known brain anatomy and neuron physiology.
20018180	Aging is accompanied by an impairment of associative memory. The medial temporal lobe and fronto-striatal network, both involved in associative memory, are known to decline functionally and structurally with age, leading to the so-called associative binding deficit and the resource deficit. Because the MTL and fronto-striatal network interact, they might also be able to support each other. We therefore employed an episodic memory task probing memory for sequences of object-location associations, where the demand on self-initiated processing was manipulated during encoding: either all the objects were visible simultaneously (rich environmental support) or every object became visible transiently (poor environmental support). Following the concept of resource deficit, we hypothesised that the elderly probably have difficulty using their declarative memory system when demands on self-initiated processing are high (poor environmental support). Our behavioural study showed that only the young use the rich environmental support in a systematic way, by placing the objects next to each other. With the task adapted for fMRI, we found that elderly showed stronger activity than young subjects during retrieval of environmentally richly encoded information in the basal ganglia, thalamus, left middle temporal/fusiform gyrus and right medial temporal lobe (MTL). These results indicate that rich environmental support leads to recruitment of the declarative memory system in addition to the fronto-striatal network in elderly, while the young use more posterior brain regions likely related to imagery. We propose that elderly try to solve the task by additional recruitment of stimulus-response associations, which might partly compensate their limited attentional resources.
20012932	Slow-wave sleep is defined as sleep stages 3 and 4 that characteristically show slow delta EEG activity during polysomnography. The percentage of slow-wave sleep normally declines with age. Sleep disorders are a common symptom of many psychiatric disorders. In polysomnographic recordings they mostly manifest as disturbances of sleep continuity. In some disorders changes in REM sleep are also found. A reduction of slow-wave sleep has most often been described in patients with depression and addictive disorders. More recent research implicates slow-wave sleep as an important factor in memory consolidation, especially the contents of declarative memory. Psychotropic drugs influence sleep in different ways. Hypnotic substances can reduce the deep sleep stages (e.g. benzodiazepines), whereas 5-HT2C antagonists increase the percentage of slow-wave sleep. Whether a selective impairment/alteration of slow-wave sleep is clinically relevant has not yet been proved.
20005600	The substantia innominata (SI) contains the nucleus basalis of Meynert, which provides the major cholinergic innervation to the entire cortical mantel and the amygdala; degeneration of nucleus basalis neurons correlates with cognitive decline in Alzheimer's disease (AD). However, whether SI atrophy occurs in individuals with amnestic mild cognitive impairment (aMCI) has not been examined thoroughly in vivo. In the present study, we developed a new protocol to measure volumetric changes in the SI from magnetic resonance imaging (MRI) scans. Participants consisted of 27 elderly controls with no cognitive impairment (NCI); 33 individuals with aMCI; and 19 patients with mild AD. SI volumes were traced on three consecutive gapless 1mm thick coronal slices. Results showed that SI volume was significantly reduced in the mild AD group compared to both NCI and aMCI participants; however, the NCI and aMCI groups did not differ from each other. Furthermore, a decrease in SI volume was related to impaired performance on declarative memory tasks even when attention was controlled.
20003499	To study the neurocognitive profile and its relationship to prefrontal dysfunction in non-demented Parkinson's disease (PD) with deficient haptic perception.Twelve right-handed patients with PD and 12 healthy control subjects underwent thorough neuropsychological testing including Rey complex figure, Rey auditory verbal and figural learning test, figural and verbal fluency, and Stroop test. Test scores reflecting significant differences between patients and healthy subjects were correlated with the individual expression coefficients of one principal component, obtained in a principal component analysis of an oxygen-15-labeled water PET study exploring somatosensory discrimination that differentiated between the two groups and involved prefrontal cortices.	We found significantly decreased total scores for the verbal learning trials and verbal delayed free recall in PD patients compared with normal volunteers. Further analysis of these parameters using Spearman's ranking correlation showed a significantly negative correlation of deficient verbal recall with expression coefficients of the principal component whose image showed a subcortical-cortical network, including right dorsolateral-prefrontal cortex, in PD patients.	PD patients with disrupted right dorsolateral prefrontal cortex function and associated diminished somatosensory discrimination are impaired also in verbal memory functions. A negative correlation between delayed verbal free recall and PET activation in a network including the prefrontal cortices suggests that verbal cues and accordingly declarative memory processes may be operative in PD during activities that demand sustained attention such as somatosensory discrimination. Verbal cues may be compensatory in nature and help to non-specifically enhance focused attention in the presence of a functionally disrupted prefrontal cortex.	
19995868	Youth who experience interpersonal trauma and have posttraumatic stress symptoms (PTSS) develop cognitive deficits that impact their development. Our goal is to investigate the function of the hippocampus in adolescents with PTSS during a memory processing task.Twenty-seven adolescents between the ages of 10-17 years (16 with PTSS and 11 healthy controls) encoded and retrieved visually presented nouns (Verbal Declarative Memory Task) while undergoing fMRI scanning.	The PTSS group demonstrated reduced activation of the right hippocampus during the retrieval component of the task. Further, severity of symptoms of avoidance and numbing correlated with reduced left hippocampal activation during retrieval.	Decreased activity of the hippocampus during a verbal memory task may be a neurofunctional marker of PTSS in youth with history of interpersonal trauma. The results of this study may facilitate the development of focused treatments and may be of utility when assessing treatment outcome for PTSS.	
19944302	Nocturnal sleep is characterized by a unique pattern of endocrine activity, which comprises reciprocal influences on the hypothalamo-pituitary-adrenal (HPA) and the somatotropic system. During early sleep, when slow wave sleep (SWS) prevails, HPA secretory activity is suppressed whereas growth hormone (GH) release reaches a maximum; this pattern is reversed during late sleep when rapid eye movement (REM) sleep predominates. SWS benefits the consolidation of hippocampus-dependent declarative memories, whereas REM sleep improves amygdala-dependent emotional memories and procedural skill memories involving striato-cortical circuitry. Manipulation of plasma cortisol and GH concentration during sleep revealed a primary role of HPA activity for memory consolidation. Pituitary-adrenal inhibition during SWS sleep represents a prerequisite for efficient consolidation of declarative memory; increased cortisol during late REM sleep seems to protect from an overshooting consolidation of emotional memories.
19940520	Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9 beta A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex x genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9 beta G allele displayed faster reaction times than the other genotype groups, 9 beta G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders.
19925184	There has been considerable debate surrounding the functions of the medial temporal lobe (MTL). Although this region has been traditionally thought to subserve long-term declarative memory only, recent evidence suggests a role in short-term working memory and even higher order perception. To investigate this issue, functional neuroimaging was used to investigate the involvement of the MTL in spatial scene perception and working memory. Healthy participants were scanned during a working memory task incorporating two factors of working memory (high vs. low demand) and spatial processing (complex vs. simple). It was found that an increase in spatial processing demand produced significantly greater activity in the posterior hippocampus and parahippocampal cortex irrespective of whether working memory demand was high or low. In contrast, there was no region within the MTL that increased significantly in activity during both the complex and the simple spatial processing conditions when working memory demand was increased. There was, however, a significant interaction effect between spatial processing and working memory in the right posterior hippocampus and parahippocampal cortex bilaterally: An increase in working memory demand produced a significant increase in activity in these areas during the complex, but not simple, spatial processing conditions. These findings suggest that although there may be a role for the MTL in both stimulus processing and working memory, increasing the latter does not necessarily increase posterior MTL involvement. We suggest that these structures may play a critical role in processing complex spatial representations, which, in turn, may form the basis of short- and long-term mnemonic processes.
19923508	General anesthesia produces multiple end points including immobility, hypnosis, sedation, and amnesia. Tonic inhibition via gamma-aminobutyric acid type A receptors (GABA(A)-Rs) may play a role in mediating behavioral end points that are suppressed by low concentrations of anesthetics (e.g., hypnosis and amnesia). GABA(A)-Rs containing the alpha4 subunit are highly concentrated in the hippocampus and thalamus, and when combined with delta subunits they mediate tonic inhibition, which is sensitive to low concentrations of isoflurane.In this study, we used a GABA(A) alpha4 receptor knockout mouse line to evaluate the contribution of alpha4-containing GABA(A)-Rs to the effects of immobility, hypnosis, and amnesia produced by isoflurane. Knockout mice and their wild-type counterparts were assessed on 3 behavioral tests: conditional fear (to assess amnesia), loss of righting reflex (to assess hypnosis), and the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation in 50% of subjects (to assess immobility).	Genetic inactivation of the alpha4 subunit reduced the amnestic effect of isoflurane, minimally affected loss of righting reflex, and had no effect on immobility.	These results lend support to the hypothesis that different sites of action mediate different anesthetic end points and suggest that alpha4-containing GABA(A)-Rs are important mediators of the amnestic effect of isoflurane on hippocampal-dependent declarative memory.	
19913043	Episodic memory, the recollection of past events in one's life, has often been considered a memory specific to humans. Recent work in a variety of species has challenged this view, and has raised important questions about the nature of episodic memory itself. We present a review of the types of task proposed as episodic-like in animals and consider that these tasks require animals to demonstrate memory for specific occasions in the past. We propose that identifying episodic memory as the memory for what happened where on a specific occasion is a more encompassing definition than one that relies on information about when an event occurred. These episodic-like tasks in animals support the view that the hippocampal system is necessary for episodic memory, and that the neural substrates of episodic memory can be dissociated from those of other forms of declarative memory.
19906514	Declarative memory impairment is frequently reported among adults with type 2 diabetes mellitus (T2DM), who also demonstrate hippocampal volume reduction. Our goals were to ascertain whether emotional memory, which is mediated by neural circuits overlapping those of declarative memory, is also affected. In addition we wanted to characterize cerebral white matter (WM) involvement in T2DM. We studied 24 middle-aged and elderly patients with T2DM who were free of obvious vascular pathology or a psychiatric disorder, and 17 age- and education-matched healthy individuals with no evidence of insulin resistance. We examined emotional and neutral memory and performed a whole-brain voxelwise WM assessment utilizing diffusion tensor imaging (DTI). We found clear evidence of impairment in declarative memory among diabetic subjects and in addition found some preliminary support to suggest a possible blunting of the memory facilitation by emotional material among female but not male diabetics. This report is also the first DTI assessment among individuals with T2DM, which after accounting for overt WM damage, revealed diffuse but predominantly frontal and temporal WM microstructural abnormalities, with extensive involvement of the temporal stem. Hierarchical regression analyses demonstrated that immediate, but not delayed, emotional memory performance was explained by temporal stem FA, independent of age, poor metabolic regulation, and systolic blood pressure. Given that the temporal lobe memory networks appear to be particularly vulnerable to the deleterious effects of T2DM, this may help explain the observed memory impairments among diabetics. Future efforts should better clarify, with a larger sample, whether emotional memory is affected in adults with T2DM and whether there are clear gender effects.
19906231	Corticosteroids, such as prednisone and dexamethasone, are commonly prescribed medications that suppress the immune system and decrease inflammation. Common side effects of long-term treatment with corticosteroids include weight gain, osteoporosis, and diabetes mellitus. This paper reviews the literature on psychiatric and cognitive changes during corticosteroid therapy and potential treatment options. Hypomania and mania are the most common mood changes during acute corticosteroid therapy, although depression has also been reported. However, depression is reported to be more common than mania during long-term treatment with corticosteroids. A decline in declarative and working memory is also reported during corticosteroid therapy. Corticosteroids are associated with changes in the temporal lobe, detected by structural, functional, and spectroscopic imaging. The mood and cognitive symptoms are dose dependent and frequently occur during the first few weeks of therapy. Other risk factors are not well characterized. Controlled trials suggest that lithium and phenytoin can prevent mood symptoms associated with corticosteroids. Lamotrigine and memantine also have been shown to reverse, at least partially, the declarative memory effects of corticosteroids. Uncontrolled trials suggest that antipsychotics, anti-seizure medications, and perhaps some antidepressants can also be useful for normalizing mood changes associated with corticosteroids. Thus, both the symptoms and treatment response are similar to those of bipolar disorder. Moreover, corticosteroid-induced mood and cognitive alterations have been shown to be reversible with dose reduction or discontinuation of treatment.
19900077	Much evidence has accumulated to indicate memory deficits in children with specific language impairment. However, most research has focused on working memory impairments in these children. Less is known about the functioning of other memory systems in this population.This study examined procedural and declarative memory in young children with and without specific language impairment.	A total of 15 children with specific language impairment and 15 non-impaired children of comparable age, gender and handedness were presented with measures of procedural and declarative memory. Procedural memory was assessed using a Serial Reaction Time (SRT) Task in which children implicitly learnt a ten-item sequence pattern. Declarative memory for verbal and visual information was assessed using paired associative learning tasks.	The results from the SRT Task showed the children with specific language impairment did not learn the sequence at levels comparable with the non-impaired children. On the measures of declarative memory, differences between the groups were observed on the verbal but not the visual task. The differences on the verbal declarative memory task were found after statistically controlling for differences in vocabulary and phonological short-term memory.	The results were interpreted to suggest an uneven profile of memory functioning in specific language impairment. On measures of declarative memory, specific language impairment appears to be associated with difficulties learning verbal information. At the same time, procedural memory is also appears to be impaired. Collectively, this study indicates multiple memory impairments in specific language impairment.	
19887015	A group of 94 nondemented patients self-referred to an outpatient memory clinic for memory difficulties were studied to determine the incidence of single versus multi-domain mild cognitive impairment (MCI) using Petersen criteria. Fifty-five community dwelling normal controls (NC) participants without memory complaints also were recruited. Tests assessing executive control, naming/lexical retrieval, and declarative memory were administered. Thirty-four patients exhibited single-domain MCI, 43 patients presented with multi-domain MCI. When the entire MCI sample (n = 77) was subjected to a cluster analysis, 14 patients were classified with amnesic MCI, 21 patients with dysexecutive MCI, and 42 patients were classified into a mixed/multi-domain MCI group involving low scores on tests of letter fluency, "animal" fluency, and delayed recognition discriminability. Analyses comparing the three cluster-derived MCI groups versus a NC group confirmed the presence of memory and dysexecutive impairment for the amnesic and dysexecutive MCI groups. The mixed MCI group produced lower scores on tests of letter fluency compared with the amnesic MCI and NC groups and lower scores on tests of naming and memory compared with the NC group. In summary, multi-domain MCI is quite common. These data suggest that MCI is a highly nuanced and complex clinical entity.
19884499	Numerous studies have shown that sleep enhances memory for motor skills learned through practice. Motor skills can, however, also be learned through observation, a process possibly involving the mirror neuron system. We investigated whether motor skill enhancement through prior observation requires sleep to follow the observation, either immediately or after a delay, to consolidate the procedural memory. Sequence-specific fingertapping performance was tested in 64 healthy subjects in a balanced design. Electromyography verified absence of overt or subliminal hand muscle activations during observation. The results show that immediate sleep is necessary for the enhancement of a motor skill through prior observation. Immediate sleep improved the speed of subsequent performance by 22 +/- 11% (mean +/- SEM) (P = 0.04) and reduced the error rate by 42 +/- 19% (P = 0.02). In contrast, no performance gains occurred if sleep was initiated more than 12 h after observation. A second study on 64 subjects ruled out explicit familiarity with the sequence or the spatiotemporal rhythm of the sequence to underlie performance improvements. The sleep-dependent observational motor learning enhancement is at least similar to that previously reported for implicit and declarative memory. The apparent prerequisite of observing real movements indicates that subjects transfer experience obtained through observation of movements to subsequent self-initiated movements, in the absence of practice. Moreover, the consolidation of this transfer requires an early sleep window. These findings could improve learning new motor skills in athletes and children, but also in patients having to remaster skills following stroke or injury.
19864436	Recent studies have reported the presence of single neurons with strong responses to visual inputs in the human medial temporal lobe. Here we show how repeated stimulus presentation--photos of celebrities and familiar individuals, landmark buildings, animals, and objects--modulates the firing rate of these cells: a consistent decrease in the neural activity was registered as images were repeatedly shown during experimental sessions. The effect of repeated stimulus presentation was not the same for all medial temporal lobe areas. These findings are consistent with the view that medial temporal lobe neurons link visual percepts to declarative memory.
19857025	World knowledge influences how we perceive the world. This study shows that this influence is at least partly mediated by declarative memory. Dutch and German participants categorized hues from a yellow-to-orange continuum on stimuli that were prototypically orange or yellow and that were also associated with these color labels. Both groups gave more "yellow" responses if an ambiguous hue occurred on a prototypically yellow stimulus. The language groups were also tested on a stimulus (traffic light) that is associated with the label orange in Dutch and with the label yellow in German, even though the objective color is the same for both populations. Dutch observers categorized this stimulus as orange more often than German observers, in line with the assumption that declarative knowledge mediates the influence of world knowledge on color categorization.
19850082	In recent years there has been significant debate about whether there is a single medial temporal lobe memory system or dissociable systems for episodic and other types of declarative memory. In addition there has been a similar debate over the dissociability of recollection and familiarity based processes in recognition memory. Here we present evidence from recent work using episodic memory tasks in animals that allows us to explore these issues in more depth. We review studies that demonstrate triple dissociations within the medial temporal lobe, with only the hippocampal system being necessary for episodic memory. Similarly we review behavioural evidence for a dissociation in a task of episodic memory in rats where animals with lesions of the fornix are only impaired at recollection of the episodic memory, not recognition within the same trial. This work, then, supports recent models of dissociable neural systems within the medial temporal lobe but also raises questions for future investigation about the interactions of these medial temporal lobe memory systems with other structures.
19847313	We all have memories that we prefer not to think about. The ability to suppress retrieval of unwanted memories has been documented in behavioral and neuroimaging research using the Think/No-Think (TNT) paradigm with adults. Attempts to stop memory retrieval are associated with increased activation of lateral prefrontal cortex (PFC) and concomitant reduced activation in medial temporal lobe (MTL) structures. However, the extent to which children have the ability to actively suppress their memories is unknown. This study investigated memory suppression in middle childhood using the TNT paradigm. Forty children aged 8-12 and 30 young adults were instructed either to remember (Think) or suppress (No-Think) the memory of the second word of previously studied word-pairs, when presented with the first member as a reminder. They then performed two different cued recall tasks, testing their memory for the second word in each pair after the TNT phase using the same first studied word within the pair as a cue (intra-list cue) and also an independent cue (extra-list cue). Children exhibited age-related improvements in memory suppression from age 8 to 12 in both memory tests, against a backdrop of overall improvements in declarative memory over this age range. These findings suggest that memory suppression is an active process that develops during late childhood, likely due to an age-related refinement in the ability to engage PFC to down-regulate activity in areas involved in episodic retrieval.
19847045	In the present study, changes in the parahippocampal white matter (PWM), in the region that includes the perforant path, were investigated, in vivo, in 14 individuals with amnestic mild cognitive impairment (aMCI) compared to 14 elderly controls with no cognitive impairment (NCI). For this purpose, (1) volumetry; (2) diffusion tensor imaging (DTI) derived measures of mean diffusivity (MD) and fractional anisotropy (FA); and (3) tractography were used. In addition, regression models were utilized to examine the association of PWM measurements with memory decline. The results from this study confirm previous findings in our laboratory and others, showing that compared to controls, individuals with aMCI have PWM volume loss. In addition to volume reduction, participants with aMCI demonstrated a significant increase in MD, but no difference in FA, both in the PWM region and in fibers modeled to pass through the PWM region. Further, the DTI metric of MD was associated with declarative memory performance, suggesting it may be a sensitive marker for memory dysfunction. These results indicate that there is general tissue loss and degradation (decreased volume; increased MD) in individuals with aMCI compared to older people with normal cognitive function. However, the microstructural organization of remaining fibers, as determined by measures of anisotropic diffusion, is not significantly different from that of controls.
19843664	To determine the neurofunctional basis of verbal memory dysfunction in women with metastatic breast cancer. This objective was based on previous research suggesting memory and other cognitive deficits in this population. We attempted to determine if verbal memory impairments were related to the most commonly studied disease parameters including adjuvant chemotherapy and chronic stress-related disruption of limbic system structures.We used functional magnetic resonance imaging to test our hypothesis that women with breast cancer would show significantly lower brain activation during verbal declarative memory tasks compared with age and education-matched healthy female controls. We also assessed several stress-related variables including diurnal cortisol levels to test our hypothesis that women with breast cancer would show higher stress and this would contribute to brain activation deficits during memory tasks.	Women with breast cancer had significantly lower prefrontal cortex activation during the memory encoding condition compared with controls. However, the breast cancer group showed significantly greater activation than controls during the recall condition in multiple, diffuse brain regions. There were no significant differences between the groups in stress-related variables. Women who were treated with cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy showed lower prefrontal cortex activation during memory encoding.	These results suggest that women with metastatic breast cancer may be at risk for verbal memory impairments as a result of altered functional brain activation profiles. These findings may be associated with chemotherapy type and/or other aspects of the breast cancer disease process.	
19817236	The stress effects induced by diverse military scenarios are usually studied under tightly controlled conditions, while only limited research has addressed realistic scenarios. This study was designed to compare the effects of two levels of realism in stressful training for escape from a sunken submarine.Thirteen qualified submariners served as subjects. All had previously participated in underwater escape training using a simulated submarine in a land-based tank submerged at a depth of 6 m; for this study, they repeated the simulator escape, following which six of them executed escape from an actual submarine lying at a depth of 30 m on the sea floor. The men were studied before the exercises, immediately after surfacing, and 2 h later. Measured variables included sympathovagal balance, salivary cortisol, perceived mood, and sleep, as well as short-term and declarative memory.	Compared to the simulator exercise in the tank, the escape at sea showed the following significant differences: 1) higher salivary cortisol values (6.33 +/- 3.9 nmol x L(-1) on shore and 13.38 +/- 7.5 nmol x L(-1) at sea); 2) greater adverse changes in mood, including vigor, tension, and ability to fall asleep; and 3) impairment in declarative memory. Responses were found to differ further for the five submariners who had prior experience of accident or injury while at sea.	The psychophysiological and cognitive effects of military exercises may be influenced by the realism of conditions and by prior exposure to life-threatening situations.	
19816844	This research aims at neurocognitive delineation of the core features of procedural learning disorder (PLD), otherwise labeled as motor coordination disorder or non-verbal learning disorder.A sample of 209 correlative outpatients (73% males), aged 6-12 years, all of them having QI ranging from 81 to 120, was clustered into the following neurobehavioural groups: PLD (n = 16), PLD plus attention deficit hyperactivity disorder (ADHD) (n = 37), ADHD combined type (n = 47), ADHD predominantly inattentive type (n = 23), specific language impairment (n = 68), and semantic-pragmatic language impairment (n = 18). Two additional groups of patients were included for some comparisons: children with periventricular leukomalacia (PVL) without learning disability (n = 8) or associating PLD (n = 17). A set of behavioural scales and neurocognitive tests was used to evaluate verbal and non-verbal IQ, attention, impulsivity control, visuo-motor coordination, declarative memory, procedural memory and learning, formal and functional dimensions of language, peer relationships and academic achievement. Parametric analysis were used to test the differences and similarities of neurobehavioural variables between groups.	Our results allow us to conclude that PLD implies a difficult acquisition of automatized motor, cognitive and communicative abilities required in school work and peer social relationships. PLD is different from autistic spectrum disorders. It is frequently associated to inattentive ADHD. Operational criteria for diagnosis of PLD are proposed, according to our results. A bilateral posterior parietal dysfunction is a plausible explanation of its physiopathology. Preserved general intelligence and formal linguistic abilities are the clues for intervention designs.	
19801276	In humans, prenatal alcohol exposure can result in significant impairments in several types of learning and memory, including declarative and spatial memory. Animal models have been useful for confirming that many of the observed effects are the result of alcohol exposure, and not secondary to poor maternal nutrition or adverse home environments. Wagner and Hunt (2006) reported that rats exposed to ethanol during the neonatal period (postnatal days [PDs] 4-9) exhibited impaired trace fear conditioning when trained as adolescents, but were unaffected in delay fear conditioning. The present series of three experiments represent a more detailed analysis of ethanol-induced deficits in trace conditioning. In Experiment 1, the dose of ethanol given to neonates was varied (3.0, 4.0, or 5.0g/kg/day). There was a dose-dependent reduction in trace conditioning, with the poorest performance observed in animals treated with the highest dose. In Experiment 2, it was found that the impairment in trace conditioning resulting from neonatal ethanol exposure was dependent on the duration of the trace interval used for training; less learning was evident in ethanol-exposed animals trained with longer trace interval durations. These results confirm other reports of delay-dependent memory deficits. Finally, Experiment 3 determined that ethanol exposure limited to the first half of the neonatal period (PDs 4-6) was more detrimental to later trace conditioning than exposure during the second half (PDs 7-9). These results support the hypothesis that trace-conditioning impairments resulting from early ethanol exposure are due to the drug's teratogenic effects on the developing hippocampus, as the findings parallel those observed in animals with discrete hippocampal lesions. Comparisons between delay and trace fear-conditioning performance in animals exposed to ethanol during the brain growth spurt provide a model system to study both selective learning impairments and possible treatment approaches for humans with fetal alcohol spectrum disorders.
19788898	The study investigated the effect of one night of sleep deprivation on dream recall at morning awakening after recovery sleep. Forty healthy subjects were studied after adaptation (A) and baseline nights (B), and a recovery (R) night following 40 h of prolonged wakefulness. Parallel to the well-known recovery sleep changes (slow-wave sleep--SWS--rebound, decreased number of awakenings and of REM sleep amount), an almost complete abolition of dream recall was found, with an around 75% decrease with respect to the adaptation and baseline nights. The number of dreams recalled by those subjects with successful recall (REC) did not significantly differ between nights. Moreover, gender and sleep stage at awakening did not affect either the proportion of REC subjects or the number of dreams recalled by REC subjects during each night. Finally, the drastic impairment of dream recall after R night was associated to a larger increase of SWS and a shorter REM sleep duration. We suggest that dream recall could have been impaired during R night because: (i) the lower number of spontaneous awakenings over the night reduced the contents available in memory as possible cues for the retrieval of dream experiences at morning; (ii) mental experiences, having been elaborated during SWS more than in the other nights, were less dreamlike (i.e., perceptually vivid and bizarre) and, thus less accessible at morning recall than those elaborated during the nights with a higher proportion of REM sleep; (iii) dream contents, as a peculiar type of episodic information, were less consolidated because of the lower effectiveness of declarative memory during recovery sleep.
19788629	Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS) disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role in control of behavior, cognition, mood, and early life programming of stress reactivity. Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, severe in 5-10% of cases. Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor patients, especially children and/or when administering high doses SGC.
19786317	This study of infant declarative memory concurrently examined brain-electrical activity and deferred imitation performance in 10-month-old infants. Continuous electroencephalogram (EEG) measures were collected throughout the activity-matched baseline, encoding (modeling) and retrieval (delayed test) phases of a within-subjects deferred imitation task. Infants were divided into two memory performance groups based on the exhibition of ordered-recall after a 24-h delay. Whereas no group differences were found in EEG collected during encoding, performance-group differences in EEG were present during retrieval. Infants who successfully displayed ordered-recall showed a pattern of increasing EEG from baseline to task at anterior temporal scalp locations, whereas infants showing no ordered-recall displayed no changes in EEG from baseline to task. These findings are discussed with respect to the biobehavioral developments underlying declarative memory abilities.
19784482	The influence of aging on memory has been extensively studied, but the importance of short-term memory and recall sequence has not. The objective of the current study was to examine the recall order of words presented on lists and to determine if age affects recall sequence. Physically and psychologically healthy male subjects were divided into two groups according to age, i.e., 23 young subjects (20 to 30 years) and 50 elderly subjects (60 to 70 years) submitted to the Wechsler Adult Intelligence Scale-Revised and the free word recall test. The order of word presentation significantly affected the 3rd and 4th words recalled (P < 0.01; F = 14.6). In addition, there was interaction between the presentation order and the type of list presented (P < 0.05; F = 9.7). Also, both groups recalled the last words presented from each list (words 13-15) significantly more times 3rd and 4th than words presented in all remaining positions (P < 0.01). The order of word presentation also significantly affected the 5th and 6th words recalled (P = 0.05; F = 7.5) and there was a significant interaction between the order of presentation and the type of list presented (P < 0.01; F = 20.8). The more developed the cognitive functions, resulting mainly from formal education, the greater the cognitive reserve, helping to minimize the effects of aging on the long-term memory (episodic declarative).
19744566	The objective of this study was to delineate a common functional network that underlies autobiographical, episodic, and semantic memory retrieval. We conducted an event-related fMRI study in which we utilized the same pictorial stimuli, but manipulated retrieval demands to extract autobiographical, episodic, or semantic memories. To assess this common network, we first examined the functional connectivity of regions identified by a previous analysis of task-related activity that were active across all three tasks. Three of these regions (left hippocampus, left lingual gyrus, and right caudate nucleus) appeared to share a common pattern of connectivity. This was confirmed in a subsequent functional connectivity analysis using these three regions as seeds. The results of this analysis showed that there was a pattern of functional connectivity that characterized all three seeds and that was common across the three retrieval conditions. Activity in inferior frontal and middle temporal cortex bilaterally, left temporoparietal junction, and anterior and posterior cingulate gyri was positively correlated with the seeds, whereas activity in posterior occipito-temporo-parietal regions was negatively correlated. These findings support the idea that a common neural network underlies the retrieval of declarative memories regardless of memory content. This proposed network consists of increased activity in regions that represent internal processes of memory retrieval and decreased activity in regions that mediate attention to external stimuli.
19744525	The aim of this experiment was to determine if a task of associative olfactory learning, based on the ethological repertory of rats and learnt rapidly in 5 successive trials, could modify slow wave sleep (SWS) and/or paradoxical sleep (PS) duration after learning and/or after a retrieval-reactivation test 24 h later. Somnopolygraphic recordings were performed for 20 h per day on trained and control (submitted to a pseudo-learning test) rats. SWS and PS durations were analyzed per 20 h and per 4 h time-periods. Compared to control rats, after learning, trained rats showed a significant increase in SWS duration counterbalanced by a significant decrease in wake duration focused on the 5-8 h post-training time-window and a significant decrease in PS duration during the 17-20 h post-training time-window. After the retrieval-reactivation test trained rats only showed a decreased PS duration compared to control rats submitted to a pseudo-retrieval test. Thus, a rather simple learning task succeeded in eliciting an increase in SWS duration in a limited time-window. As the learning task used can be compared to human associate-paired learning, this result sustains the hypothesis of a link between declarative memory and SWS. In control rats, changes in PS duration might be linked to odorized-environment exposure.
19740090	The metabotropic glutamate receptor subtype 8 (mGlu(8)) is presynaptically located and regulates the release of the transmitter. Dysfunctions of this mechanism are involved in the pathophysiology of different psychiatric disorders. mGlu(8) deficient mice have been previously investigated in a range of studies, but the results are contradictory and there are still many open questions. Therefore, we tested mGlu(8)-deficient animals in different behavioral tasks that are commonly used in neuropsychiatric research. Our results show a robust contextual fear deficit in mGlu(8)-deficient mice. Furthermore, novel object recognition, chlordiazepoxide-facilitated extinction of operant conditioning and the acoustic startle response were attenuated by mGlu(8) deficiency. We found no changes in sensory processing, locomotor activity, prepulse inhibition, phencyclidine-induced changes in locomotion or prepulse inhibition, operant conditioning, conditioned fear to a discrete cue or in animal models of innate fear and post-traumatic stress disorder. We conclude that mGlu(8) might be a potential target for disorders with pathophysiological changes in brain areas where mGlu(8) modulates glutamate and gamma-amino butyric acid (GABA) transmission. Our data especially point to anxiety disorders involving exaggerated contextual fear, such as generalized anxiety disorders, and to conditions with disturbed declarative memory.
19736629	The development of memory research is inextricably bound to the fate of patient HM. On the occasion of his death, the circumstances are remembered, which lead to the bilateral removal of parts of his medio-temporal cortex in 1953. And the importance of the subsequent more than a half-century of research about his postoperative amnesic deficits as well as remaining learning and memory functions are outlined. The early reports triggered improved animal research which together with parallel investigations on HM and patients with similar deficits eventually lead to the downfall of the up until then dominating antilocalisationist view of brain functions. This was the result of having convincingly shown that memory could be severely impaired without major changes in other cognitive functions. Later investigations lead to question the unity of memory itself and forced a more and more differentiated description of different kinds of memory and their associations with separate neuroanatomical structures. A simplified summary of the resulting recent ideas of declarative memory systems is presented together with an outline of connections to their supporting medio-temporal, diencephalic and frontal-cortical structures. Finally, an attempt is made to address the question about the impact on the person HM of not having been able to form consciously retrievable memories from age 27 until his death at age of 82, thus having to rely for a reconstruction of his life on memories from child- and young adulthood as well as single momentary short-lived experiences.
19715723	Studies in humans and animals show that dopaminergic neuromodulation originating from the substantia nigra/ventral tegmental area (SN/VTA) of the midbrain enhances hippocampal synaptic plasticity for novel events and has a motivationally energizing effect on actions through striatal mechanisms. In this review, we discuss how these mechanisms of dopaminergic neuromodulation connect to the behavioural and functional consequences that age-related structural degeneration of the SN/VTA exerts on declarative memory. We propose a framework called 'NOvelty-related Motivation of Anticipation and exploration by Dopamine' (NOMAD) which captures existing links between novelty, dopamine, long-term memory, plasticity, energization and their relation to aging. We propose that maximizing the use of this mechanism by maintaining mobility and exploration of novel environments could be a potential mechanism to slow age-related decline of memory.
22005991	Modulation of speech conveys information that is decoded within audio-sensory structures. For example, the termination of an utterance with a rise in pitch distinguishes statements and questions. This study evaluated the sensitivity of early auditory structures to such linguistic prosodic distinctions using mismatch negativity (MMN). MMN is a preattentive auditory event-related potential (ERP) sensitive to stimulus deviance. High-density ERP to pitch contour stimuli were collected in a passive listening oddball paradigm from 11 healthy subjects. Voltage analysis revealed significant MMN responses to declarative and interrogative oddball stimuli. Further, MMN was significantly larger to interrogative, than declarative, deviants, indicating non-symmetric brain processing. These MMNs demonstrate that pitch contour abstractions reflecting interrogative/ declarative distinctions can be represented in preattentive auditory sensory memory.
19713132	In recent years there has been an expansion of scientific work on consciousness. However, there is an increasing necessity to integrate evolutionary and interdisciplinary perspectives and to bring affective feelings more centrally into the overall discussion. Pursuant especially to the theorizing of Endel Tulving (1985, 2004, 2005), Panksepp (1998a, 2003, 2005) and Vandekerckhove (2009) we will look at the phenomena starting with primary-process consciousness, namely the rudimentary state of autonomic awareness or unknowing (anoetic) consciousness, with a fundamental form of first-person 'self-experience' which relies on affective experiential states and raw sensory and perceptual mental existences, to higher forms of knowing (noetic and autonoetic) and self-aware consciousness. Since current scientific approaches are most concerned with the understanding of higher declarative states of consciousness, we will focus on these vastly underestimated primary forms of consciousness which may be foundational for all forms of higher 'knowing consciousness'.
19703575	A consolidated memory recalled by a reminder enters a vulnerability phase (labilization), followed by a process of stabilization (reconsolidation). Several authors have suggested that the labilization of the consolidated memory makes the incorporation of new information possible. Here, we demonstrate updating in the framework of memory declarative reconsolidation in humans by giving an opportune verbal instruction. Volunteers learn an association between five cue-syllables (L1) and their respective response-syllables. Twenty-four hours later, the paired-associate verbal memory is labilized by exposing the subjects to the reminder, and then they receive the verbal Instruction of adding three new cue-response syllables (INFO) with their respective responses to the former list of five. The new information is incorporated into the single former L1-memory and both INFO and L1 are successfully retrieved on the third day. However, when the Instruction is not preceded by a proper reminder, or when the instruction omits the order of adding the INFO into the former L1-memory, we observed interference in retrieval of both the original and the new information, suggesting that they are encoded independently and coexist as separate memories.
19703322	The proposition that declarative memory deficits are systematically related to smaller hippocampal volume was tested in a relatively large sample (n = 95) of U.S. military veterans with and without combat-related posttraumatic stress disorder. This correlative analysis was extended by including multiple measures of verbal and visual declarative memory and multiple memory-relevant regional brain volumes that had been shown to exhibit main effects of PTSD in prior work. Small-to-moderate effects were observed on verbal declarative memory in line with a recent meta-analysis; nevertheless, little or no evidence of systematic linear covariation between memory measures and brain volumes was observed.
19702788	Recent findings clearly demonstrate that daytime naps impart substantial memory benefits compared with equivalent periods of wakefulness. Using a declarative paired associates task and a procedural motor sequence task, this study examined the effect of two lengthier durations of nocturnal sleep [either a half night (3.5 h) or a full night (7.5 h) of sleep] on over-sleep changes in memory performance. We also assessed whether subject intelligence is associated with heightened task acquisition and, more importantly, whether greater intelligence translates to greater over-sleep declarative and procedural memory enhancement. Across both tasks, we demonstrate that postsleep performance gains are nearly equivalent, regardless of whether subjects obtain a half night or a full night of sleep. Remarkably, the over-sleep memory changes observed on both tasks are very similar to findings from studies examining performance following a daytime nap. Consistent with previous research, we also observed a strong positive correlation between amount of Stage 2 sleep and motor skill performance in the full-night sleep group. This finding contrasts with a highly significant correlation between spectral power in the spindle frequency band (12-15 Hz) and motor skill enhancement only in the half-night group, suggesting that sigma power and amount of Stage 2 sleep are both important for optimal motor memory processing. While subject intelligence correlated positively with acquisition and retest performance on both tasks, it did not correlate with over-sleep changes in performance on either task, suggesting that intelligence may not be a powerful modulator of sleep's effect on memory performance.
19702458	The medial temporal lobes (MTLs) are critical for episodic memory but the functions of MTL subregions are controversial. According to memory strength theory, MTL subregions collectively support declarative memory in a graded manner. In contrast, other theories assert that MTL subregions support functionally distinct processes. For instance, one view is that perirhinal cortex (PRc) processes item information, parahippocampal cortex (PHc) processes context information, and the hippocampus binds item and context. Here, we report two experiments that tested competing predictions from these models. In these studies, subjects encoded color-word associations by imagining color either as a contextual association (context detail condition) or as a feature of the item to be encoded (item detail condition). Results showed that encoding color information as an item detail improved source recognition in amnesic patients with recollection deficits. Furthermore, event-related fMRI data from healthy subjects revealed PRc activation associated with successful retrieval of item details, whereas activation in the hippocampus and PHc was associated with recollection-based source retrieval. The qualitatively different patterns of results observed in PRc and hippocampus/PHc are inconsistent with a memory strength account and are consistent with the idea that different MTL regions process different types of episodic information.
19690610	It is well known that certain cognitive abilities decline with age. The ability to form certain new declarative memories, particularly memories for facts and events, has been widely shown to decline with advancing age. In contrast, the effects of aging on the ability to form new procedural memories such as skills are less well known, though it appears that older adults are able to acquire some new procedural skills over practice. The current study examines the effects of normal aging on procedural memory more closely by comparing the effects of aging on the encoding or acquisition stage of procedural learning versus its effects on the consolidation, or between-session stage of procedural learning. Twelve older and 14 young participants completed a sequence-learning task (the Serial Reaction Time Task) over a practice session and at a re-test session 24 hours later. Older participants actually demonstrated more sequence skill during acquisition than the young. However, older participants failed to show skill improvement at re-test as the young participants did. Age thus appears to have a differential effect upon procedural learning stages such that older adults' skill acquisition remains relatively intact, in some cases even superior, compared to that of young adults, while their skill consolidation may be poorer than that of young adults. Although the effect of normal aging on procedural consolidation remains unclear, aging may actually enhance skill acquisition on some procedural tasks.
19675245	Stressful, aversive events are extremely well remembered. Such a declarative memory enhancement is evidently beneficial for survival, but the same mechanism may become maladaptive and culminate in mental diseases such as posttraumatic stress disorder (PTSD). Stress hormones are known to enhance postlearning consolidation of aversive memories but are also thought to have immediate effects on attentional, sensory, and mnemonic processes at memory formation. Despite their significance for our understanding of the etiology of stress-related mental disorders, effects of acute stress at memory formation, and their brain correlates at the system scale, remain elusive. Using an integrated experimental approach, we probed the neural correlates of memory formation while participants underwent a controlled stress induction procedure in a crossover design. Physiological (cortisol level, heart rate, and pupil dilation) and subjective measures confirmed acute stress. Remarkably, reduced hippocampal activation during encoding predicted stress-enhanced memory performance, both within and between participants. Stress, moreover, amplified early visual and inferior temporal responses, suggesting that hypervigilant processing goes along with enhanced inferior temporal information reduction to relay a higher proportion of task-relevant information to the hippocampus. Thus, acute stress affects neural correlates of memory formation in an unexpected manner, the understanding of which may elucidate mechanisms underlying psychological trauma etiology.
19675242	The standard model of system-level consolidation posits that the hippocampus is part of a retrieval network for recent memories. According to this theory, the memories are gradually transferred to neocortical circuits with consolidation, where the connections within this circuit grow stronger and reorganized so that redundant and/or contextual details may be lost. Thus, remote memories are based on neocortical networks and can be retrieved independently of the hippocampus. To test this model, we measured regional brain activity and connectivity during retrieval with functional magnetic resonance imaging. Subjects were trained on two sets of face-location association and were tested with two different delays, 15 min and 24 h including a whole night of sleep. We hypothesized that memory traces of the locations associated with specific faces will be linked through the hippocampus for the retrieval of recently learned association, but with consolidation, the activity and the functional connectivity between the neocortical areas will increase. We show that posterior hippocampal activity related to high-confidence retrieval decreased and neocortical activity increased with consolidation. Moreover, the connectivity between the hippocampus and the neocortical regions decreased and in turn, cortico-cortical connectivity between the representational areas increased. The results provide mechanistic support for a two-level process of the declarative memory system, involving initial representation of new associations in a network including the hippocampus and subsequent consolidation into a predominantly neocortical network.
19658072	This paper provides a brief review of the developments in neurobiological research of posttraumatic stress disorder (ptsd), particularly into the link between the disorder and the central and peripheral stress-regulating processes. ptsd is an impairment of neuronal circuits and stress-regulating systems in the brain, where a critical note is played by limbic structures such as the hippocampus, the amygdala and the medial prefrontal cortex. In patients with ptsd the 'behaviour' of these neuronal circuits and systems is chronically disturbed. Characteristic symptoms are increased stress reactivity, reduction of declarative memory performance, high emotionality in response to trauma-related stimuli and over-representation of traumatic memory, all of which can be described as chronic dysregulated processes. Because of improvements in research designs and stratification of research populations, the specificity of research findings has improved and the developmental trajectories of specific ptsd parameters have been described more clearly. One of the most promising developments in the field of research designs is the current shift away from cross-sectional research designs to 'true prospective' research designs.
19657682	There are two main memory systems: declarative and procedural memory. Knowledge of these two systems in fish is scarce, and controlled laboratory studies are needed. Trace classical conditioning is an experimentally tractable model of declarative memory. We tested whether rainbow trout (Oncorhynchus mykiss) can learn by trace conditioning and form stimulus-stimulus, as opposed to stimulus-response, associations. We predicted that rainbow trout trained by trace conditioning would show appetitive behaviour (conditioned response; CR) towards the conditioned stimulus (CS; light), and that the CR would be sensitive to devaluation of the unconditioned stimulus (US; food). The learning group (L, N = 14) was trained on a CS + US contingency schedule with a trace interval of 3.4 s. The control group (CtrL, N = 4) was kept on a completely random schedule. The fish that learnt were further trained as either an experimental (L, N = 6) or a memory control (CtrM, N = 3) group. The L group had the US devalued. The CtrM group received only food. No fish in the CtrL group, but nine fish from the L group conditioned to the light. When tested, five L fish changed their CRs after US devaluation, indicating learning by stimulus-stimulus association of the light with the food. CtrM fish retained their original CRs. To the best of our knowledge, this experiment is the first to show that rainbow trout can learn by trace classical conditioning. The results indicate that the fish learnt by 'facts-learning' rather than by reflex acquisition in this study.
19656277	Growing evidence indicates that sleep facilitates learning and memory processing. Sleep curtailment is increasingly common in adolescents. The aim of this study was to examine the effects of short-term sleep curtailment on declarative memory consolidation in adolescents. A randomized, cross-over study design was chosen. Twenty-two healthy subjects, aged 14-16 years, spent three consecutive nights in the sleep laboratory with a bedtime of 9 h during the first night (adaptation), 4 h during the second (partial sleep curtailment) and 9 h during the third night (recovery). The control condition consisted of three consecutive nights with bedtimes of 9 h. Both experimental conditions were separated by at least 3 weeks. The acquisition phase for the declarative tests was between 16:00 and 18:00 hours before the second night. Memory performance was examined in the morning after the recovery night. Executive function, attention and concentration were also assessed to control for any possible effects of tiredness. During the 4-h night, we observed a curtailment of 50% of non-rapid eye movement (non-REM), 5% of slow wave sleep (SWS) and 70% of REM sleep compared with the control night. Partial sleep curtailment of one night did not influence declarative memory retrieval significantly. Recall in the paired-associate word list task was correlated positively with percentage of non-REM sleep in the recovery night. Declarative memory consolidation does not appear to be influenced by short-term sleep curtailment in adolescents. This may be explained by the high ability of adolescents to compensate for acute sleep loss. The correlation between non-REM sleep and declarative memory performance supports earlier findings.
19647982	The hippocampus is one of the most widely studied brain region. One of its functional roles is the storage and recall of declarative memories. Recent hippocampus research has yielded a wealth of data on network architecture, cell types, the anatomy and membrane properties of pyramidal cells and interneurons, and synaptic plasticity. Understanding the functional roles of different families of hippocampal neurons in information processing, synaptic plasticity and network oscillations poses a great challenge but also promises deep insight into one of the major brain systems. Computational and mathematical models play an instrumental role in exploring such functions. In this paper, we provide an overview of abstract and biophysical models of associative memory with particular emphasis on the operations performed by the diverse (inter)neurons in encoding and retrieval of memories in the hippocampus.
19634928	Sleep has been implicated as playing a critical role in memory consolidation. Emerging evidence suggests that reactivation of memories during sleep may facilitate the transfer of declarative memories from the hippocampus to the neocortex. Previous rodent studies have utilized sleep-deprivation to examine the role of sleep in memory consolidation. The present study uses a novel, naturalistic paradigm to study the effect of a sleep phase on rodent Pavlovian fear conditioning, a task with both hippocampus-dependent and -independent components (contextual vs. cued memories). Mice were trained 1 hour before their sleep/rest phase or awake/active phase and then tested for contextual and cued fear 12 or 24 hr later. The authors found that hippocampus-dependent contextual memory was enhanced if tested after a sleep phase within 24 hr of training. This enhancement was specific to context, not cued, memory. These findings provide direct evidence of a role for sleep in enhancing hippocampus-dependent memory consolidation in rodents and detail a novel paradigm for examining sleep-induced memory effects.
19632208	Neural communication between the temporal and frontal cortex underlies mature declarative memory skills. The integrity of white matter pathways connecting these regions is likely critical in supporting this communication. Little is known about the relationship between white matter and declarative memory in older children and adolescents, an age period when advanced function in this domain is established. We acquired diffusion tensor imaging (DTI) data for 22 participants (9-15 years). Multiple DTI indices were calculated for the uncinate fasciculus - the major white matter tract connecting temporal and prefrontal regions. Indices were also calculated for compartments of lobar and posterior fossa white matter. Measures of visual-perceptual and auditory-verbal memory were administered. Correlation analyses were used to examine the relations between age, DTI indices, and memory. Voxel-wise analyses were also conducted. Age-related increases in FA were evident for frontal, parietal, and temporal hemispheric white matter. Proficiency in auditory-verbal memory was related to white matter integrity in the left uncinate fasciculus as well as parietal and cerebellar white matter. Proficiency in recall of a complex design was related to integrity within parietal and temporal regions. Our findings support the role of white matter in facilitating connectivity between cerebral regions important for declarative memory.
19622690	HIV infection is often associated with frontal systems pathology and related deficits in the strategic encoding and retrieval aspects of episodic memory. However, no prior HIV studies have explicitly examined source memory, which refers to recall of information regarding the context in which a declarative memory was formed. Source memory is heavily reliant on frontal systems and strategic cognitive processes and is singly dissociable from the content of the memory (i.e., item memory), which is more dependent on medial temporal systems and automatic processes. The present study examined item and source memory in 60 individuals with HIV infection and 35 demographically similar seronegative participants. The primary finding of interest was a significant HIV effect on source (but not item) memory for complex visual stimuli. Follow-up correlational analyses showed a significant association between visual source memory errors and impairment on measures of executive functions, working memory, and higher-level list learning encoding strategies. These findings extend the hypothesized profile of strategic encoding and retrieval deficits in HIV to the construct of source memory, which may be differentially affected relative to item memory for complex visual stimuli.
19594197	Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABA(B) receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16-30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABA(A) receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABA(B) receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABA(B) receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABA(B) receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABA(B) receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABA(B) receptor agonists has been on the positive symptoms of schizophrenia, with minimal investigation of GABA(B) receptor agonists such as baclofen or gamma-hydroxybutyric acid and their effects on sleep architecture, cognition and negative symptoms in patients with schizophrenia. Further study is needed.
19586216	Many symptom validity tests (SVTs) assess performance validity via declarative memory paradigms. One widely used SVT, the Word Memory Test (WMT), uses a variety of memory tests to assess performance. It is well known that declarative memory requires the hippocampus and related medial temporal lobe structures. In the present study, WMT performance was examined in nonlitigating amnesic subjects (n = 3) with well-documented focal bilateral hippocampal atrophy who were nondemented and otherwise cognitively unimpaired compared with matched controls. The amnesic subjects had no external incentives. Amnesic subjects performed significantly below the level of matched comparison subjects but above established cutoff scores on the immediate recognition and delay recognition subtests and consistency component. In contrast, the amnesic subjects were impaired relative to our comparison subjects on the multiple-choice, paired associate, free-recall, and long delay free-recall subtests and had extremely low performance on these measures. Thus, there was a differential effect of hippocampal damage on WMT performance where the recognition subtests were performed within the normal range, yet the free recall was profoundly impaired in amnesic subjects. Such an approach where SVT performance is assessed in populations with well-known cognitive impairments adds breadth to SVT clinical interpretations.
19585672	To investigate gender difference in the effects of daytime sleep on item and source memories, which are dissociable elements of declarative memory, and the effects of sleep on recollection and familiarity, which are two processes underlying recognition.Participants saw a series of pictures with either blue or red background, and were then given a pretest for item and source memories. Then males and females respectively were randomly assigned either to a wake or a sleep condition. In the wake condition, participants remained awake until the posttest; in the sleep condition, participants slept for 1 h until awakened and asked to remain awake until the posttest.	Daytime sleep contributed to retention of source memory rather than item memory in females, whereas males undergoing daytime sleep had a trend towards increased familiarity. For females, however, neither recollection nor familiarity appeared to be influenced by daytime sleep.	The mechanism underlying gender difference may be linked with different memory traces resulting from different encoding strategies, as well as with different electrophysiological changes during daytime sleep.	
19584178	Declarative memory largely depends upon normal functioning temporal lobes (hippocampal complex) and prefrontal cortex. Animal studies suggest abnormal hippocampal function in hypothyroidism.The aim of the study was to assess declarative memory in overt and subclinical (SCH) hypothyroid patients before and after l-T(4) (LT4) replacement and in matched normal subjects.	A prospective, open-labeled interventional study was conducted at a teaching hospital.	Hypothyroid (n = 21) and SCH (n = 17) patients underwent neuropsychological tests at baseline and 3 and 6 months after LT4 replacement. Normal subjects were studied at the same time-points.	Tests of spatial, verbal, associative, and working memory; attention; and response inhibition and the Hospital Anxiety and Depression Scale were administered.	Baseline deficits in spatial, associative, and verbal memory, which rely upon the integrity of the hippocampal and frontal areas, were identified in patients with overt hypothyroidism. Spatial and verbal memory were impaired in SCH patients (P < 0.05). TSH levels correlated negatively (P < 0.05) with these deficits. After LT4 replacement, verbal memory normalized. Spatial memory normalized in the SCH group but remained impaired in the hypothyroid group. Associative memory deficits persisted in the overt hypothyroid group. Hospital Anxiety and Depression Scale scores did not correlate with cognitive function. Measures of attention and response inhibition did not differ from control subjects.	Cognitive impairment occurs in SCH and more markedly in overt hypothyroidism. These impairments appear predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing. We propose that these deficits may reflect an underlying disruption of normal hippocampal function and/or connectivity.	
19571124	The prevailing view of the medial temporal lobe (MTL) holds that its structures are dedicated to long-term declarative memory. Recent evidence challenges this position, suggesting that perirhinal cortex (PRc) in the MTL may also play a role in perceptual discriminations of stimuli with substantial visual feature overlap. Relevant neuropsychological findings in humans have been inconclusive, likely because studies have relied on patients with large and variable MTL lesions. Here, we conducted a functional magnetic resonance imaging study in healthy individuals to determine whether PRc shows a performance-related involvement in perceptual oddball judgments that is comparable to its established role in recognition memory. Morphed faces were selected as stimuli because of their large degree of feature overlap. All trials involved presentation of displays with three faces. The perceptual oddball task required identification of the face least similar to the other display members. The memory task involved forced-choice recognition of a previously studied face. When levels of behavioral performance were matched, we observed comparable levels of activation in right PRc for both tasks. Moreover, right PRc activity differentiated between accurate and inaccurate trials in both tasks. Together these results indicate that declarative memory demands are not a prerequisite for a performance-related engagement of PRc and that the introduction of such declarative memory demands in an otherwise closely matched perceptual task does not necessarily lead to an increase in PRc involvement. As such our findings show that declarative memory and perception are not as clearly separable at the level of MTL functioning as traditionally thought.
19559446	Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory. Straight memory deficits and sleep disturbances are well-known in patients with schizophrenia. This study tested the hypothesis that patients with schizophrenia have a deficit in procedural and declarative memory consolidation after a short midday nap when compared to healthy controls and patients with remitted to moderate major depression. Following a normal night's sleep, 22 healthy subjects, 20 patients with major depression and 21 patients with schizophrenia were studied in a napping and wake condition in a random-order cross-over design, early in the afternoon. To test declarative memory, the Rey-Osterrieth Complex Figure Test respectively the Taylor Complex Figure Test and, for procedural learning, a mirror tracing task were performed. The present study is the first to demonstrate significant differences between individuals with schizophrenia, depression and healthy matched controls with regard to measures of sleep and memory performance after a short period of daytime sleep (napping). In particular we found that a daytime nap of only about 40min led to improvement of declarative memory performance in all investigated groups, whereas no beneficial effect was seen on procedural performance in the group of medicated patients with schizophrenia in contrast to healthy controls and patients with remitted to moderate major depression.
19555648	In Alzheimer's disease (AD), the impairment of declarative memory coincides with the accumulation of extracellular amyloid-beta protein (Abeta) and intraneuronal tau aggregates. Dementia severity correlates with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Abeta oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Abeta oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically evoked LTD in the CA1 region. Abeta-enhanced LTD was mediated by mGluR or NMDAR activity. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Abeta-facilitated LTD was mimicked by the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble Abeta. We conclude that soluble Abeta oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression.
19553460	Although hippocampal-cortical interactions are crucial for the formation of enduring declarative memories, synaptic events that govern long-term memory storage remain mostly unclear. We present evidence that neuronal structural changes, i.e., dendritic spine growth, develop sequentially in the hippocampus and anterior cingulate cortex (aCC) during the formation of recent and remote contextual fear memory. We found that mice placed in a conditioning chamber for one 7 min conditioning session and exposed to five footshocks (duration, 2 s; intensity, 0.7 mA; interstimulus interval, 60 s) delivered through the grid floor exhibited robust fear response when returned to the experimental context 24 h or 36 d after the conditioning. We then observed that their fear response at the recent, but not the remote, time point was associated with an increase in spine density on hippocampal neurons, whereas an inverse temporal pattern of spine density changes occurred on aCC neurons. At each time point, hippocampal or aCC structural alterations were achieved even in the absence of recent or remote memory tests, thus suggesting that they were not driven by retrieval processes. Furthermore, ibotenic lesions of the hippocampus impaired remote memory and prevented dendritic spine growth on aCC neurons when they were performed immediately after the conditioning, whereas they were ineffective when performed 24 d later. These findings reveal that gradual structural changes modifying connectivity in hippocampal-cortical networks underlie the formation and expression of remote memory, and that the hippocampus plays a crucial but time-limited role in driving structural plasticity in the cortex.
19553381	The perirhinal and entorhinal cortices are critical components of the medial temporal lobe (MTL) declarative memory system. Study of their specific functions using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI), however, has suffered from severe magnetic susceptibility signal dropout resulting in poor temporal signal-to-noise (tSNR) and thus weak BOLD signal detectability. We have demonstrated that higher spatial resolution in the z-plane leads to improved BOLD fMRI signal quality in the anterior medial temporal lobes when using a 16-element surface coil array at 3 T (Tesla). Using this technique, the present study investigated the roles of the anterior medial temporal lobe, particularly the entorhinal and perirhinal cortices, in both object and spatial memory. Participants viewed a series of fractal images and were instructed to encode either the object's identity or location. Object and spatial recognition memory were tested after 18-sec delays. Both the perirhinal and entorhinal cortices were active during the object and spatial encoding tasks. In both regions, object encoding was biased to the left hemisphere, whereas spatial encoding was biased to the right. A similar hemispheric bias was evident for recognition memory. Recent animal studies suggest functional dissociations among regions of the entorhinal cortex for spatial vs. object processing. Our findings suggest that this process-specific distinction may be expressed in the human brain as a hemispheric division of labor.
19548167	The Weather Prediction (WP) Task is a classical task of probabilistic category learning generally used for examining the dissociation of procedural and declarative memory. The current study focuses on performance of children with language impairment (LI) and compares their performance to that of typically developing (TD) children and adults with the aim of testing the procedural deficit hypothesis of LI (PDH; Ullman & Pierpont, 2005), which states that language impairment is not a specific linguistic phenomenon, but results from the dysfunction of a more general cognitive system: the procedural system. To test the generality of the procedural impairment, we needed a task that is dissimilar from language in that it does not build on sequential information. Children with language impairment show deficient learning on the Weather Prediction Task, which already appears at the early stages of the task. These results, in line with the PDH, point to the deficit of the procedural system in language impairment going beyond the language system. Whether this deficit is selective to the procedural system or is complemented by deficits in the declarative system is the subject of future studies.
19546306	The cytokine IL-6 has been considered to exert neuromodulating influences on the brain, with promoting influences on sleep. Sleep enhances the consolidation of memories, and, in particular, late nocturnal sleep also represents a period of enhanced IL-6 signaling, due to a distinctly enhanced availability of soluble IL-6 receptors during this period, enabling trans-signaling of IL-6 to neurons. Thus, a contribution of IL-6 to sleep-dependent memory consolidation is hypothesized. To test this hypothesis, we compared effects of intranasally administered IL-6 (vs. placebo) on sleep-dependent consolidation of declarative (neutral and emotional texts, 2-dimensional object location) and procedural (finger sequence tapping) memories in 17 healthy young men. IL-6 distinctly improved the sleep-related consolidation of emotional text material (P<0.03), which benefits mostly from sleep in the second night-half, in which rapid eye movement sleep (REM) dominates the non-REM-REM sleep cycle. During this second night-half, the amount of electroencephalogram slow-wave activity (0.5-4 Hz) distinctly increased after IL-6 (P<0.01). Other types of memory were not affected. The ability of IL-6 to enhance sleep-associated emotional memory consolidation highlights an example of a functional interaction between the central nervous and immune system.
19545598	Cycloheximide (CHI), an inhibitor of protein synthesis, is widely used for studying the mechanisms of consolidation of long-term memory (LTM). High concentrations of CHI inhibit the protein synthesis in brain homogenates by more than 80% and impair LTM consolidation. For understanding the mechanisms of consolidation, it is important to know how protein synthesis inhibitors affect hippocampal neurons. However, the effect of CHI on protein synthesis in CA1 and CA3 hippocampal pyramidal neurons is still poorly understood. In the present work, the state of ribosomes in CA1 and CA3 pyramidal neurons from the dorsal hippocampus of Wistar rats 1, 2, 4, and 72 h after the introcerebroventricular (i.c.v.) injection of a high concentration of CHI was determined using the fluorescent dye acridine orange. We showed that CHI induces great differences in the dynamics of the intensity of protein synthesis in CA1 and CA3 pyramidal neurons. The suppression of the intensity of protein synthesis in CA1 pyramidal neurons 1h after the injection of CHI was more than threefold stronger than in CA3, and by 4h, it was most pronounced in CA3 neurons. We suggest that the protein synthesis in CA1 pyramidal neurons contributes significantly to the synaptic consolidation of declarative memory in the first critical period.
19538748	Neuroimaging studies have proved that hippocampus relate to the deficient of memory in patients with post-traumatic stress disorder (PTSD). Many studies in healthy subjects also shown that insular cortex (IC) be involved in the declarative memory. This study was designed to investigate whether insular cortex is involved in declarative memory deficits in patients with PTSD.Twelve subjects with PTSD and 12 subjects without PTSD victims underwent functional magnetic resonance imaging and magnetic resonance imaging. All subjects performed encoding and retrieval memory tasks during the fMRI session. Voxel-based morphometry method was used to analyze gray-matter volume, and the Statistical Parametric Mapping (SPM2) was used to analyze activated brain areas when performing tasks.	Grey matter volume was significantly reduced bilaterally in the insular cortex of PTSD subjects than non-PTSD. PTSD group also had lower level of activation in insular cortex when performing word encoding and retrieval tasks than non-PTSD group.	The study provides evidence on structural and function abnormalities of the insular cortex in patients with PTSD. Reduced grey-matter volume in insular cortex may be associated with declarative memory deficits in patients with PTSD.	
19533679	The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway is important for memory processing, but the identity of its downstream effectors as well as its actual participation in the consolidation of nonaversive declarative long-term memory (LTM) remain unknown. Here, we show that training rats in an object recognition (OR) learning task rapidly increased nitrites/nitrates (NOx) content in the CA1 region of the dorsal hippocampus while posttraining intra-CA1 microinfusion of the neuronal NO synthase (nNOS) inhibitor L-NN hindered OR LTM retention without affecting memory retrieval or other behavioral variables. The amnesic effect of L-NN was not state dependent, was mimicked by the sGC inhibitor LY83583 and the PKG inhibitor KT-5823, and reversed by coinfusion of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and the PKG activator 8-bromoguanosine 3',5'-cyclic monophosphate (8Br-cGMP). SNAP did not affect the amnesic effect of LY83583 and KT-5823. Conversely, 8Br-cGMP overturned the amnesia induced by LY83583 but not that caused by KT-5823. Intra-CA1 infusion of the beta-adrenergic receptor blocker timolol right after training hindered OR LTM and, although coadministration of noradrenaline reversed the amnesia caused by L-NN, LY83583, and KT5823, the amnesic effect of timolol was unaffected by coinfusion of 8Br-cGMP or SNAP, indicating that hippocampal beta-adrenergic receptors act downstream NO/sGC/PKG signaling. We also found that posttraining intra-CA1 infusion of function-blocking anti-brain-derived neurotrophic factor (BDNF) antibodies hampered OR LTM retention, whereas OR training increased CA1 BDNF levels in a nNOS- and beta-adrenergic receptor-dependent manner. Taken together, our results demonstrate that NO/sGC/PKG signaling in the hippocampus is essential for OR memory consolidation and suggest that beta-adrenergic receptors link the activation of this pathway to BDNF expression during the consolidation of declarative memories.
19499575	The medial temporal lobe (MTL), a set of heavily interconnected structures including the hippocampus and underlying entorhinal, perirhinal and parahippocampal cortex, is traditionally believed to be part of a unitary system dedicated to declarative memory. Recent studies, however, demonstrated perceptual impairments in amnesic individuals with MTL damage, with hippocampal lesions causing scene discrimination deficits, and perirhinal lesions causing object and face discrimination deficits. The degree of impairment on these tasks was influenced by the need to process complex conjunctions of features: discriminations requiring the integration of multiple visual features caused deficits, whereas discriminations that could be solved on the basis of a single feature did not. Here, we address these issues with functional neuroimaging in healthy participants as they performed a version of the oddity discrimination task used previously in patients. Three different types of stimuli (faces, scenes, novel objects) were presented from either identical or different viewpoints. Consistent with studies in patients, we observed increased perirhinal activity when participants distinguished between faces and objects presented from different, compared to identical, viewpoints. The posterior hippocampus, by contrast, showed an effect of viewpoint for both faces and scenes. These findings provide convergent evidence that the MTL is involved in processes beyond long-term declarative memory and suggest a critical role for these structures in integrating complex features of faces, objects, and scenes into view-invariant, abstract representations.
19482039	We studied five patients with semantic memory disorders, four with semantic dementia and one with herpes simplex virus encephalitis, to investigate the involvement of semantic conceptual knowledge in object use. Comparisons between patients who had semantic deficits of different severity, as well as the follow-up, showed that the ability to use objects was largely preserved when the deficit was mild but progressively decayed as the deficit became more severe. Naming was generally more impaired than object use. Production tasks (pantomime execution and actual object use) and comprehension tasks (pantomime recognition and action recognition) as well as functional knowledge about objects were impaired when the semantic deficit was severe. Semantic and unrelated errors were produced during object use, but actions were always fluent and patients performed normally on a novel tools task in which the semantic demand was minimal. Patients with severe semantic deficits scored borderline on ideational apraxia tasks. Our data indicate that functional semantic knowledge is crucial for using objects in a conventional way and suggest that non-semantic factors, mainly non-declarative components of memory, might compensate to some extent for semantic disorders and guarantee some residual ability to use very common objects independently of semantic knowledge.
19476636	It has been reported that consolidation of motor skill, a type of non-declarative memories, requires protein synthesis, as hippocampus-dependent declarative memory does. However, little is known about the importance of protein synthesis in maintenance and especially post-retrieval reconsolidation of acrobatic motor skill. Here, we show that protein synthesis is essential not only for the consolidation but also for the maintenance and reconsolidation of a rotarod-running skill. Intra-ventricle infusion of the protein synthesis inhibitor anisomycin 0 h but not 2 h post-training caused a severe deficit in the acquisition of the rotarod-running skill. Protein synthesis inhibition (PSI) also caused a deficit in the maintenance of the rotarod-running skill, as well-trained rats demonstrated a deficit in the rotarod-running performance upon treatment with anisomycin. Similarly, PSI impaired the post-retrieval reconsolidation of the rotarod-running skill: well-trained rats treated with anisomycin 0 h but not 0.5, 2 and 4 h after the task performance exhibited amnesia for the running skill later on. Interestingly, rats treated with anisomycin 6 and 12 h post-retrieval exhibited amnesia for the running skill. Thus, protein synthesis is essential not only for the consolidation but also for the maintenance and post-retrieval reconsolidation of rotarod-running acrobatic motor skill.
19463794	Cognitive deficits and hippocampal atrophy, features that are shared with aging and dementia, have been described in type 2 diabetes mellitus (T2DM). T2DM is associated with obesity, hypertension, dyslipidemia, hypothalamic pituitary adrenocortical (HPA) axis abnormalities and inflammation, all of which have been shown to negatively impact the brain. However, since most reports in T2DM focused on glycemic control, the relative contribution of these modifying factors to the impairments observed in T2DM remains unclear. We contrasted 41 middle-aged dementia-free volunteers with T2DM (on average 7 years since diagnosis) with 47 age-, education-, and gender-matched non-insulin resistant controls on cognition and brain volumes. HPA axis activity and other modifiers that accompany T2DM were assessed to determine their impact on brain and cognition. Individuals with T2DM had specific verbal declarative memory deficits, reduced hippocampal and prefrontal volumes, and impaired HPA axis feedback control. Diminished cortisol suppression after dexamethasone and dyslipidemia were associated with decreased cognitive performance, whereas obesity was negatively related to hippocampal volume. Moreover, prefrontal volume was influenced by worse glycemic control. Thus, obesity and altered cortisol levels may contribute to the impact of T2DM on the hippocampal formation, resulting in decreased verbal declarative memory performance.
19463709	The hippocampus is essential for consolidation of declarative information and spatial navigation. Alzheimer's disease (AD) diagnosis tends to be preceded by a long prodromal period and mild cognitive impairment (MCI). Our goal was to test whether amnestic MCI comprises two different subgroups, with hippocampal and non-hippocampal memory impairment, that vary with respect to spatial navigation ability. A total of 52 patients were classified into two subgroups: non-amnestic MCI (naMCI) (n=10) and amnestic MCI (aMCI) (n=42). The aMCI subgroup was further stratified into memory impairment of hippocampal type-hippocampal aMCI (HaMCI) (n=10) (potential preclinical AD) and isolated retrieval impairment-non-hippocampal (NHaMCI) (n=32). Results were compared to control (n=28) and AD (n=21) groups. We used the Hidden Goal Task, a human analogue of the Morris Water Maze, to examine spatial navigation either dependent (egocentric) or independent of individual's position (allocentric). Overall, the HaMCI group performed poorer on spatial navigation than the NHaMCI group, especially in the latter trials when the HaMCI group exhibited limited capacity to learn and the NHaMCI group exhibited a learning effect. Finally, the HaMCI group performed almost identically as the AD group. Spatial navigation deficit is particularly pronounced in individuals with hippocampus-related memory impairment and may signal preclinical AD.
19448852	Neurobiological findings and clinical data suggest that dissociative experience inhibits conditioning processes, but experimental studies are lacking. The aim of our study was to determine whether high states of dissociative experience would specifically alter emotional learning, but not declarative knowledge.We used an aversive differential delay conditioning procedure in 33 unmedicated patients with borderline personality disorder (BPD) and 35 healthy controls.	Patients with BPD who had high state dissociative experiences (BPD D+) showed diminished acquisition of differential aversive delay conditioning with respect to emotional learning compared with those who did not experience dissociative symptoms (BPD D-) and healthy controls (skin conductance response; interaction dissociation x quadratic time x type, p = 0.009). Specifically, the control group and the BPD D- subgroup showed an increase in valence and arousal to the conditioned stimulus (CS+) during the conditioning procedure (all p < 0.012) and demonstrated differential skin conductance responses in the acquisition and extinction phases. In contrast, the BPD D+ subgroup showed no increase in valence and arousal to CS+ or differential response regarding skin conductance. We examined general psychopathology, trauma history, perceptual differences and posttraumatic stress disorder as confounding factors, but we found no evidence of bias.	Subdividing the BPD group reduced power. In addition, because our sample included only women, the generalizability of our results is constrained. Furthermore, we performed no separate analysis of the influence of different aspects of dissociation on the learning process.	Emotional, amygdala-based learning processes seem to be inhibited during state dissociative experience. State dissociative experience may alter acquisition and extinction processes and should be closely monitored in exposure-based psychotherapy.	
19440084	Excessive corticosteroid exposure is associated with atrophic effects on the human hippocampus and amygdala. These effects seem to be, at least in part, mediated through corticosteroid-induced release of glutamate. We previously reported that lamotrigine, a glutamate release inhibitor, significantly improved declarative memory but did not change hippocampal volume, as compared with placebo, in corticosteroid-treated patients. To our knowledge, no data are available on preventing or reversing the impact of corticosteroids on the amygdala.We examined the effects of 24 weeks of randomized placebo-controlled lamotrigine therapy on amygdala volume and mood in 28 corticosteroid-treated patients (n = 12, placebo; n = 16, lamotrigine). Amygdala volumes were measured from tracings of the magnetic resonance images from weeks 0 and 24. Mood was assessed every 2 weeks with the Hamilton Depression Rating Scale and the Young Mania Rating Scale.	An analysis of covariance revealed that patients on lamotrigine had significantly larger left amygdala volume at week 24 than patients on placebo after controlling for baseline volume. Neither exit nor week 24 analysis of covariance of Hamilton Depression Rating Scale and Young Mania Rating Scale revealed a significant difference between lamotrigine and placebo groups.	Results suggest that lamotrigine attenuated the effects of corticosteroids on the left amygdala. Larger trials are warranted to confirm these findings.	
19437417	Neural processing in the hippocampus (HPC) during sleep is important for declarative memory storage. Previously, we have shown that alternations of sleep-like REM and non-REM brain states that involve changing patterns of synchronized oscillatory network activity in the HPC [i.e., theta and the slow oscillation (SO), respectively] robustly and differentially influence excitatory synaptic transmission in a variety of hippocampal pathways. Given that state in the HPC is dependent on variations in cholinergic tone in both sleep and under urethane anesthesia, in the present study we induced theta and SO states via systemic cholinergic manipulations in urethane-anesthetized rats to confirm similar changes in synaptic responsiveness. This was conducted using linear multiprobe recordings and current source density analysis of electrically evoked potentials in commissural and temporal ammonic inputs to CA1 and medial and lateral perforant path inputs to dentate gyrus (DG). Cholinergic agonism and antagonism induced theta and the SO, respectively, and similarly to the case with spontaneous states, also diminished and promoted, respectively, excitatory synaptic currents in all pathways (except for the medial perforant path input to DG which showed the opposite modulation). These results suggest that both state and cholinergic tone bias the hippocampal network during natural sleep across REM and non-REM episodes and that this modulation may play an important role in the consolidation of declarative memories.
19428501	The serotonergic system is implicated in the regulation of mood and cognition. Acute tryptophan depletion (ATD) is an experimental procedure for lowering central serotonin levels. Here, the effects of ATD on psychomotor processing, declarative memory, working memory, executive functions and attention are discussed. The most robust finding is that ATD impairs the consolidation of episodic memory for verbal information. Semantic memory appears to be unaffected by ATD although a limited variety of tasks examined effects in this domain. Similarly, evidence suggests ATD does not influence verbal, spatial and affective working memory. Most studies investigating effects on executive functions have produced non-specific or negative findings. In terms of attention, ATD either does not affect or may improve focused attention and ATD likely does not impact sustained and divided attention or attentional set-shifting. Although ATD is known to affect mood in certain vulnerable populations, the effects of ATD on cognition in non-vulnerable participants are independent of mood changes. Suggestions for future directions and implications for psychiatric illnesses are discussed.
19424440	Mounting evidence implicates sleep in the consolidation of various kinds of memories. We investigated the effect of sleep on memory for face identity, a declarative form of memory that is indispensable for nearly all social interaction. In the acquisition phase, observers viewed faces that they were required to remember over a variable retention period (0-36 hours). In the test phase, observers viewed intermixed old and new faces and judged seeing each before. Participants were classified according to acquisition and test times into seven groups. Memory strength (d') and response bias (c) were evaluated. Substantial time spent awake (12 hours or more) during the retention period impaired face recognition memory evaluated at test, whereas sleep per se during the retention period did little to enhance the memory. Wakefulness during retention also led to a tightening of the decision criterion. Our findings suggest that sleep passively and transiently shelters face recognition memory from waking interference (exposure) but does not actively aid in its long-term consolidation.
19413472	In explicit sequence learning tasks, an improvement in performance (skill) typically occurs after sleep-leading to the recent literature on sleep-dependent motor consolidation. Consolidation can also be facilitated during wakefulness if declarative knowledge for the sequence is reduced through a secondary cognitive task. Accordingly, declarative and procedural consolidation processes appear to mutually interact. Here we used TMS to test the hypothesis that functions in the dorsolateral prefrontal cortex (DLPFC) that support declarative memory formation indirectly reduce the formation of procedural representations. We hypothesize that disrupting the DLPFC immediately after sequence learning would degrade the retention or the consolidation of the sequence within the declarative memory system and thus facilitate consolidation within procedural memory systems, evident as wakeful off-line skill improvement. Inhibitory theta-burst TMS was applied to the left DLPFC (n = 10), to the right DLPFC (n = 10), or to an occipital cortical control site (n = 10) immediately after training on the serial reaction time task (SRTT). All groups were retested after eight daytime hours without sleep. TMS of either left or right DLPFC lead to skill improvements on the SRTT. Increase in skill was greater following right DLPFC stimulation than left DLPFC stimulation; there was no improvement in skill for the control group. Across all participants, free recall of the sequence was inversely related to the improvements in performance on the SRTT. These results support the hypothesis of interference between declarative and procedural consolidation processes and are discussed in the framework of the interactions between memory systems.
19403795	Memory systems are known to be influenced by feedback and error processing, but it is not well known what aspects of outcome contingencies are related to different memory systems. Here we use the Rescorla-Wagner model to estimate prediction errors in an fMRI study of stimulus-outcome association learning. The conditional probabilities of outcomes for a given stimulus are manipulated so that associations are either learnable or unlearnable (pseudorandom). The delay between stimulus and outcome is jittered so that we can separately compare activity for either stimulus processing or feedback processing. We find that hippocampus and anterior cingulate are differentially active primarily at feedback processing: Learnable associations are correlated with significantly more hippocampal activity and significantly less anterior cingulate activity than unlearnable associations. We also find that positive prediction errors modulate feedback processing in the midbrain for both types of associations. We suggest that learnable associations use more declarative memory, unlearnable associations involve more uncertainty monitoring, and, in both kinds of associations, positive prediction errors provide a reinforcement signal.
19397863	Previous studies have reported conflicting evidence concerning the contribution of declarative memory to advantageous decision-making on the Iowa Gambling Task (IGT). One study, in which the measurement of psychophysiology during the task necessitated a 10-s delay between card selections, found that six participants with amnesia due to hippocampal damage failed to develop a preference for advantageous decks over disadvantageous decks [Gutbrod, K., Krouzel, C., Hofer, H., Muri, R., Perrig, W., & Ptak, R. (2006). Decision-making in amnesia: Do advantageous decisions require conscious knowledge of previous behavioural choices? Neuropsychologia, 44(8), 1315-1324]. However, a single-case study (where psychophysiology was not measured and no delay between card selections occurred) showed that an amnesic patient developed normal preference for advantageous decks [Turnbull, O. H., & Evans, C. E. (2006). Preserved complex emotion-based learning in amnesia. Neuropsychologia, 44(2), 300-306]. We sought to resolve these discrepant findings by examining IGT performances in five patients with profound amnesia (WMS-III General Memory Index M=63) and bilateral hippocampal damage caused by anoxia (n=4) or herpes simplex encephalitis (n=1). In one administration of the IGT, psychophysiology measurements were utilized and a 6-s delay was interposed between card selections. In a second administration, no delay between card selections was interposed. While age-, sex-, and education-matched healthy comparison participants showed significant learning with a gradual preference for advantageous decks in both conditions, amnesic patients, irrespective of IGT administration condition and extent of medial temporal lobe damage, failed to develop this preference. These findings strongly discount the possibility that the delay between card selections explains why amnesic participants fail to learn in the IGT, and suggest instead a significant role for medial temporal lobe declarative memory systems in the type of complex decision-making tapped by the IGT.
19388889	The volatile anesthetic sevoflurane exhibits neuroprotective properties when assessed for motor function and histopathology after cerebral ischemia in rats. Damage of hippocampal neurons after ischemia relates to a number of cognitive deficits that are not revealed by testing animals for motor function. Therefore, the present study evaluates cognitive and behavioral function as well as hippocampal damage in rats subjected to cerebral ischemia under sevoflurane compared with fentanyl/nitrous oxide (N(2)O)/O(2) anesthesia.Thirty-four rats were trained for 10 days using a hole-board test to detect changes in cognitive and behavioral function. Rats were randomly assigned to the following groups: (A) sham/fentanyl/N(2)O/O(2) (n=7); (B) ischemia/fentanyl/N(2)O/O(2) (n=10); (C) sham/2.0 vol% sevoflurane in O(2)/air (n=7); and (D) ischemia/2.0 vol% sevoflurane in O(2)/air (n=10). Cerebral ischemia was produced by unilateral common carotid artery occlusion combined with hemorrhagic hypotension (mean arterial blood pressure 40 mmHg for 45 min). Temperature, arterial blood gases, and pH were maintained constant. Cerebral blood flow was measured using laser-Doppler flowmetry. After surgery, cognitive and behavioral function was re-evaluated for 10 days. On day 11, the brains were removed for histopathologic evaluation (hematoxylin/eosin-staining).	Cognitive testing revealed deficits in declarative and working memory in ischemic rats anesthetized with fentanyl/N(2)O. Rats anesthetized with sevoflurane during ischemia showed a significantly better outcome. Hippocampal damage was significantly worse with fentanyl/N(2)O.	The present data add to previous investigations showing that sevoflurane prevents a deficit in cognitive function and histopathological damage induced by cerebral ischemia in rats.	
19377414	Parkinson's disease (PD) is a chronic progressive disorder mainly affecting the motor system. PD is only partially controlled by symptomatic dopaminergic treatment. Therefore, motor rehabilitation can be used in PD to reduce complications and to train patients in the use of compensatory movement strategies. Rehabilitative practice is largely dependent on the efficiency of motor learning, i.e. the acquisition of new abilities or the adaptation of pre-existing ones. Although patients with PD are able to improve their motor performance through practice, the amount and persistence of clinical benefit are uncertain. Both ''implicit'' (procedural) and ''explicit'' (declarative) features of motor learning have been extensively investigated in patients with PD using neuropsychological testing, serial reaction time paradigms, and analysis of reaching movements. Evidence from these studies suggests an early impairment of ''explicit'' learning in PD, while ''implicit'' learning is relatively preserved. The consolidation of learned motor tasks is defective in PD and the mechanisms of motor learning seem to be independent from dopamine-replacement therapy. The knowledge of motor learning in PD is critical in designing more effective rehabilitative protocols.
19376098	Stress leads to an enhanced activity of the hypothalamus-pituitary adrenal (HPA) axis resulting in an increased release of glucocorticoids from the adrenal cortex. These hormones influence target systems in the periphery as well as in the brain. The present review paper describes the impact of the human stress hormone cortisol on episodic long-term memory. Starting out with our early observation that stress as well as cortisol treatment impaired declarative memory, experiments by the author are described, which result in an enhanced understanding of how cortisol influences memory. The main conclusions are that stress or cortisol treatment temporarily blocks memory retrieval. The effect is stronger for emotional arousing material independent of its valence. In addition cortisol only influences memory when a certain amount of testing induced arousal occurs. A functional magnetic resonance imaging (fMRI) study suggests that the neuronal correlate of the cortisol induced retrieval blockade is a reduced activity of the hippocampus. In contrast to the effects on retrieval cortisol enhances memory consolidation. Again this effect is often stronger for emotionally arousing material and sometimes occurs at the cost of memory for neutral material. A fMRI study revealed that higher cortisol levels were associated with a stronger amygdala response to emotional stimuli. Thus stimulatory effects of cortisol on this structure might underlie the cortisol induced enhancement of emotional memory consolidation. The findings presented are in line with models derived from experiments in rodents and are of relevance for our understanding of stress associated psychiatric disorders.
19375946	Participants struck 500 golf balls to a concealed target. Outcome feedback was presented at the subjective or objective threshold of awareness of each participant or at a supraliminal threshold. Participants who received fully perceptible (supraliminal) feedback learned to strike the ball onto the target, as did participants who received feedback that was only marginally perceptible (subjective threshold). Participants who received feedback that was not perceptible (objective threshold) showed no learning. Upon transfer to a condition in which the target was unconcealed, performance increased in both the subjective and the objective threshold condition, but decreased in the supraliminal condition. In all three conditions, participants reported minimal declarative knowledge of their movements, suggesting that deliberate hypothesis testing about how best to move in order to perform the motor task successfully was disrupted by the impoverished disposition of the visual outcome feedback. It was concluded that sub-optimally perceptible visual feedback evokes implicit processes.
19348959	Memories are not stored as exact copies of our experiences. As a result, remembering is subject not only to memory failure, but to inaccuracies and distortions as well. Although such distortions are often retained or even enhanced over time, sleep's contribution to the development of false memories is unknown. Here, we report that a night of sleep increases both veridical and false recall in the Deese-Roediger-McDermott (DRM) paradigm, compared to an equivalent period of daytime wakefulness. But while veridical memory deteriorates across both wake and sleep, false memories are preferentially preserved by sleep, actually showing a non-significant improvement. The same selectivity of false over veridical memories was observed in a follow-up nap study. Unlike previous studies implicating deep, slow-wave sleep (SWS) in declarative memory consolidation, here veridical recall correlated with decreased SWS, a finding that was observed in both the overnight and nap studies. These findings lead to two counterintuitive conclusions - that under certain circumstances sleep can promote false memories over veridical ones, and SWS can be associated with impairment rather than facilitation of declarative memory consolidation. While these effects produce memories that are less accurate after sleep, these memories may, in the end, be more useful.
19338508	As critical as waking brain function is to cognition, an extensive literature now indicates that sleep supports equally important, different yet complementary operations. This review will consider recent and emerging findings implicating sleep and specific sleep-stage physiologies in the modulation, regulation, and even preparation of cognitive and emotional brain processes. First, evidence for the role of sleep in memory processing will be discussed, principally focusing on declarative memory. Second, at a neural level several mechanistic models of sleep-dependent plasticity underlying these effects will be reviewed, with a synthesis of these features offered that may explain the ordered structure of sleep, and the orderly evolution of memory stages. Third, accumulating evidence for the role of sleep in associative memory processing will be discussed, suggesting that the long-term goal of sleep may not be the strengthening of individual memory items, but, instead, their abstracted assimilation into a schema of generalized knowledge. Fourth, the newly emerging benefit of sleep in regulating emotional brain reactivity will be considered. Finally, and building on this latter topic, a novel hypothesis and framework of sleep-dependent affective brain processing will be proposed, culminating in testable predictions and translational implications for mood disorders.
19337726	Emotional processing measures are sensitive to acute administration of clinically useful antidepressant drugs. We wished to test the hypothesis that these models would also be able to detect agents likely to cause depression as an adverse effect. The anti-obesity drug and cannabinoid type 1 receptor antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use.Thirty healthy adult volunteers were randomly assigned to receive a single dose of rimonabant (20 mg) or lactose placebo in a double-blind, between-groups design. Three hours after medication administration, subjects undertook an emotional processing test battery including facial emotion recognition, emotional word attentional dot probe, self-relevant word classification, emotional and declarative memory and the emotion-potentiated acoustic startle response. Subjective state was assessed via self-report measures.	A single dose of rimonabant did not alter subjective mood. However, rimonabant selectively reduced incidental recall of positive self-relevant adjectives, an effect contrary to that seen following the administration of antidepressants. There were no effects of rimonabant on the other measures of emotional processing.	These results suggest that a single dose of rimonabant decreases positive emotional memory in the absence of changes in subjective state. Further studies are required to examine whether rimonabant might produce a wider range of negative emotional biases with repeated treatment.	
19320982	The hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD), the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silicomodel of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML). We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated.The in silicoSBML model reflected the in vivoaging of the hippocampus and increased plasma cortisol and negative feedback to the hypothalamic pituitary axis. Aging induced a 12% decrease in hippocampus activity (HA), increased to 30% by acute and 40% by chronic elevations in cortisol. The biological intervention attenuated the cortisol associated decrease in HA by 2% in the acute cortisol simulation and by 8% in the chronic simulation.	Both acute and chronic elevations in cortisol secretion increased aging-associated hippocampal atrophy and a loss of HA in the model. We suggest that this first SMBL model, in tandem with in vitroand in vivostudies, may provide a backbone to further frame computational cortisol and brain aging models, which may help predict aging-related brain changes in vulnerable older people.	
19320630	The importance of sleep for memory consolidation has become a major focus of research. While it is known that abstaining alcohol-dependent patients often have sleep disorders and that there is some cognitive impairment during early abstention a possible interaction of disturbed sleep with overnight memory consolidation has not been addressed in a study as yet.Twenty-four alcohol-dependent patients with a short abstention period (mean 21.9 +/- 7.6 days) were compared with 12 patients with an abstention period of several months (115.7 +/- 43.8 days). Groups did not differ with respect to daily alcohol consumption before treatment, duration of alcohol dependence, and age. Before sleep all patients learned a list of semantically associated word pairs and a face name association task to a fixed criterion (at least 60% of correct recall) and they performed a mirror tracing task. After a polysomnographically registered night the patients were tested for retention of the learned declarative material by cued recall and had to perform the mirror tracing task again.	The groups did not differ with respect to sleep parameters or sleep-associated memory consolidation. Across both groups the duration of alcohol dependence correlated negatively with the amount of non-REM sleep and recall in the face name association task correlated negatively with daily alcohol consumption before abstention. Among the longer-term abstainers the duration of abstention correlated with the amount of slow wave sleep.	Our data support the hypothesis that chronic and high alcohol consumption negatively affects sleep and declarative memory consolidation during the first months of abstention. Between an abstention period of a few weeks and of several months no change in sleep parameters and nightly memory consolidation could be demonstrated, however.	
19301996	Recognition memory based on familiarity judgments is a form of declarative memory that has been repeatedly associated with the anterior medial temporal lobe. It has been argued that this region sustains familiarity-based recognition not only by retrieving item-specific information but also by coding for those semantic aspects of an event that support later familiarity-based recognition. Here, we used event-related fMRI to directly examine whether the contribution of anterior medial temporal lobe to declarative memory indeed results from its role in processing semantic aspects of an event. For this purpose, a sentence comprehension task was employed which varied the demands of semantic and syntactic processing of the sentence-final word. By presenting those sentence-final words together with new words in a subsequent incidental recognition memory test, we were able to determine the mnemonic consequences of presenting words in different sentential contexts. Results showed that enhanced semantic processing during comprehension activates regions in medial temporal lobe cortex and leads to response suppression in partly overlapping regions when the word is successfully retrieved. Data from a behavioral follow-up study support the view that enhanced semantic processing at study enhances familiarity-based remembering in a subsequent test phase.
19300446	Converging evidence suggests that each parahippocampal and hippocampal subregion contributes uniquely to the encoding, consolidation and retrieval of declarative memories, but their precise roles remain elusive. Current functional thinking does not fully incorporate the intricately connected networks that link these subregions, owing to their organizational complexity; however, such detailed anatomical knowledge is of pivotal importance for comprehending the unique functional contribution of each subregion. We have therefore developed an interactive diagram with the aim to display all of the currently known anatomical connections of the rat parahippocampal-hippocampal network. In this Review, we integrate the existing anatomical knowledge into a concise description of this network and discuss the functional implications of some relatively underexposed connections.
19295510	The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been proposed as a possible candidate for involvement in the pathophysiology of bipolar disorder (BD). To determine whether an association exists between the BDNF Val66Met genotype and morphometric abnormalities of the brain regions involved in memory and learning in BD and healthy subjects. Forty-two BD patients and 42 healthy subjects were studied. Interactions between BDNF Val66Met genotype and diagnosis in gray (GM) volumes were analyzed using an optimized voxel-based morphometry technique. Declarative memory function was assessed with the California Verbal Learning Test II. Left and right anterior cingulate GM volumes showed a significant interaction between genotype and diagnosis such that anterior cingulate GM volumes were significantly smaller in the Val/Met BD patients compared with the Val/Val BD patients (left P=0.01, right P=0.01). Within-group comparisons revealed that the Val/Met carriers showed smaller GM volumes of the dorsolateral prefrontal cortex compared with the Val/Val subjects within the BD patient (P=0.01) and healthy groups (left P=0.03, right P=0.03). The Val/Met healthy subjects had smaller GM volumes of the left hippocampus compared with the Val/Val healthy subjects (P<0.01). There was a significant main effect of diagnosis on memory function (P=0.04), but no interaction between diagnosis and genotype was found (P=0.48). The findings support an association between the BDNF Val66Met genotype and differential gray matter content in brain structures, and suggest that the variation in this gene may play a more prominent role in brain structure differences in subjects affected with BD.
19294950	The effects of REM sleep and slow wave sleep (SWS) deprivation on sleep-dependent motor and declarative memory consolidation.Randomized, within-subject, cross-over study.	Weekly (women: monthly) sleep laboratory visits, with retest 60 hours later.	Twelve healthy subjects (6 men) aged between 20 and 30 years.	REM sleep deprivation, SWS deprivation, or undisturbed sleep.	We deprived subjects once each of REM sleep and SWS, and once let them sleep undisturbed through the night. After each night, we tested declarative and procedural memory consolidation. We tested memory performance by a verbal paired associate task and a sequential finger-tapping task at 21:00 on the study night and again 60 hours later. Although REM sleep and SWS awakenings led to a significant reduction of the respective sleep stages, memory consolidation remained unaffected. We also found a significant correlation between the declarative task and sleep spindles in the undisturbed condition, especially the sleep spindles in the first third of the night.	We suggest that word-pair learning relies on stage 2 sleep spindles and requires little SWS. Their sleep dependent consolidation is not affected by SWS deprivation. Simple motor tasks may either be consolidated in stage 2 sleep or depend on only small amounts of REM sleep. Their sleep dependent consolidation is not influenced by REM sleep deprivation.	
19280578	The main disabilities in non-verbal learning disorder (NLD) are: the acquisition and automating of motor and cognitive processes, visual spatial integration, motor coordination, executive functions, difficulty in comprehension of the context, and social skills. AIMS. To review the research to date on NLD, and to discuss whether the term 'procedural learning disorder' (PLD) would be more suitable to refer to NLD.A considerable amount of research suggests a neurological correlate of PLD with dysfunctions in the 'posterior' attention system, or the right hemisphere, or the cerebellum. Even if it is said to be difficult the delimitation between NLD and other disorders or syndromes like Asperger syndrome, certain characteristics contribute to differential diagnosis. Intervention strategies for the PLD must lead to the development of motor automatisms and problem solving strategies, including social skills.	The basic dysfunction in NLD affects to implicit learning of routines, automating of motor skills and cognitive strategies that spare conscious resources in daily behaviours. These limitations are partly due to a dysfunction in non-declarative procedural memory. Various dimensions of language are also involved: context comprehension, processing of the spatial and emotional indicators of verbal language, language inferences, prosody, organization of the inner speech, use of language and non-verbal communication; this is why the diagnostic label 'PLD' would be more appropriate, avoiding the euphemistic adjective 'non-verbal'.	
19285462	A dominant view in the learning and memory literature states that a subset of anatomically related structures within the medial temporal lobe (MTL), including the hippocampus, entorhinal, perirhinal, and parahippocampal cortices, forms a functionally related system specialized for declarative memory but not for perception. However, recent reports challenge this view, suggesting instead that the medial temporal lobe is not only important for memory, but also critical for certain forms of perception. In this review, I argue that little or no conclusive evidence currently exists to support the latter view. Experimental studies that have examined the perceptual functions of the MTL in monkeys are inconclusive because they fail to isolate perceptual from mnemonic task demands. Evaluation of conflicting results from studies in human amnesic patients suggests that extraneous damage to extra-MTL areas may underlie the reported perceptual deficits in the group of amnesic patients at the heart of this debate. See the related Review from Baxter, "Involvement of Medial Temporal Lobe Structures in Memory and Perception," in this issue of Neuron.
19265570	The clinical use of benzodiazepines (BZs) is hampered by sedation and cognitive deterioration. Although genetic and pharmacological studies suggest that alpha1- and alpha5-containing GABA(A) receptors mediate and/or modulate these effects, their molecular substrate is not fully elucidated. By the use of two selective ligands: the alpha1-subunit affinity-selective antagonist beta-CCt, and the alpha5-subunit affinity- and efficacy-selective antagonist XLi093, we examined the mechanisms of behavioural effects of diazepam in the tests of spontaneous locomotor activity and water-maze acquisition and recall, the two paradigms indicative of sedative- and cognition-impairing effects of BZs, respectively. The locomotor-activity decreasing propensity of diazepam (significant at 1.5 and 5 mg/kg) was antagonized by beta-CCt (5 and 15 mg/kg), while it tended to be potentiated by XLi093 in doses of 10 mg/kg, and especially 20 mg/kg. Diazepam decreased acquisition and recall in the water maze, with a minimum effective dose of 1.5 mg/kg. Both antagonists reversed the thigmotaxis induced by 2 mg/kg diazepam throughout the test, suggesting that both GABA(A) receptor subtypes participate in BZ effects on the procedural component of the task. Diazepam-induced impairment in the declarative component of the task, as assessed by path efficiency, the latency and distance before finding the platform across acquisition trials, and also by the spatial parameters in the probe trial, was partially prevented by both, 15 mg/kg beta-CCt and 10 mg/kg XLi093. Combining a BZ with beta-CCt results in the near to control level of performance of a cognitive task, without sedation, and may be worth testing on human subjects.
19252155	The presence of schizotypal personality traits in some people with bipolar disorder, together with reports of greater cognitive dysfunction in patients with a history of psychotic features compared with patients without such a history, raises questions about the nosological relationship between bipolar disorder with psychotic features and bipolar disorder without psychotic features.To test the impact of a history of DSM-IV-defined psychosis on the neuropsychological status of participants with bipolar disorder while statistically controlling for confounding factors such as mood, medication, alcohol misuse/dependence and childhood abuse, and to evaluate the impact of schizotypal personality traits (and thus potential vulnerability to psychotic illness) on the cognitive performance of people with bipolar disorder and their healthy relatives.	Neuropsychological data were obtained for 25 participants with type I bipolar disorder and a history of psychosis, 24 with type I bipolar disorder but no history of psychosis and 61 unaffected relatives. Schizotypal traits were measured with the Schizotypal Personality Scale (STA). Childhood trauma was measured with the Childhood Trauma Questionnaire.	The group with a history of psychosis performed significantly worse than the healthy relatives on measures of verbal working memory, cognitive flexibility and declarative memory. Nevertheless, the two bipolar disorder groups did not differ significantly from each other on any cognitive measure. Scores on the STA were negatively associated with verbal working and declarative memory, but positively associated with visual recall memory.	'Psychotic' and 'non-psychotic' subtypes of bipolar disorder may lie on a nosological continuum that is most clearly defined by verbal memory impairment.	
19251443	Sleep benefits memory consolidation. The reviewed studies indicate that this consolidating effect is not revealed under all circumstances but is linked to specific psychological conditions. Specifically, we discuss to what extent memory consolidation during sleep depends on the type of learning materials, type of learning and retrieval test, different features of sleep and the subject population. Post-learning sleep enhances consolidation of declarative, procedural and emotional memories. The enhancement is greater for weakly than strongly encoded associations and more consistent for explicitly than implicitly encoded memories. Memories associated with expected reward gain preferentially access to sleep-dependent consolidation. For declarative memories, sleep benefits are more consistently revealed with recall than recognition procedures at retrieval testing. Slow wave sleep (SWS) particularly enhances declarative memories whereas rapid eye movement (REM) sleep preferentially supports procedural and emotional memory aspects. Declarative memory profits already from rather short sleep periods (1-2 h). Procedural memory profits seem more dose-dependent on the amount of sleep following the day after learning. Children's sleep with high amounts of SWS distinctly enhances declarative memories whereas elderly and psychiatric patients with disturbed sleep show impaired sleep-associated consolidation often of declarative memories. Based on the constellation of psychological conditions identified we hypothesize that access to sleep-dependent consolidation requires memories to be encoded under control of prefrontal-hippocampal circuitry, with the same circuitry controlling subsequent consolidation during sleep.
19251274	Although the consolidation of several memory systems is enhanced by sleep in adults, recent studies suggest that sleep supports declarative memory but not procedural memory in children. In the current study, the influence of sleep on emotional declarative memory (recognition task) and procedural memory (mirror tracing task) in 20 healthy children (10-13 years of age) was examined. After sleep, children showed an improvement in declarative memory. Separate analysis with respect to the emotional stimulus content revealed that sleep enhances the recognition of emotional stimuli (p>.001) rather than neutral stimuli (p=.084). In the procedural task, however, no sleep-enhanced memory improvement was observed. The results indicate that sleep in children, comparable to adults, enhances predominantly emotional declarative memory; however, in contrast to adults, it has no effect on the consolidation of procedural memory.
19246915	Age-related cognitive decline might involve selective deterioration of specific brain systems. We studied the relationship between age and cognition by comparing cognitive function of older and younger high functioning men.A cross-sectional study comparing neuropsychological test battery performance of younger (18-60 years) and older (61-85 years) men.	Older men showed impaired psychomotor speed, working memory, attention, declarative verbal memory and executive functions. Impairment in executive function was prominent and not explained by psychomotor slowing, impaired working memory or attention. Regression models showed a non-linear relationship between age and executive function with a change of slopes in the mid-50s. The relationship of age with verbal memory was linear.	The nonlinear change in late middle age is consistent with the hypothesis that an age-related selective diatheses impacts selectively on executive function.	
19234620	We have worked to develop rich communicative environments as a way to study the real-world demands that communication places on language-and-memory-in-use by focusing on the impact of declarative memory impairments on social interaction. Here, we analyse procedural discourse-the practice of telling another person how to do something (e.g., giving directions).To facilitate comparison to previous research on procedural discourse, this study includes an analysis of the procedural steps produced by target participants. This study also offers a novel approach by focusing on the collaborative and interactional nature of how procedural discourse is produced to meet the demands of real-world communication.	Procedural discourse samples were obtained on nine individuals with hippocampal amnesia and nine comparison participants each interacting with a clinician. Using traditional procedural and linguistic-based measures and interactional discourse measures, we analysed target participants' individual contribution to procedural descriptions and contributions of both the clinician and participant across the samples. OUTCOMES #ENTITYSTARTX00026; RESULTS: No significant group differences were observed for procedural and linguistic-based measures. Rather, participants with amnesia were more reliably distinguished on interactional discourse measures (e.g., lack of engagement and support for clinician, less detail and personalisation of procedural steps, difficulty in shifting social stance).	These findings accord with our previous research suggesting that hippocampal amnesia disrupts the flexible deployment of declarative knowledge and the ability to shift social stances/perspectives to meet the demands of social interaction. These findings contribute to the evolving portrait of language-and-memory-in-use and further support the value of examining interactional aspects of communication in the empirical study of brain-behaviour relationships.	
19224116	Schizophrenia is a major mental disorder which is characterized by several cognitive deficits. Investigations of the neural basis of memory dysfunctions using neuroimaging techniques suggest that the hippocampus plays an important role in declarative memory impairment. The goal of this study was to investigate possible dysfunctions in cerebral activation in schizophrenic patients during both word and face recognition memory tasks. We tested 22 schizophrenics and 24 controls matched by gender, age, handedness and parental socioeconomic status. Compared to healthy volunteers, patients with schizophrenia showed decreased bilateral hippocampal activation during word and face recognition tasks. The whole brain analysis also showed a pattern of cortical and subcortical hypoactivation for both verbal and non-verbal recognition. This study provides further evidence of hippocampal involvement in declarative memory impairments of schizophrenia.
19222321	Patients with remitted bipolar disorder (BD) have persistent cognitive deficits, but the nature and specificity of this deficit remain unclear. The authors evaluated the executive hypothesis of BD by determining whether (a) patients' executive deficits qualify as differential deficits, that is, that these significantly exceed deficits in other cognitive domains; (b) deficits in particular executive functions are evident, and (c) executive difficulties mediate declarative memory deficits in BD. The cognitive performance of 63 prospectively verified euthymic bipolar patients was compared with controls, using J. Baron and R. Trieman's (1980) method of testing for differences in nonindependent correlations. There were no differential deficits within the executive domain. Patients' generic executive performance was differentially impaired relative to primary verbal memory and retention in declarative memory, but not relative to their declarative recall, recognition, or their psychomotor performance. However, patients' executive deficit was not an artifact of their poor psychomotor performance. Executive performance accounted for all but a trivial portion of the between-group variance in declarative memory. Persistent cognitive difficulties in euthymic bipolar disorder (EBD) are thus usefully characterized as a generic dysexecutive syndrome.
19217757	Diffusion tensor imaging (DTI) is a relatively new technique used to detect changes in the anisotropic diffusion of white matter. The study of the disruption of brain connectivity may increase our understanding of cognitive deficits associated with schizophrenia. Here we analysed DTI data in 25 patients with DSM-IV schizophrenia and 24 healthy controls. Two complementary measures, fractional anisotropy (FA) and the apparent diffusion coefficient (ADC), were considered and analysed using voxel-based morphometry. Declarative memory functions were also investigated and their associations with DTI data were analysed. FA was significantly reduced, and the ADC increased in the left sub-gyral white matter of the temporal lobe, which involves the posterior part of the fornix. In the schizophrenic group, females had lower FA than males in the genu of the corpus callosum. Memory functions correlate with FA values. These data provide further evidence for the disruption of white matter connectivity in the left medial temporal lobe, and for its contribution to the declarative memory deficit in schizophrenia.
19209999	How the memory of adults evolves from the memory abilities of infants is a central problem in cognitive development. The popular solution holds that the multiple memory systems of adults mature at different rates during infancy. The early-maturing system (implicit or nondeclarative memory) functions automatically from birth, whereas the late-maturing system (explicit or declarative memory) functions intentionally, with awareness, from late in the first year. Data are presented from research on deferred imitation, sensory preconditioning, potentiation, and context for which this solution cannot account and present an alternative model that eschews the need for multiple memory systems. The ecological model of infant memory development (N. E. Spear, 1984) holds that members of all species are perfectly adapted to their niche at each point in ontogeny and exhibit effective, evolutionarily selected solutions to whatever challenges each new niche poses. Because adults and infants occupy different niches, what they perceive, learn, and remember about the same event differs, but their raw capacity to learn and remember does not.
19204651	A previous study found improvements in verbal declarative memory in patients with Posttraumatic Stress Disorder (PTSD) following one year of open-label paroxetine treatment. The purpose of the present study was to replicate prior findings and to extend the previous study by comparing the effects of paroxetine versus placebo on cognition in patients with PTSD.Eighteen participants with PTSD underwent assessment of neuropsychological function, following which they were randomized to receive controlled-release (CR) paroxetine or placebo, given in a variable dose in a double- blind manner for three months. Neuropsychological testing was then repeated. Subjects who had received placebo were then treated with open-label paroxetine CR and re-assessed.	Paroxetine CR treatment resulted in a significant increase in verbal declarative memory function in the group as a whole, as measured by the Wechsler Memory Scale-Revised, the Selective Reminding Test, and novel paragraph recall, and explicit recall of neutral words. Although we found patterns of improved test performance with paroxetine versus placebo treatment, these differences were not statistically significant.	These findings replicate an earlier finding that open label treatment with paroxetine CR is associated with improvements in verbal declarative memory function. The current study did not show a statistically significant difference between the effects of paroxetine and placebo on memory function, which may in part be related to our small sample size.	
19194375	Rapid eye movement (REM) sleep has been considered important for the consolidation of memories, particularly of procedural skills. REM sleep, in contrast to slow-wave sleep (SWS), is hallmarked by the high, wake-like activity of the neurotransmitter acetylcholine (ACh), which promotes certain synaptic plastic processes underlying the formation of memories. Here, we show in healthy young men that off-line consolidation of a motor skill during a period of late sleep with high amounts of REM sleep depends essentially on high cholinergic activity. After a 3-h sleep period during the early night to satisfy the need for SWS, subjects learned a procedural finger sequence tapping task and a declarative word-pair learning task. After learning, they received either placebo or a combination of the muscarinic receptor antagonist scopolamine (4 microg/kg bodyweight, intravenously) and the nicotinic receptor antagonist mecamylamine (5 mg, orally), and then slept for another 3 h, ie, the late nocturnal sleep period, which is dominated by REM sleep. Retrieval was tested the following evening. Combined cholinergic receptor blockade significantly impaired motor skill consolidation, whereas word-pair memory remained unaffected. Additional data show that the impairing effect of cholinergic receptor blockade is specific to sleep-dependent consolidation of motor skill and does not occur during a wake-retention interval. Taken together, these results identify high cholinergic activity during late, REM sleep-rich sleep as an essential factor promoting sleep-dependent consolidation of motor skills.
19162087	The Tg2576 transgenic mouse is an extensively characterized animal model for Alzheimer's disease (AD). Similar to AD, these mice suffer from progressive decline in several forms of declarative memory including contextual fear conditioning and novel object recognition (NOR). Recent work on this and other AD animal models suggests that initial cognitive deficits are due to synaptic dysfunction that, with the correct intervention, are fully treatable. We recently reported that acute calcineurin (CaN) inhibition with FK506 ameliorates one form of declarative memory (contextual fear conditioning) impairment in 5 months old Tg2576. This study tested whether acute CaN inhibition rescues deficits in an additional form of declarative memory, spontaneous object recognition, by employing the NOR paradigm. Furthermore, we determined whether FK506 rescue of NOR deficits depends on the retention interval employed and therefore is restricted to short-term, intermediate-term, or long-term memory (STM, ITM or LTM, respectively). In object recognition, Tg2576 are unimpaired when NOR is tested as a STM task and CaN inhibition with FK506 does not influence NOR STM performance in Tg2576 or WT mice. Tg2576 were impaired in NOR compared to WT mice when a 4 or 24h retention interval was employed to model ITM and LTM, respectively. Acute CaN inhibition prior to and during the training session reversed these deficits in Tg2576 mice with no effect on WT performance. Our findings demonstrate that aberrant CaN activity mediates object recognition deficits in 5 months old Tg2576 when NOR is employed as a test for ITM and LTM. In human AD, CaN inhibition may lead the way for therapeutics to improve declarative memory performance as demonstrated in a mouse model for AD.
19152736	Transient global amnesia (TGA) is an episodic dysfunction of declarative memory that usually resolves within 12 hours and whose underlying pathophysiological mechanisms are still unclear. Recent studies, on the basis of transient focal high-signal abnormalities in the hippocampus on diffusion-weighted imaging (DWI), suggest involvement of memory circuits in the temporo-mesial region. Out of a total of 65 patients presenting with acute or subacute TGA between May 2004 and May 2008, we retrospectively analysed 21 in whom a DWI sequence was performed. Five patients showed a focal hippocampal signal alteration both on DWI and on conventional T2; this alteration was no longer detectable on follow-up MRI two months later. The presence of transient DWI and T2 alterations in the hippocampal formation suggests that TGA could have a multifactorial, non-vascular aetiology. The presence of local susceptibility to neuronal metabolic stress emerges as a likely hypothesis.
19150098	Pure progressive amnesia, a form of progressive focal cortical atrophy is thought to represent the early stages of a rare form of Alzheimer's disease (AD). This syndrome is characterized by the insidious and slowly progressive breakdown of memory, in the absence of a significant impairment in other cognitive domains or in the realm of behavior. The aims of the present study were to contribute to the characterization of this poorly documented type of amnesia, to compare it with other forms of amnestic syndromes resulting from lesions to the medial temporal lobes and to discuss its potential pathophysiological basis.We carried out three single case studies in patients presenting with pure progressive amnesia. They all underwent a neuropsychological evaluation that included an extensive assessment of spatial and recognition memory, along with brain magnetic resonance imaging and a cerebral blood flow study.	All three patients had a severe deficit in the storage of context-free information, along with a severe visual recognition memory impairment, as previously reported in a case study on a patient with pure progressive amnesia (Cognitive Neuropsychology 23 (2006) 1230-1247). Yet, spatial memory remained well preserved, and patients maintained totally independent in everyday life. In addition, a significant atrophy of the medial temporal structures was found.	This specific pattern of impairment differs from other types of amnestic syndromes after medial temporal damage and raises the question of lesional topography, as well as possible compensatory phenomena. We suggest that pure progressive amnesia results from selective damage to the ventral subhippocampal route into the hippocampal formation leading to impaired context-free memory. Spatial memory may remain intact because the dorsal parahippocampal route into the hippocampus remains functional. Pure progressive amnesia may contribute to a better understanding of the neural systems involved in declarative memory and provide a better understanding into the nature of the memory impairment that characterizes the initial stages of AD.	
19140178	The hippocampus is involved in declarative memory and produces new neurons throughout adulthood. Numerous experiments have been aimed at testing the possibility that adult neurogenesis is required for learning and memory. However, progress has been encumbered by the fact that abating adult neurogenesis usually affects other biological processes, confounding the interpretation of such experiments. In an effort to circumvent this problem, we used a reverse approach to test the role of neurogenesis in hippocampus-dependent learning, exploiting the low levels of adult neurogenesis in the MRL/MpJ strain of mice compared with other mouse strains. We observed that adult MRL/MpJ mice produce 75% fewer new neurons in the dentate gyrus than age-matched C57BL/6 mice. Learning-induced synaptic remodeling, spatial learning, and visual recognition learning were reduced in MRL/MpJ mice compared with C57BL/6 mice. When MRL/MpJ mice were allowed unlimited access to running wheels, neurogenesis along with spatial learning and visual recognition learning were increased to levels comparable to those in running C57BL/6 mice. Together, these results suggest that adult neurogenesis is correlated with spatial learning and visual recognition learning, possibly by modulating morphological plasticity in the dentate gyrus.
19139852	Propranolol is found to reduce physiological hyper-responsiveness in post traumatic stress disorder (PTSD), possibly by affecting reconsolidation after the reactivation of traumatic memories. Cortisol is found to attenuate declarative memory retrieval, but it is unknown whether it also reduces physiological responses to emotional memories.To examine whether the effects of propranolol on physiological responding to emotional memories can also be found in healthy controls and to investigate the immediate and prolonged effects of cortisol on physiological responding to emotional memories, we tested these effects in 79 healthy young men.	After preparing a script of a negative disturbing memory, participants were instructed to imagine this event 1 week later after ingestion of either 35 mg cortisol, 80 mg propranolol, or a placebo. Physiological responding to the script-driven imagery was recorded. Another week later, after washout, the imagery was repeated again. During all three sessions as well as 8 months later, subjective emotional reactions to the memories were assessed.	The emotionality of the memories was reduced over time, which was not affected by the treatments, however. The personal emotional script did evoke higher skin conductance responses than a neutral story, which decreased 1 week later, but no effects were found of either propranolol or cortisol on this responsiveness.	Whereas healthy males do show psychophysiological responding to personal emotional scripts, the effects of cortisol and propranolol on physiological responses to emotional memories might be specific to clinical groups characterized by hyper-responsiveness, like PTSD. Future studies using longer-acting doses and more elaborate reactivation procedures in both healthy men and women could shed more light on the effects of cortisol and propranolol on psychophysiological responding to emotional memories.	
19135404	The function of the human hippocampus is a contentious subject among neuroscientists. Theoreticians have long viewed the hippocampus as a computational device, with researchers in humans increasingly adopting this perspective, buoyed by recent reports that its role is not limited to declarative memory. Here, we set out a new strategy for discovering the nature of information processing within the human hippocampus. We argue that novelty responses, measured by functional magnetic resonance imaging, provide a window into the neural representations and computations sustained by the hippocampus. More generally, we suggest that a renewed emphasis on the information processing qualities of the human hippocampus offers the promise of a long awaited union between theoretical and empirical research across species.
19123250	Temporal difference learning (TD) is a popular algorithm in machine learning. Two learning signals that are derived from this algorithm, the predictive value and the prediction error, have been shown to explain changes in neural activity and behavior during learning across species. Here, the predictive value signal is used to explain the time course of learning-related changes in the activity of hippocampal neurons in monkeys performing an associative learning task. The TD algorithm serves as the centerpiece of a joint probability model for the learning-related neural activity and the behavioral responses recorded during the task. The neural component of the model consists of spiking neurons that compete and learn the reward-predictive value of task-relevant input signals. The predictive-value signaled by these neurons influences the behavioral response generated by a stochastic decision stage, which constitutes the behavioral component of the model. It is shown that the time course of the changes in neural activity and behavioral performance generated by the model exhibits key features of the experimental data. The results suggest that information about correct associations may be expressed in the hippocampus before it is detected in the behavior of a subject. In this way, the hippocampus may be among the earliest brain areas to express learning and drive the behavioral changes associated with learning. Correlates of reward-predictive value may be expressed in the hippocampus through rate remapping within spatial memory representations, they may represent reward-related aspects of a declarative or explicit relational memory representation of task contingencies, or they may correspond to reward-related components of episodic memory representations. These potential functions are discussed in connection with hippocampal cell assembly sequences and their reverse reactivation during the awake state. The results provide further support for the proposal that neural processes underlying learning may be implementing a temporal difference-like algorithm.
20721295	Objective. To assess the ability of Alzheimer's disease (AD) patients to perceive emotional information and to assign subjective emotional rating scores to audiovisual presentations. Materials and Methods. 24 subjects (14 with AD, matched to controls for age and educational levels) were studied. After neuropsychological assessment, they watched a Neutral story and then a story with Emotional content. Results. Recall scores for both stories were significantly lower in AD (Neutral and Emotional: P = .001). CG assigned different emotional scores for each version of the test, P = .001, while ratings of AD did not differ, P = .32. Linear regression analyses determined the best predictors of emotional rating and recognition memory for each group among neuropsychological tests battery. Conclusions. AD patients show changes in emotional processing on declarative memory and a preserved ability to express emotions in face of arousal content. The present findings suggest that these impairments are due to general cognitive decline.
19095545	The multiagent optimization system (MAOS) is a nature-inspired method, which supports cooperative search by the self-organization of a group of compact agents situated in an environment with certain sharing public knowledge. Moreover, each agent in MAOS is an autonomous entity with personal declarative memory and behavioral components. In this paper, MAOS is refined for solving the traveling salesman problem (TSP), which is a classic hard computational problem. Based on a simplified MAOS version, in which each agent manipulates on extremely limited declarative knowledge, some simple and efficient components for solving TSP, including two improving heuristics based on a generalized edge assembly recombination, are implemented. Compared with metaheuristics in adaptive memory programming, MAOS is particularly suitable for supporting cooperative search. The experimental results on two TSP benchmark data sets show that MAOS is competitive as compared with some state-of-the-art algorithms, including the Lin-Kernighan-Helsgaun, IBGLK, PHGA, etc., although MAOS does not use any explicit local search during the runtime. The contributions of MAOS components are investigated. It indicates that certain clues can be positive for making suitable selections before time-consuming computation. More importantly, it shows that the cooperative search of agents can achieve an overall good performance with a macro rule in the switch mode, which deploys certain alternate search rules with the offline performance in negative correlations. Using simple alternate rules may prevent the high difficulty of seeking an omnipotent rule that is efficient for a large data set.
19087482	To investigate potential changes and associations in clinical dimensions and cognitive functioning after the first 6 weeks of pharmacological treatment as the relation between cognitive and clinical change may have an impact in determining the importance of cognition as a treatment target.Patients (n = 42) completed a brief battery of 5 neurocognitive tests within 72 hours of commencing, and 6 weeks after, standard pharmacological treatment. The cognitive testing comprised 5 domains: attention, visuomotor speed, declarative memory, working memory, and executive function. Volunteers (n = 43) were recruited to control for practice effects.	Patients and control subjects improved over time in the raw scores in cognitive tests. Patients' performance, at baseline and end point assessments, was below that of the control subjects in all cognitive variables, except the Stroop interference score. No interaction effect between time and group was found. Further, after controlling for practice effects and adjusting for multiple comparisons, patients' cognitive performance showed no significant improvement. Accordingly, there was no association between clinical improvement and cognitive change. This lack of association was also observed in the subgroup of people who showed decreased scores in negative symptoms.	Cognitive response is not clearly enhanced by antipsychotic drugs and it is not a by-product of clinical recovery during the acute phase (first 6 weeks) of a first-episode nonaffective psychosis.	
19084409	Bilateral damage to the human hippocampus profoundly impairs the ability to form long-term, consciously accessible memories, producing a classic amnesic syndrome. However, the effect of hippocampal damage on our ability to recognize items via a feeling of familiarity is hotly disputed. Dual-process theory predicts no effect, whereas declarative memory theory predicts impairment of all types of recognition memory. Here, we demonstrate a striking material specificity in the effect of focal hippocampal damage: Recognition memory is impaired for words but intact for faces. The latter finding is incompatible with declarative memory theory, whereas the former constrains dual-process theory by revealing the limitations of postulated extrahippocampal familiarity-based processes. We suggest that the hippocampus boosts recognition of well-known stimuli (high-frequency words) by activating pre-experimental associations that enrich the context of their presentation. By contrast, recognition memory for some kinds of previously unfamiliar stimuli (unfamiliar faces) may be supported by extrahippocampal familiarity-based processes, at least over short intervals.
19081708	To gain insight into memory disturbances in Complex Posttraumatic Stress Disorder (Complex PTSD), we investigated declarative memory function and medial temporal lobe activity in patients and healthy non-traumatized controls. A case-control study was performed in nine patients with Complex PTSD and nine controls. All respondents performed a declarative memory task with neutral and emotional, negative words during functional magnetic resonance imaging. Memory performance of neutral words was impaired in Complex PTSD with a relative conservation of recall of negative words. Deep encoding of later remembered negative words, as well as correct recognition of negative words and false alarms, was associated with an enhanced Blood Oxygenation Level Dependent (BOLD) response in the left hippocampus extending into the parahippocampal gyrus of Complex PTSD patients compared with controls. Post-hoc volumetric comparisons did not reveal significant anatomical differences in the medial temporal lobe between Complex PTSD patients and controls. We conclude that in Complex PTSD preferential recall of negative words is associated with increased activation in the left hippocampus and parahippocampal gyrus during both successful and false recall. These findings support a model of an abnormally functioning hippocampus in Complex PTSD.
18929316	Although we still lack any consensus function(s) for sleep, accumulating evidence suggests it plays an important role in homeostatic restoration, thermoregulation, tissue repair, immune control and memory processing. In the last decade an increasing number of reports continue to support a bidirectional and symbiotic relationship between sleep and memory. Studies using procedural and declarative learning tasks have demonstrated the need for sleep after learning in the offline consolidation of new memories. Furthermore, these consolidation benefits appear to be mediated by an overnight neural reorganization of memory that may result in a more efficient storage of information, affording improved next-day recall. Sleep before learning also appears to be critical for brain functioning. Specifically, one night of sleep deprivation markedly impairs hippocampal function, imposing a deficit in the ability to commit new experiences to memory. Taken together, these observations are of particular ecologic importance from a professional and education perspective when considering that sleep time continues to decrease across all age ranges throughout industrialized nations.
19068249	The lower-than-average cognitive performance of individuals with bilateral cerebral palsy found in previous studies does not always refer to an abnormal performance or clinically significant impairment. We aimed to establish the percentage of persons with bilateral cerebral palsy who present neuropsychologic impairment, and its relationship to perinatal data and motor signs. Forty children, adolescents, and adults (age range, 6-38 years; 15 females and 25 males) with bilateral cerebral palsy were neuropsychologically assessed. Vocabulary was impaired in 85% of participants, language comprehension in 13-48%, visuoperceptual abilities in 60%, visuospatial abilities in 90%, short-term memory in 21-58%, declarative memory in 47-67%, and praxis comprehension in 20%, with executive deficits in 58-74%. Perinatal data (intrauterine growth and birth weight) contributed to explaining memory impairment. Among cerebral palsy subtypes (spastic, mixed, and dyskinetic), forms of impairment differed only in short-term verbal memory. No persons with dyskinetic cerebral palsy experienced impairment in immediate memory or working visual memory. We conclude that visuospatial deficit is the most frequent impairment in people with bilateral cerebral palsy. Moreover, short-term memory impairment seems sensitive to perinatal complications, and differs among bilateral cerebral palsy subtypes.
19056409	The study examined the extent to which time-related gains in cognitive performance, so-called Flynn effects, generalize across sub-factors of episodic memory (recall and recognition) and semantic memory (knowledge and fluency). We conducted time-sequential analyses of data drawn from the Betula prospective cohort study, involving four age-matched samples (35-80 years; N=2996) tested on the same battery of memory tasks on either of four occasions (1989, 1995, 1999, and 2004). The results demonstrate substantial time-related improvements on recall and recognition as well as on fluency and knowledge, with a trend of larger gains on semantic as compared with episodic memory [Rönnlund, M., & Nilsson, L. -G. (2008). The magnitude, generality, and determinants of Flynn effects on forms of declarative memory: Time-sequential analyses of data from a Swedish cohort study. Intelligence], but highly similar gains across the sub-factors. Finally, the association with markers of environmental change was similar, with evidence that historical increases in quantity of schooling was a main driving force behind the gains, both on the episodic and semantic sub-factors. The results obtained are discussed in terms of brain regions involved.
19046157	Hartshorne and Ullman (2006) presented naturalistic language data from 25 children (15 boys, 10 girls) and showed that girls produced more past tense overregularization errors than did boys. In particular, girls were more likely to overregularize irregular verbs whose stems share phonological similarities with regular verbs. It was argued that the result supported the Declarative/Procedural model of language, a neuropsychological analogue of the dual-route approach to language. In the current study we present experimental data that are inconsistent with these naturalistic data. Eighty children (40 males, 40 females) aged 5;0-6;9 completed a past tense elicitation task, a test of declarative memory, and a test of non-verbal intelligence. The results revealed no sex differences on any of the measures. Instead, the best predictors of overregularization rates were item-level features of the test verbs. We discuss the results within the context of dual versus single route debate on past tense acquisition.
19032118	OBJECTIVE AND SCOPE: This review article used data from an extensive literature search (including MEDLINE database searches) to explore the relationships between sleep, memory and Alzheimer's disease (AD). The importance of taking into account circadian rhythmicity and acetylcholine (ACh) levels when considering acetylcholinesterase inhibitors, galantamine in particular, in the treatment of patients with AD is discussed.Moderate changes of circadian rhythms may occur as part of the normal ageing process, but patients with AD exhibit circadian rhythm disturbances extending beyond those observed in non-demented elderly and this may lead to severe disruption of the sleep-wake cycle. Indeed, ACh plays an active role in maintaining a normal sleep pattern, which is important for memory consolidation. Low levels of ACh during slow-wave sleep compared with wakefulness have been shown to be critical for the consolidation of declarative memory. This suggests the existence of a circadian rhythm in central cholinergic transmission which modulates memory processes, with high ACh levels during wakefulness and reduced levels during slow-wave sleep. When using cholinesterase inhibitors to stimulate central cholinergic transmission in AD, respecting the natural circadian fluctuations of central cholinergic transmission may therefore be an important factor for patient improvement. Interfering with nocturnal cholinergic activity can add to memory problems and induce sleep disorders. Available data suggest that the type of cholinesterase inhibitor used and the time of administration may be critical with regard to the possible development of such disturbances. Plasma levels of galantamine, for example, are high during the waking day and lower at night, supporting a cholinergic stimulation that mirrors the physiological circadian rhythm of cholinergic activity. This may have beneficial implications with regard to sleep and memory.	The pharmacokinetic properties of cholinesterase inhibitors may need to be taken into account to avoid interference with sleep architecture and to achieve optimum benefits from treatment on cognitive processes.	
19028019	Previous evidence indicates that stress hormone effects on memory consolidation depend on concurrent emotional arousal-induced noradrenergic activity. Here, we asked whether this is also true for stress effects on memory retrieval and hypothesized that administration of the beta-adrenoceptor antagonist propranolol would block the effects of stress on declarative and procedural retrieval performance. In a double-blind, placebo-controlled, crossover study, 44 healthy young men learned a list of emotional and neutral words (declarative memory task) and completed a serial reaction time task (procedural memory task). On the following day, participants received either a placebo or 40 mg propranolol orally. One hour later, they were exposed to stress (socially evaluated cold pressor test (SECPT)) or a control condition 30 min prior to retention testing. Stress selectively enhanced the retrieval of emotionally arousing words. Pretreatment with propranolol had no effect on memory alone but blocked the stress-induced memory enhancement for emotional words, confirming the importance of noradrenergic activity in stress effects on memory retrieval. Memory for neutral words and the procedural task was neither affected by stress nor by propranolol. The present findings suggest that stress (hormone) effects on emotional memory retrieval require concurrent noradrenergic activation. Procedural memory retrieval and the retrieval of neutral verbal material appear to be less susceptible to stress.
18989664	Acallosal participants usually do not display any disconnection signs in tasks requiring an explicit or declarative type of response. They can accurately compare stimuli placed in each hand and they perform normally on lateralized recognition tasks. They, however, show impairment in tasks assessing interdependent motor control, bilateral coordination and they are also unable to intermanually transfer an implicit procedural motor skill. These deficits suggest that compensation might be limited when a motor component is involved. Alternately, it is also possible that interhemispheric transmission in callosal agenesis might be limited when implicit or unconscious processes are involved (Berlucchi et al. in Neuropsychologia 33:923-936, 1995; De Guise et al. in Brain 122:1049-1062, 1999). The aim of the present study was to assess interhemispheric transfer in two distinct nondeclarative tasks, namely visuoperceptual skill learning and perceptual priming, with a lateralized version of the fragmented picture task developed by Snodgrass et al. (Behav Res Methods Inst Comp 19:270-274, 1987) that did not involve any motor component. The performance of five acallosal and one early-callosotomized individuals was compared to that of control participants divided into four groups (n = 10) according to which hemisphere was trained (left or right) and which response mode was used (manual or verbal). Visuoperceptual skill learning was observed in all control groups except for the group submitted to training of the left hemisphere in the manual modality of response. The acallosal and early-callosotomized participants did not show any implicit learning of the visuoperceptual skill on any of the conditions. The evaluation of the perceptual priming effect in the second part of the testing revealed that the priming effect was restricted to the trained hemisphere in participants without corpus callosum, as opposed to all neurogically intact participants who presented interhemispheric transfer of the priming effect. These findings indicate that the compensatory pathways, most probably subcortical commissures, are insufficient to allow interhemispheric transfer of perceptual priming, confirming the limits of neural plasticity in the absence of the corpus callosum. They also support the dissociation between declarative and nondeclarative memory in the split-brain and acallosal participants suggested by Berlucchi et al. (1995) and observed by De Guise et al. (Brain 122:1049-1062, 1999). These results are further discussed within the context of neurobiological theories of memory systems.
18989110	To gain a complete understanding of how the brain functions, both in illness and good health, data from multiple levels of analysis must be integrated. Technical advances have made direct recordings of neuronal activity deep inside the human brain tractable, providing a rare glimpse into cellular processes during long-term memory formation. Recent findings using intracranial recordings in the medial temporal lobe inform current neural network models of memory, and may lead to a more comprehensive understanding of the neural basis of memory-related processes.These recordings have shown that cells in the hippocampus appear to support declarative learning by distinguishing novel and familiar stimuli via changes in firing patterns. Some cells with highly selective and invariant responses have also been described, and these responses seem to represent abstract concepts such as identity, rather than superficial perceptual features of items. Importantly, however, both selective and globally responsive cells are capable of changing their preferred stimulus depending on the conscious demands of the task.	Firing patterns of human medial temporal lobe neurons indicate that cells can be both plastic and stable in terms of the information that they code; although some cells show highly selective and reproducible excitatory responses when presented with a familiar object, other cells change their receptive fields in line with changes in experience and the cognitive environment.	
18980399	The grouping of list items is known to improve serial memory accuracy and constrain the nature of temporal errors. A recent study (M. T. Maybery, F. B. R. Parmentier, & D. M. Jones, 2002) showed that grouping results in a temporal organization of the participants' responses that mimics the list structure but not the timing of its presentation. Here the authors tested the prediction that the temporal grouping of responses should yield the same pattern of response time (RT) irrespective of the method of grouping at presentation. Comparing temporal, location, and voice grouping, the results show that although these methods impact on recall accuracy to varying degrees, all 3 conditions produce significant and equivalent peaks in RT at the first position of each group. The RT data were accurately simulated through a model based on ACT-R's (J. R. Anderson & M. Matessa, 1997) basic principles. Altogether, the data suggest that the temporal organization of responses in verbal serial recall results from (a) declarative knowledge about the list's structure that is independent of the perceptual means by which grouping is induced at presentation and (b) the level of activation of the items per se.
18958185	Past research has concentrated on the stress system and personality in order to explain the variance found in cognitive performance in old age. A growing body of research is starting to focus on genetic polymorphism as an individual difference factor to explain the observed heterogeneity in cognitive function. While the functional mechanism is still under investigation, polymorphism of the 5-HT(2A) receptor gene (-1438A/G) has been linked to certain behavioral and physiological outcomes, including cortisol secretion, the expression of certain personality traits, and memory performance. It was the goal of the present study to investigate the association between the -1438A/G polymorphism and stress hormone secretion, stress-related psychological measures, and cognitive performance in a group of adults between the ages of 50 and 65. To examine these associations, 101 middle-aged adults were recruited, completed a battery of psychological questionnaires and were administered a battery of cognitive tasks that assess frontal lobe and hippocampal function. Basal and stress-reactive salivary cortisol levels were collected, at home and in the laboratory. Analyses on psychological measures showed that participants with the GG genotype reported significantly higher levels of neuroticism compared to the AG group and higher levels of depression and more emotion-based coping strategies compared to both the AG and AA group. In terms of cortisol secretion, the AA genotype was related to a significantly higher awakening cortisol response (ACR) compared to the AG and GG group and the GG genotype group displayed a greater increase in cortisol secretion following a psychosocial stressor compared to the two other groups. On measures of cognitive performance, the AA genotype group performed significantly better on a test of declarative memory and selective attention compared to the other two groups. Together, these results suggest that carriers of the GG genotype are more susceptible to low mood and display a greater potential for an overactive stress system, which may influence cognitive function in later years.
18948358	The 22q13 deletion syndrome (Phelan-McDermid syndrome) is characterised by a global developmental delay, absent or delayed speech, generalised hypotonia, autistic behaviour and characteristic phenotypic features. Intranasal insulin has been shown to improve declarative memory in healthy adult subjects and in patients with Alzheimer disease.To assess if intranasal insulin is also able to improve the developmental delay in children with 22q13 deletion syndrome.	We performed exploratory clinical trials in six children with 22q13 deletion syndrome who received intranasal insulin over a period of 1 year. Short-term (during the first 6 weeks) and long-term effects (after 12 months of treatment) on motor skills, cognitive functions, or autonomous functions, speech and communication, emotional state, social behaviour, behavioural disorders, independence in daily living and education were assessed.	The children showed marked short-term improvements in gross and fine motor activities, cognitive functions and educational level. Positive long-term effects were found for fine and gross motor activities, nonverbal communication, cognitive functions and autonomy. Possible side effects were found in one patient who displayed changes in balance, extreme sensitivity to touch and general loss of interest. One patient complained of intermittent nose bleeding.	We conclude that long-term administration of intranasal insulin may benefit motor development, cognitive functions and spontaneous activity in children with 22q13 deletion syndrome.	
18947361	Syntactic persistence is a tendency for speakers to reproduce sentence structures independently of accompanying meanings, words, or sounds. The memory mechanisms behind syntactic persistence are not fully understood. Although some properties of syntactic persistence suggest a role for procedural memory, current evidence suggests that procedural memory (unlike declarative memory) does not maintain the abstract, relational features that are inherent to syntactic structures. In a study evaluating the contribution of procedural memory to syntactic persistence, patients with anterograde amnesia and matched control speakers reproduced prime sentences with different syntactic structures; reproduced 0, 1, 6, or 10 neutral sentences; then spontaneously described pictures that elicited the primed structures; and finally made recognition judgments for the prime sentences. Amnesic and control speakers showed significant and equivalent syntactic persistence, despite the amnesic speakers' profoundly impaired recognition memory for the primes. Thus, syntax is maintained by procedural-memory mechanisms. This result reveals that procedural memory is capable of supporting abstract, relational knowledge.
18926983	Skilled athletes often maintain that overthinking disrupts performance of their motor skills. Here, we examined whether these experiences have a basis in verbal overshadowing, a phenomenon in which describing memories for ineffable perceptual experiences disrupts later retention. After learning a unique golf-putting task, golfers of low and intermediate skill either described their actions in detail or performed an irrelevant verbal task. They then performed the putting task again. Strikingly, describing their putting experience significantly impaired higher skill golfers' ability to reachieve the putting criterion, compared with higher skill golfers who performed the irrelevant verbal activity. Verbalization had no such effect, however, for lower skill golfers. These findings establish that the effects of overthinking extend beyond dual-task interference and may sometimes reflect impacts on long-term memory. We propose that these effects are mediated by competition between procedural and declarative memory, as suggested by recent work in cognitive neuroscience.
18925971	Autism is characterized by impairments in social interaction, communicative capacity and behavioral flexibility. Some cognitive theories can be useful for finding a relationship between these irregularities and the biological mechanisms that may give rise to this disorder. Among such theories are mentalizing deficit, weak central coherence and executive dysfunction, but none of them has been able to explain all three diagnostic symptoms of autism. These cognitive disorders may be related among themselves by faulty learning, since several research studies have shown that the brains of autistic individuals have abnormalities in the cerebellum, which plays a role in procedural learning. In keeping with this view, one may postulate the possibility that declarative memory replaces faulty procedural memory in some of its functions, which implies making conscious efforts in order to perform actions that are normally automatic. This may disturb cognitive development, resulting in autism symptoms. Furthermore, this mnesic imbalance is probably involved in all autism spectrum disorders. In the present work, this theory is expounded, including preliminary supporting evidence.
18922628	The medial temporal lobe (MTL) is essential for declarative memory formation, but also a frequent source of seizures. To decrease the risk of amnestic impairments after temporal lobectomy, functional magnetic resonance imaging (fMRI) is increasingly used to establish pre-operative measures for a prognosis of postoperative memory performance. The present study addresses one of the major challenges in clinical fMRI, the interpretation of activation pattern in single subjects. Before investigating patients however, it must be first assessed to which extent the verbal memory paradigm can be used to determine the lateralization and the functional neuroanatomy of MTL-activity. Therefore, this study took a "step backwards" by first examining healthy subjects without known MTL pathology.An implicit verbal encoding task was applied to a group of ten healthy volunteers using fMRI.	At the group level the MTL activation was strongly left-lateralized and separated into three distinct clusters. At the individual level, the lateralization of MTL-activity could be determined in 9 of 10 subjects. In contrast, its localization was inter-individually highly variable. In each case, only one of the three group activation clusters was detected.	The present study shows that fMRI can be used to assess the lateralization of brain activity related to verbal encoding even in individual subjects. For the routine use in a clinical setting however, the results of verbal memory paradigms must at present be treated with care if they are used to support decisions as to how far the resection of one MTL can be extended.	
18854218	Memory reconsolidation is defined as a process in which the retrieval of a previously consolidated memory returns to a labile state which is then subject to stabilization. The reminder is the event that begins with the presentation of the learned cue and triggers the labilization-reconsolidation process. Since the early formulation of the hypothesis, several controversial items have arisen concerning the conditions that define reconsolidation. It is herein proposed that two diagnostic features characterize reconsolidation, namely: the labilization of the reactivated memory and the specificity of the reminder structure. To study this proposal, subjects received two different training sessions on verbal material on Day 1 and Day 2, respectively. Finally, they were tested for the first and second acquired memories on Day 3. It is demonstrated that the human declarative memory fulfills the two requirements that define the process. First, the reactivated memory is impaired by a new learning only when it is given closely after the reminder, revealing that the memory is labilized. Second, the omission of at least one of the reminder's components prevents labilization. Therefore, results show that the new learning fails to produce an amnesic effect on the target memory either when the reminder omits the learned cue or includes the beginning of the reinforcement.
18853937	To test whether instrumental conditioning of sensorimotor rhythm (SMR; 12-15 Hz) has an impact on sleep parameters as well as declarative memory performance in humans.Randomized, parallel group design	10 instrumental conditioning sessions, pre- and posttreatment investigation including sleep evaluations	27 healthy subjects (13 male)	SMR-conditioning (experimental group) or randomized-frequency conditioning (control group); declarative memory task before and after a 90-min nap	The experimental group was trained to enhance the amplitude of their SMR-frequency range, whereas the control group participated in a randomized-frequency conditioning program (i.e., every session a different 3-Hz frequency bin between 7 and 20 Hz). During pre- and posttreatment the subjects had to attend the sleep laboratory to take a 90-min nap (2:00-3:30 pm) and to perform a declarative memory task before and after sleep. The experimental design was successful in conditioning an increase in relative 12-15 Hz amplitude within 10 sessions (d = 0.7). Increased SMR activity was also expressed during subsequent sleep by eliciting positive changes in different sleep parameters (sleep spindle number [d = 0.6], sleep onset latency [d = 0.7]); additionally, this increased 12-15 Hz amplitude was associated with enhancement in retrieval score computed at immediate cued recall (d = 0.9).	Relative SMR amplitude increased over 10 instrumental conditioning sessions (in the experimental group only) and this "shaping of one's own brain activity" improved subsequent declarative learning and facilitated the expression of 12-15 Hz spindle oscillations during sleep. Most interestingly, these electrophysiological changes were accompanied by a shortened sleep onset latency.	
18838037	Chronic elevations of endogenous cortisol levels have been shown to alter medial temporal cortical structures and to be accompanied by declarative memory impairments and depressive symptoms in human adults. These effects of elevated endogenous levels of cortisol have not been directly studied in adolescents. Because adolescents with Cushing syndrome show endogenous elevations in cortisol, they represent a unique natural model to study the effects of prolonged hypercortisolemia on brain function, and memory and affective processes during this developmental stage. Using functional magnetic resonance imaging (fMRI), we compared 12 adolescents with Cushing syndrome with 22 healthy control adolescents on amygdala and anterior hippocampus activation during an emotional faces encoding task. None of these adolescents manifested depressive symptoms. Encoding success was assessed using a memory recognition test performed after the scan. The fMRI analyses followed an event-related design and were conducted using the SPM99 platform. Compared to healthy adolescents, patients with Cushing syndrome showed greater left amygdala and right anterior hippocampus activation during successful face encoding. Memory performance for faces recognition did not differ between groups. This first study of cerebral function in adolescents with chronic endogenous hypercortisolemia due to Cushing syndrome demonstrates the presence of functional alterations in amygdala and hippocampus, which are not associated with affective or memory impairments. Such findings need to be followed by work examining the role of age and related brain maturational stage on these effects, as well as the identification of possible protective factors conferring resilience to affective and cognitive consequences in this disease and/or during this stage of cerebral development.
18832332	Both emotion and sleep are independently known to modulate declarative memory. Memory can be facilitated by emotion, leading to enhanced consolidation across increasing time delays. Sleep also facilitates offline memory processing, resulting in superior recall the next day. Here we explore whether rapid eye movement (REM) sleep, and aspects of its unique neurophysiology, underlie these convergent influences on memory. Using a nap paradigm, we measured the consolidation of neutral and negative emotional memories, and the association with REM-sleep electrophysiology. Subjects that napped showed a consolidation benefit for emotional but not neutral memories. The No-Nap control group showed no evidence of a consolidation benefit for either memory type. Within the Nap group, the extent of emotional memory facilitation was significantly correlated with the amount of REM sleep and also with right-dominant prefrontal theta power during REM. Together, these data support the role of REM-sleep neurobiology in the consolidation of emotional human memories, findings that have direct translational implications for affective psychiatric and mood disorders.
18823239	Healthy aging has been shown to modulate the neural circuitry underlying simple declarative memory; however, the functional impact of negative stimulus valence on these changes has not been fully investigated. Using BOLD fMRI, we explored the effects of aging on behavioral performance, neural activity, and functional coupling during the encoding and retrieval of novel aversive and neutral scenes. Behaviorally, there was a main effect of valence with better recognition performance for aversive greater than neutral stimuli in both age groups. There was also a main effect of age with better recognition performance in younger participants compared to older participants. At the imaging level, there was a main effect of valence with increased activity in the medial-temporal lobe (amygdala and hippocampus) during both encoding and retrieval of aversive relative to neutral stimuli. There was also a main effect of age with older participants showing decreased engagement of medial-temporal lobe structures and increased engagement of prefrontal structures during both encoding and retrieval sessions. Interestingly, older participants presented with relatively decreased amygdalar-hippocampal coupling and increased amygdalar-prefrontal coupling when compared to younger participants. Furthermore, older participants showed increased activation in prefrontal cortices and decreased activation in the amygdala when contrasting the retrieval of aversive and neutral scenes. These results suggest that although normal aging is associated with a decline in declarative memory with alterations in the neural activity and connectivity of brain regions underlying simple declarative memory, memory for aversive stimuli is relatively better preserved than for neutral stimuli, possibly through greater compensatory prefrontal cortical activity.
18817883	Although the parietal cortex is not conventionally thought of as a major component of the neural systems that mediate declarative memory, many fMRI studies of recognition memory have found that correctly identified old items produce greater activation than correctly rejected new items throughout parietal cortex. This effect is usually heavily lateralized to the left. However, the vast majority of previous studies have used verbal materials. Does the left-lateralization of this effect result from the left hemisphere's role in language or does it suggest the possibility of a specialized role for the left hemisphere in recognition memory that applies across stimulus domains? To address this question, we directly compared recognition memory for words and faces in two event-related fMRI experiments with a total of 38 subjects. In the second experiment, we included a manipulation of recognition difficulty. Despite extensive material-specific lateralization in terms of the brain's overall response to stimuli revealed by a direct comparison of words and faces, the parietal old/new effect did not exhibit material-specific lateralization. Rather, the lateralization of the effect depended on the region of parietal cortex in question. In lateral parietal cortex, the effect was left-lateralized. In medial parietal cortex, the effect was bilateral. These findings indicate that the left-lateralization of the parietal old/new effect is unrelated to the left hemisphere's role in language and raises the possibility of a specialized role for the left hemisphere in recognition memory.
18809228	In the present study, as part of a more extensive longitudinal investigation of the in vivo anatomical markers of early and incipient AD in our laboratory, three groups of elderly participants were followed with yearly clinical evaluations and high resolution MRI scans over a 6-year period (baseline and 5 years of follow-up). At baseline, participants consisted of: (1) 35 old subjects with no cognitive impairment (controls); (2) 33 participants with amnestic mild cognitive impairment (MCI); and (3) 14 patients with very mild AD. 11 participants with amnestic MCI received a diagnosis of AD over the follow-up period and 9 controls declined in cognitive function. T1 weighted MRI scans were acquired using a 3D SPGR pulse sequence. At baseline, both the amnestic MCI and mild AD groups differed from the controls in hippocampal and entorhinal cortex volume, but not from each other. Longitudinal analyses showed that the rate of atrophy of the entorhinal cortex and hippocampus for the stable controls differed significantly from MCI participants who converted to AD and the AD groups. Furthermore, longitudinal decreases in hippocampal and entorhinal volume were related to longitudinal decline in declarative memory performance. These findings suggest that the rate of atrophy of mesial temporal lobe structures can differentiate healthy from pathological aging.
18775088	Memory deficits are common in depressed patients and may persist after recovery. The aim of the present study was to determine whether memory impairments were present in young women at increased familial risk of depression and whether memory performance was related either to cortisol secretion or to allelic variation in the promoter region of the serotonin transporter gene (5-HTT).Young women (n=35, age range 16-21 years) with no personal history of depression but with a depressed parent (FH+) carried out the Rey Auditory Verbal Learning Test (RAVLT). They also provided samples for the measurement of waking salivary cortisol and for 5-HTT genotyping. An age-matched control group of women (n=31) with no family history of depression were similarly studied.	The FH+ participants had decreased immediate recall and recognition memory compared to controls. The impairment in recall, but not recognition, correlated negatively with increased cortisol secretion in FH+ subjects. There was no significant effect of 5-HTT allelic status on either memory or waking cortisol secretion.	Impairments in declarative memory are present in young women at increased genetic risk of depression and may be partly related to increased cortisol secretion. Further studies are needed to explore the neural mechanisms underlying the memory impairments and whether they predict the development of clinical illness.	
18769510	The medial temporal lobe memory system matures relatively early and supports rudimentary declarative memory in young infants. There is considerable development, however, in the memory processes that underlie declarative memory performance during infancy. Here we consider age-related changes in encoding, retention, and retrieval in the context of current knowledge about the brain systems that may underlie these memory processes. While changes in infants' encoding may be attributed to rapid myelination during the first year of life, improvements in long-term retention and flexible retrieval are likely due to the prolonged development of the dentate gyrus. Future studies combining measures of brain and behavior are critical in improving our understanding of how brain development drives memory development during infancy and early childhood.
18767068	Magnetic resonance imaging (MRI) in association with Jacobian-modulated voxel-based morphometry (VBM) was used to test for regional variation in gray matter over the menstrual cycle. T1-weighted anatomical images were acquired using a spoiled gradient recalled acquisition sequence in 21 women. Each subject was scanned twice: once during the postmenstrual late-follicular phase (Days 10-12 after onset of menses), and once during the premenstrual late-luteal phase (1-5 days before the onset of menses). Gray matter was relatively increased in the right anterior hippocampus and relatively decreased in the right dorsal basal ganglia (globus pallidus/putamen) in the postmenstrual phase. Verbal declarative memory was increased in the postmenstrual vs. premenstrual phase. This first report of human brain structural plasticity associated with the endogenous menstrual cycle extends well-established animal findings of hormone-mediated hippocampal plasticity to humans, and has implications for understanding alterations in cognition and behavior across the menstrual cycle.
18763887	Human anterograde amnesia can result from a variety of etiologies, including hypoxic brain injury and anterior communicating artery (ACoA) aneurysm rupture. Although each etiology can cause a similarly severe disruption in declarative memory for verbal and visual material, there may be differences in incrementally acquired, feedback-based learning, as well as generalization. Here, 6 individuals who survived hypoxic brain injury, 7 individuals who survived ACoA aneurysm rupture, and 13 matched controls were tested on 2 tasks that included a feedback-based learning phase followed by a transfer phase in which familiar information is presented in new ways. In both tasks, the ACoA group was slow on initial learning, but those patients who completed the learning phase went on to transfer as well as controls. In the hypoxic group, 1 patient failed to complete either task; the remaining hypoxic group did not differ from controls during learning of either task, but was impaired on transfer. These results highlight a difference in feedback-based learning in 2 amnesic etiologies, despite similar levels of declarative memory impairment.
18723430	We investigated how the hippocampus and its adjacent mediotemporal structures contribute to contextual and noncontextual declarative memory retrieval by manipulating the amount of contextual information across two levels of the same contextual dimension in a source memory task. A first analysis identified medial temporal lobe (MTL) substructures mediating either contextual or noncontextual retrieval. A linearly weighted analysis elucidated which MTL substructures show a gradually increasing neural activity, depending on the amount of contextual information retrieved. A hippocampal engagement was found during both levels of source memory but not during item memory retrieval. The anterior MTL including the perirhinal cortex was only engaged during item memory retrieval by an activity decrease. Only the posterior parahippocampal cortex showed an activation increasing with the amount of contextual information retrieved. If one assumes a roughly linear relationship between the blood-oxygenation level-dependent (BOLD) signal and the associated cognitive process, our results suggest that the posterior parahippocampal cortex is involved in contextual retrieval on the basis of memory strength while the hippocampus processes representations of item-context binding. The anterior MTL including perirhinal cortex seems to be particularly engaged in familiarity-based item recognition. If one assumes departure from linearity, however, our results can also be explained by one-dimensional modulation of memory strength.
18720101	This study investigated developmental and sex-related differences in affective decision making, using a two-deck version of Children's Gambling Task administered to 3- and 4-year-old children. The main findings were that 4-year-old children displayed better decision-making performance than 3-year-olds. This effect was independent of developmental changes in inductive reasoning, language, and working memory. There were also sex differences in decision-making performance, which were apparent only in 3-year-old children and favored girls. Moreover, age predicted awareness of task and the correlation between the latter and decision-making performance was significant, but only in 4-year-old children. This study thus indicates that there is a remarkable developmental leap in affective decision making, whose effects are apparent around the age of 4, which according to our results, also marks the age when the correlation of declarative knowledge and decision-making performance becomes significant.
18703147	Lesion and imaging studies have demonstrated that encoding of declarative memories, i.e. consciously accessible events and facts, is supported by processes within the rhinal cortex and the hippocampus, two substructures of the mediotemporal lobe (MTL). Successful memory formation has, for instance, been shown to be accompanied by the rhinal N400 component, followed by a hippocampal positivity, as well as by transient rhinal-hippocampal phase synchronization. However, it has been an open question, which mediotemporal electroencephalogram (EEG) measures predict memory formation most accurately. Therefore, we analyzed and compared the association of different mediotemporal EEG measures with successful memory formation. EEG characteristics were extracted from intracranial rhinal and hippocampal depth recordings in 31 epilepsy patients performing a continuous word recognition paradigm. Classical event-related potential measures, rhinal-hippocampal synchronization, as well as inter-trial phase-locking and power changes within rhinal cortex and hippocampus were evaluated. We found that inter-trial phase-locking is superior to other EEG measures in predicting subsequent memory. This means that memory formation is related to the precise timing of EEG phases within the MTL with respect to stimulus onset. In particular, early rhinal and hippocampal phase-locking in the alpha/beta range reaching its maximum already between 100 and 300 ms after stimulus onset appears to be a precursor of successful memory formation. Our data suggest that early mediotemporal phase adjustments constitute a relevant mechanism underlying declarative memory encoding.
18609007	Profound loss of awareness for the past in amnesia has implications for our understanding of memory and belief systems, and how they may become disrupted in neurological conditions. We report the case of CW, a professional musician who became severely amnesic in 1985 following herpes simplex viral encephalitis (HSVE) at the age of 46 years. For many years CW stated several times a day that he had just woken up. He frequently wrote this in his diary too. When shown examples of his diary entries or videos of himself playing or conducting music, he recognised both his handwriting and himself on the video screen but stated vehemently that he "was not conscious then". In a previous paper (Wilson, Baddeley, & Kapur 1995), it was suggested that this lack of awareness for the past was a delusion, defined as a strongly held belief in the face of contradictory evidence (rather than implying any kind of psychiatric disorder per se). As a contribution to the academic debate regarding theories of "self", in the present paper we will review this explanation of CW's state as it had been in those early years, and we will also consider two other possibilities - namely, that CW had suffered from a loss of "autobiographical self" or "extended consciousness" (see Damasio, 2000, pp. 198-199), and that his verbal reports simply reflected a form of coping strategy to help him deal with the limited evidence he had available in "declarative" memory.
18608881	Backward recall of automatic word sequences involves declarative and working memory abilities known to be impaired in the early stages of cognitive decline. Yet its utility in the diagnosis of mild cognitive impairment and mild dementia has not been studied in detail. We analysed word sequence production in 234 participants drawn from three categories: subjective cognitive impairment, mild cognitive impairment, and mild dementia in Alzheimer's disease. The names of the months were used as a diagnostic target for investigating forward versus backward sequence production. Forward production remained normal across categories. In contrast, backward speed was significantly decreased in mild cognitive impairment. In dementia both speed and accuracy were impaired. Backward production had significant diagnostic classificatory power. We conclude that word sequence production yields data relevant to the diagnosis of dementia with a minimum of time and expense.
18593645	Recent evidence suggests that slow EEG rhythms are involved in post-learning plasticity. However, the relationships between memory consolidation and hippocampal EEG features remain unclear. Here, we assessed the effects of both procedural and declarative learning on qualitative and quantitative measures of sleep by recording stereo-EEG (SEEG) directly from the hippocampus and the neocortex in a group of epileptic patients undergoing pre-surgical evaluations. Following a baseline night, sleep was recorded after administration of a declarative (paired-associate word list learning task) and a procedural (sequential finger tapping) task. Patients were tested before going to bed (test) and after sleep in the following morning (retest). At retest, we found that patients recalled correctly more word pairs compared to the pre-sleep test (declarative task), and they were slightly faster in performing the motor task (procedural task). Standard polysomnography showed an increase in the amount of slow-wave sleep (SWS) only after procedural learning, paralleled by an increase of hippocampal SEEG power in the very low frequency range (VLF, 0.5-1 Hz) during the first NREM sleep cycle. Moreover, procedural performance enhancement and SEEG power increase in the hippocampal VLF were significantly correlated, indicating a link between procedural memory consolidation and slow hippocampal SEEG rhythms. These findings are consistent with the hypothesis of synaptic homeostasis occurring during sleep, suggesting that hippocampal slow oscillations are associated with local processes of post-learning synaptic downscaling.
18591482	Lesions of the hippocampus and related structures produce profound anterograde amnesia. The amnesia is specific to what has been called "explicit," "declarative," and "episodic" memory. These memories are frequently believed to be central to the human condition, requiring such advanced cognitive functions as attention and even consciousness. However, the hippocampus and associated structures are evolutionarily conserved, which argues that the memories of lower mammals should be qualitatively similar in nature. Just as attention and arousal are critical components of appropriate memory formation in humans, an emerging body of evidence suggests that these processes bear on the firing patterns of hippocampal neurons in rodents. Here the evidence favoring this hypothesis is discussed and then the potential anatomical basis for such modulation is considered.
18590373	Acquisition of interactive skills involves the use of internal and external cues. Experiment 1 showed that when actions were interdependent, learning was effective with and without external cues in the single-task condition but was effective only with the presence of external cues in the dual-task condition. In the dual-task condition, actions closer to the feedback were learned faster than actions farther away but this difference was reversed in the single-task condition. Experiment 2 tested how knowledge acquired in single and dual-task conditions would transfer to a new reward structure. Results confirmed the two forms of learning mediated by the secondary task: A declarative memory encoding process that simultaneously assigned credits to actions and a reinforcement-learning process that slowly propagated credits backward from the feedback. The results showed that both forms of learning were engaged during training, but only at the response selection stage, one form of knowledge may dominate over the other depending on the availability of attentional resources.
18585709	Patients with temporal lobe epilepsy are frequently afflicted with psychiatric comorbidity and deficits in spatial and other forms of declarative memory. The relationship between epilepsy and psychopathology is poorly understood, so that systematic research in this area is important. In the present study, we characterized various behaviors and learning and memory in a mouse model in which major aspects of mesial temporal lobe epilepsy can be reproduced. In this model, a single unilateral injection of kainate into the dorsal hippocampus induces a nonconvulsive status epilepticus, followed by development of spontaneous recurrent seizures and ipsilateral lesions of CA1, CA3c and dentate hilus neurons. Unexpectedly, the epileptic mice exhibited only few alterations in a behavioral test battery used to investigate locomotor activity and function, emotionality, depression-related behavior and learning and memory. In contrast to recent experiments with the same test battery in epileptic mice generated by systemic administration of pilocarpine, mice with focal kainate administration did not exhibit reduced explorative behavior or increases of anxiety-related behavior. However, similar to pilocarpine-treated mice, a decrease in depression-like behavior was observed in the forced swimming test. In the Morris water maze test, kainate-treated animals exhibited retarded acquisition and impaired retention of visual-spatial information. Our data suggest that the focal kainate model of mesial temporal lobe epilepsy may contribute to understanding the neurobiological mechanisms underlying the association between epilepsy and behavioral or cognitive alterations.
18585467	Understanding the contribution of the brain white matter pathways to declarative verbal memory processes has been hindered by the lack of an adequate model in humans. An attractive and underexplored approach to study white matter region functionality in the living human brain is through the use of non-aprioristic models which specifically search disrupted white matter pathways. For this purpose, we employed voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 46 multiple sclerosis patients with their performance on declarative verbal memory storage and retrieval. White matter correlating with storage was in the temporal lobe-particularly lateral to the hippocampus and in the anterior temporal stem-, in the thalamic region and in the anterior limb of the internal capsule, all on the left hemisphere, and also in the right anterior temporal stem. The same volumes were relevant for retrieval, but to them were added temporo-parieto-frontal paramedian bundles, particularly the cingulum and the fronto-occipital fasciculus. These 3D maps indicate the white matter regions most critically involved in declarative verbal memory in humans.
18582848	In animal models, corticosteroids are associated with changes in hippocampal structure and functioning that are prevented by glutamate release inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Cushing's disease and prescription corticosteroid administration are also associated with memory impairment and hippocampal atrophy. Use of NMDA receptor antagonists to attenuate corticosteroid effects in humans has not been investigated. We examine the NMDA receptor antagonist memantine in patients receiving corticosteroids.Twenty outpatients receiving long-term oral corticosteroid therapy were randomized to 8 weeks of memantine (maximum dose 20 mg/day) and 8 weeks of placebo in a double-blind fashion, with a 4-week washout period between courses. Declarative memory was assessed with the Hopkins Verbal Learning Test (HVLT) and mood with the Hamilton Rating Scale for Depression and Young Mania Rating Scale. Changes in outcome measures were compared during memantine and placebo exposure.	Seventeen participants completed both treatment phases and were used in the analysis. Significant improvement (p < .05) in total and delayed recall on the HVLT was observed with memantine as compared with placebo. No significant changes in mood were observed.	Memantine therapy was associated with improvement in declarative memory but not mood in patients receiving prescription corticosteroids.	
18570207	Several studies have shown marked differences in the neural localization of language functions in the brains of left-handed individuals when compared with right-handers. Previous experiments involving functional lateralization have demonstrated cerebral blood flow patterns that differ concordantly with subject handedness while performing language-related tasks. The effect of handedness on function in specific stages of memory processing, however, is a largely unexplored area. We used a paired-associates verbal memory task to elicit activation of neural areas related to declarative memory, examining the hypothesis that there are differences in activation in the medial temporal lobe (MTL) between handedness groups. 15 left-handed and 25 right-handed healthy adults were matched for all major demographic and neuropsychological variables. Functional and structural imaging data were acquired and analyzed for group differences within MTL subregions. Our results show that activation of the MTL during declarative memory processing varies with handedness. While both groups showed activation in left and right MTL subregions, the left-handed group showed a statistically significant increase in the left hippocampus and amygdala during both encoding and recall. No increases in activation were found in the right-handed group. This effect was found in the absence of any differences in performance on the verbal memory task, structural volumetric disparities, or functional asymmetries. This provides evidence of functional differences between left-handers and right-handers, which extends to declarative memory processes.
18562045	Cognitive inhibition processes were found to be deficient early in the clinical course of Alzheimer's disease (AD). The inhibition of redundant information is a precondition for efficient cognitive processing and presumably modulated by prefrontal attentional networks. Deficits in the suppression of the evoked potential P50 response to paired clicks are well known in schizophrenic patients and undergo cholinergic modulation. In this study, we aimed to investigate inhibitory gating deficits of P50 in AD and their relation to neuropsychological measures.P50 suppression was assessed in 19 AD-patients in comparison to a young and elderly control group (n=17 each) and related to MMSE and specific neuropsychological assessments.	Patients showed reduced sensory gating compared to healthy elderly (p<0.021) and exhibited significantly higher N40-P50-amplitudes. There were no age or gender effects in controls. Frontal neuropsychological tests (TMT-B, verbal fluency) and working memory requiring inhibition, but not declarative memory functions, were significantly correlated with inhibitory gating and test amplitude in both, AD-patients and controls.	The results support an early inhibitory deficit interfering with executive functions and working memory in AD independent from physiological aging. P50 gating might be applicable as a marker for inhibition deficits and thereby be important for prognosis estimation.	
18561960	Nootropic, antioxidant, and neuroprotective properties have been shown in a standardized ethanol extract of Ptychopetalum olacoides (POEE), a medicinal plant traditionally used by the Amazonian elderly population. It has been revealed that POEE mechanisms of action include anticholinesterase effects, and involve beta-adrenergic and dopamine D(1) receptors. The purpose of this study was to verify the role of serotonin receptors in the promnesic effects of this standardized extract. The step-down task in mice and selective serotonin antagonists were used. The study reveals that POEE promnesic effects on short-term (acquisition, consolidation and retrieval) and long-term (retrieval) declarative aversive memories are increased by 5HT(2A) (but not 5HT(1A)) serotonin antagonists (spiperone and pindolol, respectively). The observed synergism between POEE and spiperone can be interpreted as the combined effects of two subeffective doses of two 5HT antagonists, or the known synergism between an acetylcholinesterase inhibitor (POEE) and a 5HT antagonist. In conclusion it is suggested that 5HT(2A) serotonin receptors are relevant for the promnesic effects of this extract, adding to its multiple mechanisms of action.
18554731	Caffeine, the world's most common psychoactive substance, is used by approximately 90% of North Americans everyday. Little is known, however, about its benefits for memory. Napping has been shown to increase alertness and promote learning on some memory tasks. We directly compared caffeine (200mg) with napping (60-90min) and placebo on three distinct memory processes: declarative verbal memory, procedural motor skills, and perceptual learning. In the verbal task, recall and recognition for unassociated words were tested after a 7h retention period (with a between-session nap or drug intervention). A second, different, word list was administered post-intervention and memory was tested after a 20min retention period. The non-declarative tasks (finger tapping task (FTT) and texture discrimination task (TDT)) were trained before the intervention and then retested afterwards. Naps enhanced recall of words after a 7h and 20min retention interval relative to both caffeine and placebo. Caffeine significantly impaired motor learning compared to placebo and naps. Napping produced robust perceptual learning compared with placebo; however, naps and caffeine were not significantly different. These findings provide evidence of the limited benefits of caffeine for memory improvement compared with napping. We hypothesize that impairment from caffeine may be restricted to tasks that contain explicit information; whereas strictly implicit learning is less compromised.
18528674	We describe the case of a 51-year-old man who developed acute partial anterior communicating artery syndrome (ACoAS) due to a nonruptured aneurysm of that artery. The patient presented with anterograde memory deficits, particularly impaired delayed recall, whereas his declarative learning and retrograde memory were relatively spared. Full ACoAS is usually associated with confabulations and personality change, which did not present in the case reported here. However, the patient presented with the flat affect and reduced drive typical of frontal lobe disorder. Clinical and neuropsychological assessment largely ruled out other causal factors involved in the symptomatology. Upon follow-up 2 years after onset of the AcoAS, the patient's neuropsychological performance had remained stable, yet his affective resonance and, in part, his spatial orientation had improved. We conclude that malformations of the intracranial arterial system ought to be taken into account as differential diagnosis of acute memory disorders.
18503512	Growing evidence suggests that declarative memory benefits from the modulatory effects of emotion and sleep. The primary goal of the present study was to determine whether these two factors interact to enhance memory or they act independently of each other. Twenty-eight volunteers participated in the study. Half of them were sleep deprived the night immediately following the exposure to emotional and non-emotional images, whereas the control group slept at home. Their memory for images was tested 1 week later along the valence and arousal dimension of emotion with the remember-know procedure. As emotional events appear to gain preference during encoding, via the modulatory effect of amygdala on prefrontal and medial temporal lobe regions, conscious retrieval of emotional pictures (relative to neutral ones) was expected to be less disrupted by sleep loss. Results indicated that emotional images were more richly experienced in memory than neutral, particularly those with high arousal and positive valence. Even though sleep deprivation resulted in behavioral impairment at retrieval of both emotional and neutral images, results revealed that remember-based recognition accuracy and its underlying process of recollection for emotional images were less influenced by the lack of sleep (the mean difference between control and sleep-deprived subjects was around 40% higher for neutral images than for emotional images). Familiarity, however, was affected by neither emotion nor sleep. Taken together, these results suggest that emotion and sleep influence differentially the subjective experience of remembering and knowing and the underlying processes of recollection and familiarity through brain mechanisms probably involving amygdala- and hippocampo-neocortical networks respectively.
18499253	Tests of object recognition memory, or the judgment of the prior occurrence of an object, have made substantial contributions to our understanding of the nature and neurobiological underpinnings of mammalian memory. Only in recent years, however, have researchers begun to elucidate the specific brain areas and neural processes involved in object recognition memory. The present review considers some of this recent research, with an emphasis on studies addressing the neural bases of perirhinal cortex-dependent object recognition memory processes. We first briefly discuss operational definitions of object recognition and the common behavioural tests used to measure it in non-human primates and rodents. We then consider research from the non-human primate and rat literature examining the anatomical basis of object recognition memory in the delayed nonmatching-to-sample (DNMS) and spontaneous object recognition (SOR) tasks, respectively. The results of these studies overwhelmingly favor the view that perirhinal cortex (PRh) is a critical region for object recognition memory. We then discuss the involvement of PRh in the different stages--encoding, consolidation, and retrieval--of object recognition memory. Specifically, recent work in rats has indicated that neural activity in PRh contributes to object memory encoding, consolidation, and retrieval processes. Finally, we consider the pharmacological, cellular, and molecular factors that might play a part in PRh-mediated object recognition memory. Recent studies in rodents have begun to indicate the remarkable complexity of the neural substrates underlying this seemingly simple aspect of declarative memory.
18485487	Neuropsychological deficits are often described in patients with bipolar disorder (BD). Some symptoms and/or associated characteristics of BD can be more closely associated to those cognitive impairments. We aimed to explore cognitive neuropsychological characteristics of type I bipolar patients (BPI) in terms of lifetime suicide attempt history.We studied 39 BPI outpatients compared with 53 healthy controls (HC) matched by age, educational and intellectual level. All subjects were submitted to a neuropsychological assessment of executive functions, decision-making and declarative episodic memory.	When comparing BDI patients, regardless of suicide attempt history or HC, we observed that bipolar patients performed worse than controls on measures of memory, attention, executive functions and decision-making. Patients with a history of suicide attempt performed worse than non-attempters on measures of decision-making and there were a significant negative correlation between the number of suicide attempts and decision-making results (block 3 and net score). We also found significant positive correlation between the number of suicide attempts and amount of errors in Stroop Color Word Test (part 3).	The sample studied can be considered small and a potentially confounding variable - medication status - were not controlled.	Our results show the presence of neuropsychological deficits in memory, executive functions, attention and decision-making in BPI patients. Suicide attempts BPI scored worse than non-suicide attempt BPI on measures of decision-making. More suicide attempts were associated with a worse decision-making process. Future research should explore the relationship between the association between this specific cognitive deficits in BPIs, serotonergic function and suicide behavior in bipolar patients as well other diagnostic groups.	
18484550	Memory deficits and sleep disturbances are common clinical features of schizophrenia. Sleep is supposed to promote memory consolidation and the antipsychotic olanzapine is suggested to improve both sleep and memory functions. Therefore we performed a study to analyse the acute effects of olanzapine on distinct sleep parameters and sleep-related memory consolidation in parallel.We studied 26 patients with schizophrenia on stable antipsychotic medication with amisulpride (age range 19-44 years). Immediately before polysomnography and the morning after we performed neuropsychological tasks. Before the third night in the sleep laboratory, patients received either olanzapine or a placebo.	We found a significant positive association for slow wave sleep and declarative memory performance in schizophrenia at baseline. Additionally, Stage 2 sleep spindle density was positively related to overnight memory consolidation. Olanzapine caused a significant increase in the amount of slow wave sleep in accordance with recent studies, but led also to a significant decrease in sleep spindle density, which had not been described before. Memory performance the next morning was not different between the two groups.	Since not only slow wave sleep but also sleep spindles are supposed to promote sleep-related memory consolidation, we suggest that a putative positive effect on memory performance by slow wave sleep augmentation is neutralised by the decrease in sleep spindles due to olanzapine.	
18469677	An isolated prolonged episode of transient amnesia can be a major manifestation of transient global amnesia (TGA) and transient epileptic amnesia (TEA). We report a case of transient amnesia associated with a left temporal tumor and try to elucidate the possible mechanism of the amnesia.A 67-year-old right-handed man with the past history of migraine developed a transient declarative amnesia with a permanent memory gap for 5 hours. During the attack, he drove for 100 km flawlessly, but was not aware of his memory deficit. Selective retrograde amnesia during the episode was also observed. Investigations revealed an impaired verbal memory on neuropsychological tests, a possible metastatic tumor in the left temporal lobe by cerebral MRI, isolated wicket temporal spikes in the left mesial temporal area by sphenoidal electroencephalogram (EEG), and an additional brief phase of confusion. No recurrence of a similar attack occurred by 17 months after treatment with radiotherapy and chemotherapy.	This case serves to emphasize that transient dense anterograde amnesia resembling TGA might possibly occur as a manifestation of TEA and that there is a risk of subsequent epileptic features. The amnesia in this case also supports the hypothesis of spreading depression in patients with TGA and migraine and could support the epileptic hypothesis for the pathogenesis of TGA.	
18469541	The aim of this study was to further characterize the memory-enhancing profile of S 18986 a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. S 18986 was studied in two mouse models of age-related memory deficits, using radial maze paradigms involving long-term/declarative memory and short-term/working memory. Aged mice exhibited severe deficits when compared with their younger counterparts in the two behavioural tests. S 18986 at the dose of 0.1 mg/kg selectively improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on short-term retention of successive arm-visits in the short-term/working memory test. This study confirms the memory-enhancing properties of S 18986 and, in line with emerging data on multiple AMPA modulators, highlights the relevance of targeting AMPA receptors in the development of new memory enhancers.
18465470	Source monitoring refers to cognitive processes involved in making attributions about the origins of memories, knowledge, and beliefs. One particular type of source monitoring with ample practical significance is reality monitoring, i.e., the ability to discriminate between internally vs. externally generated memories. Abundant evidence indicates that exposure to acute stress enhances declarative memory consolidation. To date, no study has looked at whether exposure to acute stress during the consolidation phase may promote reality monitoring performance. The authors examined this by administering cold pressor stress (CPS) or a control procedure to participants (N = 80) after they had either performed or only imagined performing simple motor acts, and assessing reality monitoring 24 h later. When compared with the control condition, CPS significantly elevated salivary free cortisol concentrations and enhanced reality monitoring. Stress-induced cortisol responses, however, were found not to be related to improved reality monitoring performance. Our findings are consistent with the view that post-learning stress hormone-related activity may modulate source memory consolidation.
18465374	Neuroimaging studies have highlighted important issues related to structural and functional brain changes found in sufferers of psychological trauma that may influence their ability to synthesize, categorize, and integrate traumatic memories.Literature review and critical analysis and synthesis.	Traumatic memories are diagnostic symptoms of post-traumatic stress disorder (PTSD), and the dual representation theory posits separate memory systems subserving vivid re-experiencing (non-hippocampally dependent) versus declarative autobiographical memories of trauma (hippocampally dependent). But the psychopathological signs of trauma are not static over time, nor is the expression of traumatic memories. Multiple memory systems are activated simultaneously and in parallel on various occasions. Neural circuitry interaction is a crucial aspect in the development of a psychotherapeutic approach that may favour an integrative translation of the sensory fragments of the traumatic memory into a declarative memory system.	The relationship between neuroimaging findings and psychological approaches is discussed for greater efficacy in the treatment of psychologically traumatized patients.	
18446697	Learning and memory are complex processes that researchers have been attempting to unravel for over a century in order to gain a clear view of the underlying mechanisms.To review the basic cellular and molecular mechanisms involved in the process of procedural retention, to offer an overall view of the fundamental mechanisms involved in storing information by means of theories and models of memory, and to discuss the different types of memory and the role played by the cerebellum as a modulator of procedural memory.	Experimental results from recent decades have opened up new areas of study regarding the participation of the biochemical and cellular processes related to the consolidation of information in the nervous system.	The neuronal circuits involved in acquiring and consolidating memory are still not fully understood and the exact location of memory in the nervous system remains unknown. A number of intrinsic and extrinsic factors interfere in these processes, such as molecular (long-term potentiation and depression) and cellular mechanisms, which respond to communication and transmission between nerve cells. There are also factors that have their origin in the outside environment, which use the association of events to bring about the formation of new memories or may divert the subject from his or her main focus. Memory is not a singular occurrence; it is sub-divided into declarative and non-declarative or, when talking about the time it lasts, into short and long-term memory. Moreover, given its relation with neuronal mechanisms of learning, memory cannot be said to constitute an isolated process.	
18445531	The striatum has been shown to be a key region in the processing of reward-related information. The head of the caudate nucleus has been implicated in processing performance feedback, or in other words, information about the outcomes of one's actions. However, feedback provides multiple types of information, and it is not clear which of these types of information drive a caudate response. We sought to determine whether the signal in the caudate differed when feedback was informative but only arbitrarily related to performance versus when it provided information about goal achievement. To do this, we used functional magnetic resonance imaging (fMRI) to examine caudate activation during a feedback-based paired associate word-learning task. During an initial round of 60 distinct trials, participants chose one of two responses on each trial and received feedback about whether their responses were correct. On the subsequent two rounds, the 60 trials were repeated and participants chose their responses based on their memory of the correct answer. The caudate nuclei were strongly engaged only during the second two rounds, when feedback reflected the accuracy of memory. These results support the idea that feedback-based caudate activation is context dependent: the caudate can be engaged in feedback-based declarative memory tasks, but it is more strongly engaged when feedback is "earned" by performance than when it is informative but not tied to goal achievement.
18442861	The nature, neural underpinnings, and etiology of deficits in verbal declarative memory in patients with schizophrenia remain unclear. To examine the contributions of genes and environment to verbal recall and recognition performance in this disorder, the California Verbal Learning Test was administered to a large population-based Finnish twin sample, which included schizophrenic and schizoaffective patients, their non-ill monozygotic (MZ) and dizygotic (DZ) co-twins, and healthy control twins. Compared with controls, patients and their co-twins showed relatively greater performance deficits on free recall compared with recognition. Intra-pair differences between patients and their non-ill co-twins in hippocampal volume and memory performance were highly positively correlated. These findings are consistent with the view that genetic influences are associated with reduced verbal recall in schizophrenia, but that non-genetic influences further compromise these abnormalities in patients who manifest the full-blown schizophrenia phenotype, with this additional degree of disease-related declarative memory deficit mediated in part by hippocampal pathology.
18442322	Aging is associated with deficits in long-term declarative memory formation, and wide differences in performance can be observed among aged individuals. The cellular substrates of these deficits and the reasons for such marked individual differences are not yet fully understood. In the present study, morphologic parameters of synapses and synaptic mitochondria in stratum molecolare of CA1 hippocampal region were investigated in aged (26- to 27-month-old) female rats after a single trial inhibitory avoidance task. In this memory protocol animals learn to avoid a dark compartment in which they received a mild, inescapable foot shock. Rats were tested 3 and 6 or 9 hours after the training, divided into good and bad responders according to their performance (retention times above or below 100 seconds, respectively) and immediately sacrificed. The number of synapses and synaptic mitochondria per cubic micrometer of tissue (numeric density), the average area of synapses and volume of synaptic mitochondria, the total area of synapses per cubic micrometer of tissue, the percentage of perforated synapses and the overall volume of mitochondria per cubic micrometer of tissue were evaluated. In the good responder group, the numeric density of synapses and mitochondria was significantly higher and the average mitochondrial volume was significantly smaller 9 hours versus 6 hours after the training. No significant differences were observed among bad responders. Thus, better performances in passive avoidance memory task are correlated with more efficient plastic remodeling of synaptic contacts and mitochondria in hippocampal CA1. Present findings indicate that maintenance of synaptic plastic reactivity during aging is a critical requirement for preserving long-term memory consolidation.
18441295	Sleep supports the consolidation of memory in adults. Childhood is a period hallmarked by huge demands of brain plasticity as well as great amounts of efficient sleep. Whether sleep supports memory consolidation in children as in adults is unclear. We compared effects of nocturnal sleep (versus daytime wakefulness) on consolidation of declarative (word-pair associates, two-dimensional [2D] object location), and procedural memories (finger sequence tapping) in 15 children (6-8 yr) and 15 adults. Beneficial effects of sleep on retention of declarative memories were comparable in children and adults. However, opposite to adults, children showed smaller improvement in finger-tapping skill across retention sleep than wakefulness, indicating that sleep-dependent procedural memory consolidation depends on developmental stage.
18413609	Associative reinforcement provides a powerful explanation of learned behavior. However, an unproven but long-held conjecture holds that spatial learning can occur incidentally rather than by reinforcement. Using a carefully controlled virtual-reality object-location memory task, we formally demonstrate that locations are concurrently learned relative to both local landmarks and local boundaries but that landmark-learning obeys associative reinforcement (showing "overshadowing" and "blocking" or "learned irrelevance"), whereas boundary-learning is incidental, showing neither overshadowing nor blocking nor learned irrelevance. Crucially, both types of learning occur at similar rates and do not reflect differences in levels of performance, cue salience, or instructions. These distinct types of learning likely reflect the distinct neural systems implicated in processing of landmarks and boundaries: the striatum and hippocampus, respectively [Doeller CF, King JA, Burgess N (2008) Proc Natl Acad Sci USA 105:5915-5920]. In turn, our results suggest the use of fundamentally different learning rules by these two systems, potentially explaining their differential roles in procedural and declarative memory more generally. Our results suggest a privileged role for surface geometry in determining spatial context and support the idea of a "geometric module," albeit for location rather than orientation. Finally, the demonstration that reinforcement learning applies selectively to formally equivalent aspects of task-performance supports broader consideration of two-system models in analyses of learning and decision making.
18408152	How the memory systems centered on the hippocampus and dorsal striatum interact to support behavior remains controversial. We used functional MRI while people learned the locations of objects by collecting and replacing them over multiple trials within a virtual environment comprising a landmark, a circular boundary, and distant cues for orientation. The relative location of landmark and boundary was occasionally changed, with specific objects paired with one or other cue, allowing dissociation of learning and performance relative to either cue. Right posterior hippocampal activation reflected learning and remembering of boundary-related locations, whereas right dorsal striatal activation reflected learning and remembering of landmark-related locations. Within the right hippocampus, anterior processing of environmental change (spatial novelty) was dissociated from posterior processing of location. Behavioral studies show that landmark-related learning obeys associative reinforcement, whereas boundary-related learning is incidental [Doeller CF, Burgess N (2008) Proc Natl Acad Sci USA 105:5909-5914]. The distinct incidental hippocampal processing of boundaries is suggestive of a "geometric module" or "cognitive map" and may explain the hippocampal support of incidental/observational learning in "declarative" or "episodic" memory versus the striatal support of trial-and-error learning in "procedural" memory. Finally, the hippocampal and striatal systems appear to combine "bottom-up," simply influencing behavior proportional to their activations, without direct interaction, with "top-down" ventromedial prefrontal involvement when both are similarly active.
18394726	The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT(1A) receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT(1A) receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.
18394590	Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha1, alpha2, alpha3 or alpha5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha1 and/or alpha5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist ss-CCt exhibiting a preferential affinity for alpha1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.
18394470	The hippocampus is crucial for the consolidation of new declarative long-term memories. Genetic and behavioral experimentation have revealed that several protein kinases are critical for the formation of hippocampus-dependent long-term memories. Cyclic-AMP dependent protein kinase (PKA) is a serine-threonine kinase that has been strongly implicated in the expression of specific forms of hippocampus-dependent memory. We review evidence that PKA is required for hippocampus-dependent memory in mammals, and we highlight some of the proteins that have been implicated as targets of PKA. Future directions and open questions regarding the role of PKA in memory storage are also described.
18391183	The last decade has brought forth convincing evidence for a role of sleep in non-declarative memory. A similar function of sleep in episodic memory is supported by various correlational studies, but direct evidence is limited. Here we show that cued recall of face-location associations is significantly higher following a 12-h retention interval containing sleep than following an equally long period of waking. Furthermore, retention is significantly higher over a 24-h sleep-wake interval than over an equally long wake-sleep interval. This difference occurs because retention during sleep was significantly better when sleep followed learning directly, rather than after a day of waking. These data demonstrate a beneficial effect of sleep on memory that cannot be explained solely as a consequence of reduced interference. Rather, our findings suggest a competitive consolidation process, in which the fate of a memory depends, at least in part, on its relative stability at sleep onset: Strong memories tend to be preserved, while weaker memories erode still further. An important aspect of memory consolidation may thus result from the removal of irrelevant memory "debris."
20011622	Neuroimaging of declarative memory is not an endeavor divorced from psychology but, instead, is another path through which a more complete understanding of memory has emerged. Specifically, neuroimaging allows us to determine if differences between memory states emerge from quantitatively or qualitatively distinct underlying encoding operations. Further, it has allowed for greater specification of the putative control operations adopted when we make decisions about our memories. We describe some examples of insights provided by neuroimaging into the many and varied processes that support encoding and retrieval of declarative memory.
18387566	At a certain stage of development, virtually all children use some kind of external finger-based number representation. However, only little is known about how internal traces of this early external representation may still influence calculation even when finger calculation ceases to be an efficient tool in mental calculation. In the present study, we provide evidence for a disproportionate number of split-five errors (i.e., errors with a difference of +/-5 from the correct result) in mental addition and subtraction (e.g., 18 - 7 = 6). We will argue that such errors may have different origins. For complex problems and initially also for simple problems they are due to failure to keep track of 'full hands' in counting or calculation procedures. However, for simple addition problems split-five errors may later also be caused by mistakes in directly retrieving the result from declarative memory. In general, the present results are interpreted in terms of a transient use of mental finger patterns - in particular the whole hand pattern - in children's mental calculation.
18384046	Neurocognitive deficits in fragile X-associated tremor/ataxia syndrome (FXTAS) involve attentional control, working memory, executive functioning, and declarative and procedural learning. To date, no studies comparing FXTAS with other dementias have been done. We characterize the dementia in FXTAS, comparing it with Alzheimer's disease. Retrospective chart review of 68 adults (50 men, 18 women) with FXTAS. 20 men with FXTAS dementia were matched by age, gender, and education to patients with mild Alzheimer's dementia (AD). Neuropsychological measures were compared between the two groups: Boston Naming Test (BNT), phonemic fluency (Controlled Oral Word Association Test), digit span forward (DSF) and backward (DSB). Comparisons were based on analysis of covariance and t-tests to assess significant differences between groups. 50% of men with FXTAS and no women were cognitively impaired. On mean scores of verbal fluency (22.83 in FXTAS vs. 28.83 in AD, P = 0.112), working memory (DSB, 4.80 in AD vs. 5.41 in FXTAS, P = 0.359), and language (BNT, 48.54 in AD vs. 54.20 in FXTAS, P = 0.089), there were no significant differences. Digit span forward, measuring attention, was significantly higher in subjects with FXTAS dementia (8.59, vs. 7.10 in AD, P = 0.010). Individuals with FXTAS have significant cognitive deficits, on the order of those in AD although the cognitive profiles in these dementias are not similar. Further research is needed to outline the neuropsychiatric profile in FXTAS and the correlation of genetic markers with the progression and severity of cognitive loss.
18378013	Serotonin (5-HT) is involved in behaviors such as sleep, eating, memory, in mental disorders like anxiety and depression and plays an important role in the modulation of stress. On the other hand, exposure to stress influence learning as well as declarative and non-declarative memory. These effects are dependent on the type of stressor, their magnitude, and the type of memory. The striatum has been associated with non-declarative procedural memory, while the information about stress effects on procedural memory and their relation with striatal serotonin is scarce. The objective of this study was to evaluate the effects of stress on the modifications of the striatal serotonergic system. In Experiment 1, the effects of either 60 min of restraint (R) or exposure to the elevated T-maze (ETM) was assessed. Exposure to ETM decreased 5-HT concentration and to R increased 5-HT activity ([metabolite]/[neurotransmitter]). In Experiment 2, we evaluated the effects of restraint on ETM trained immediately, 24 or 48 h after restraint. No effects were detected in acquisition or escape latencies, while retention latencies were lower in all groups compared with the non-restrained group, although significant effects were detected immediately and 24h after restraint. The memory impairment seems to be associated with changes in striatal serotonergic system, given that 5-HT concentration increased, while serotonergic activity decreased. The differences in the activity of 5-HT detected in each experiment could be explained by the effects of different stressors on the serotonergic neurons ability to synthesize the neurotransmitter. Thus, we suggest that exposure to stress impairs procedural memory and that striatal serotonin modulates this effect.
18374494	For the past two decades, researchers have shown that elevated levels of circulating stress hormones may negatively impact cognitive performance in older adults. As well, genetic polymorphism of the apolipoprotein E gene (APOE) has been found to contribute to impairment in cognitive performance in old age. To date, only one study has reported a relationship between APOE status and cortisol levels, however the relationship was only found to be significant in dementia patients, with a trend observed in healthy controls.The goal of the present investigation was to examine the acute and long-term relationship between APOE status, cortisol secretion, and declarative memory performance in older adults.	Two sample cohorts were assessed. In the first cohort, 24-h basal serum cortisol levels were obtained once a year over eight years to assess changes in basal cortisol levels over time. Declarative memory was also obtained in this group at three time-points over five years. In the second cohort, basal and stress-induced cortisol levels as well as basal declarative memory was tested.	In the first cohort, E4 carriers were found to secrete higher serum cortisol levels than non-E4 carriers during the first 24-h visit (p=0.04) to the laboratory. However, this group difference did not remain over subsequent years. Furthermore, declarative memory performance over years did not significantly differ according to APOE status. In the second cohort, no significant group differences were found for basal or reactive cortisol levels (ps>0.05), and no group difference was found for acute declarative memory performance.	The findings in this study suggest minimal to no significant effect of APOE status on cortisol secretion or declarative memory in non-demented older adults.	
18367613	Conditions with chronically elevated glucocorticoid levels are usually associated with declarative memory deficits. Considerable evidence suggests that long-term glucocorticoid exposure may cause cognitive impairment via cumulative and long-lasting influences on hippocampal function and morphology. However, because elevated glucocorticoid levels at the time of retention testing are also known to have direct impairing effects on memory retrieval, it is possible that such acute hormonal influences on retrieval processes contribute to the memory deficits found with chronic glucocorticoid exposure. To investigate this issue, we examined memory functions and hippocampal volume in 24 patients with rheumatoid arthritis who were treated either chronically (5.3 +/- 1.0 years, mean +/- SE) with low to moderate doses of prednisone (7.5 +/- 0.8 mg, mean +/- SE) or without glucocorticoids. In both groups, delayed recall of words learned 24 h earlier was assessed under conditions of either elevated or basal glucocorticoid levels in a double-blind, placebo-controlled crossover design. Although the findings in this patient population did not provide evidence for harmful effects of a history of chronic prednisone treatment on memory performance or hippocampal volume per se, acute prednisone administration 1 h before retention testing to either the steroid or nonsteroid group impaired word recall. Thus, these findings indicate that memory deficits observed under chronically elevated glucocorticoid levels result, at least in part, from acute and reversible glucocorticoid effects on memory retrieval.
18363806	Transient or lasting increases in glucocorticoids accompany deficits in hippocampus-dependent memory formation. Recent data indicate that the formation and consolidation of declarative and spatial memory are mechanistically related to different patterns of hippocampal network oscillations. These include gamma oscillations during memory acquisition and the faster ripple oscillations (approximately 200 Hz) during subsequent memory consolidation. We therefore analysed the effects of acutely applied glucocorticoids on network activity in mouse hippocampal slices. Evoked field population spikes and paired-pulse responses were largely unaltered by corticosterone or cortisol, respectively, despite a slight increase in maximal population spike amplitude by 10 microm corticosterone. Several characteristics of sharp waves and superimposed ripple oscillations were affected by glucocorticoids, most prominently the frequency of spontaneously occurring sharp waves. At 0.1 microm, corticosterone increased this frequency, whereas maximal (10 microm) concentrations led to a reduction. In addition, gamma oscillations became slightly faster and less regular in the presence of high doses of corticosteroids. The present study describes acute effects of glucocorticoids on sharp wave-ripple complexes and gamma oscillations in mouse hippocampal slices, revealing a potential background for memory deficits in the presence of elevated levels of these hormones.
18359168	In contrast to the substantial number of studies investigating the effects of stress on declarative memory, effects of stress on working memory have received less attention. We compared working memory (numerical n-back task with single digits) in 40 men exposed either to psychosocial stress (Trier Social Stress Test (TSST)) or a control condition. Task difficulty was varied using two conditions (2-back vs. 3-back). Salivary cortisol (as a marker of hypothalamus-pituitary-adrenal (HPA) activity) and salivary alpha-amylase (sAA as a marker of sympathetic nervous system (SNS) activity) were assessed immediately before and three times after the stress or control condition. As expected stress resulted in an increase in cortisol, sAA, and negative affect. Subjects exposed to stress showed significant working memory impairments in both workload conditions. The analysis of variance indicated a main effect of stress for reaction time as well as accuracy. In addition, for reaction time a stress-block interaction occurred. Follow up tests revealed that only during the first block at each level of difficulty performance was significantly impaired by stress. Thus, the effects of stress became smaller the longer the task was performed. Results provide further evidence for impaired working memory after acute stress and illustrate the time course of this phenomenon.
18339600	Declarative knowledge and experiences are represented in the association cortex and are recalled by reactivation of the neural representation. Electrophysiological experiments have revealed that associations between semantically linked visual objects are formed in neural representations in the temporal and limbic cortices. Memory traces are created by the reorganization of neural circuits. These regions are reactivated during retrieval and contribute to the contents of a memory. Two different types of retrieval signals are suggested as follows: automatic and active. One flows backward from the medial temporal lobe during the automatic retrieval process, whereas the other is conveyed as a top-down signal from the prefrontal cortex to the temporal cortex during the active retrieval process. By sending the top-down signal, the prefrontal cortex manipulates and organizes to-be-remembered information, devises strategies for retrieval and monitors the outcome. To further understand the neural mechanism of memory, the following two complementary views are needed: how the multiple cortical areas in the brain-wide network interact to orchestrate cognitive functions and how the properties of single neurons and their synaptic connections with neighbouring neurons combine to form local circuits and to exhibit the function of each cortical area. We will discuss some new methodological innovations that tackle these challenges.
18329948	The methodologies of cognitive architectures and functional magnetic resonance imaging can mutually inform each other. For example, four modules of the ACT-R (adaptive control of thought - rational) cognitive architecture have been associated with four brain regions that are active in complex tasks. Activity in a lateral inferior prefrontal region reflects retrieval of information in a declarative module; activity in a posterior parietal region reflects changes to problem representations in an imaginal module; activity in the anterior cingulate cortex reflects the updates of control information in a goal module; and activity in the caudate nucleus reflects execution of productions in a procedural module. Differential patterns of activation in such central regions can reveal the time course of different components of complex cognition.
18321871	What is the role of the left prefrontal cortex in the controlled retrieval of learned information? We present a theory of declarative retrieval that posits that the amount of control exerted by this region during retrieval is inversely proportional to 1) the frequency and recency of previous experiences with the retrieved memory and 2) the associative strength between the current context and the retrieved memory. This theory is rational in the sense that it claims that declarative retrieval is highly sensitive to the statistical regularities in the environment. We demonstrate how our theory produces precise predictions of response time and neural activity during recall and test these predictions in an experiment that manipulates the frequency of previous experiences and the associative strength to the retrieval cues. Our findings suggest that the control process performed by the left prefrontal cortex directly reflects the demands of the environment on memory.
18316233	Learning deficits may be part of the early symptoms of Huntington's disease (HD). Here we characterized implicit and explicit aspects of sequence learning in 11 pre-symptomatic HD gene carriers (pHD) and 11 normal controls. Subjects moved a cursor on a digitizing tablet and performed the following tasks: SEQ: learning to anticipate the appearance of a target sequence in two blocks; VSEQ: learning a sequence by attending to the display without moving for one block, and by moving to the sequence in a successive block (VSEQ test). Explicit learning was measured with declarative scores and number of anticipatory movements. Implicit learning was measured as a strategy change reflected in movement time. By the end of SEQ, pHD had a significantly lower number of correct anticipatory movements and lower declarative scores than controls, while in VSEQ and VSEQ test these indices improved. During all three tasks, movement time changed in controls, but not in pHD. These results suggest that both explicit and implicit aspects of sequence learning may be impaired before the onset of motor symptoms. However, when attentional demands decrease, explicit, but not implicit, learning may improve.
18314098	Visualizing spatial material is a cornerstone of human problem solving, but human visualization capacity is sharply limited. To investigate the sources of this limit, we developed a new task to measure visualization accuracy for verbally-described spatial paths (similar to street directions), and implemented a computational process model to perform it. In this model, developed within the Adaptive Control of Thought-Rational (ACT-R) architecture, visualization capacity is limited by three mechanisms. Two of these (associative interference and decay) are longstanding characteristics of ACT-R's declarative memory. A third (spatial interference) is a new mechanism motivated by spatial proximity effects in our data. We tested the model in two experiments, one with parameter-value fitting, and a replication without further fitting. Correspondence between model and data was close in both experiments, suggesting that the model may be useful for understanding why visualizing new, complex spatial material is so difficult.
18308794	The potential memory-enhancing properties of two dopamine agonists currently used in patients with Parkinson's disease, piribedil (1, 10 mg/kg/day, subcutaneously) and bromocriptine (5 mg/kg/day, subcutaneously), were evaluated in three experiments. Although piribedil (10 mg/kg) and bromocriptine equally enhanced spontaneous object recognition in young adult rats (experiment A), only piribedil displayed beneficial effects against aging-related memory impairments in two radial-maze experiments in mice. First (experiment B), a two-stage paradigm of spatial discrimination was used to assess relational/declarative memory in aged mice; piribedil (1 and 10 mg/kg) selectively and significantly improved the performances of aged mice in the critical tests for relational/declarative memory, whereas bromocriptine had no effect. Second, in a novel working memory task (experiment C), vehicle- or bromocriptine-treated aged mice displayed, compared with (vehicle) younger controls, a severe and persistent deficit in short-term retention of successive arm-visits, performing close to chance whichever the retention interval. Performances of piribedil (10 mg/kg) group remarkably improved across testing-days and reached young adults' level. The restoration of specific mnemonic impairments, in aged mice, highlights the memory-enhancing properties of piribedil. The efficacy of this drug in treating cognitive impairment of Parkinson's disease should now be assessed in more specific models.This work was published in an abstract form: ECNP Abstracts, 2005 (P8060 & P8065).
18306303	Currently, there is a general agreement that two distinct cognitive operations, recollection and familiarity, contribute to performance on recognition memory tests. However, there is a controversy about whether recollection and familiarity reflect different memory processes, mediated by distinct neural substrates (dual-process models), or whether they are the expression of memory traces of different strength in the context of a unitary declarative memory system (unitary-strength models). Critical in this debate is the status of recognition memory in hippocampal amnesia and, in particular, whether the various structures in the medial temporal lobe (MTL) contribute differentially to the recollection and familiarity components of recognition. The present study aimed to explore the relative contribution of recollection and familiarity to recognition of words that had been previously read or that had been previously generated in a group of severely amnesic patients with cerebral damage restricted to the hippocampus. A convergent pattern of results emerged when we used a subjective-based (remember/know; R/K) and an objective-based (process dissociation procedure; PDP) methods to estimate the contribution of recollection and familiarity to recognition performance. In both PDP and R/K procedures, healthy controls disclosed significantly higher recollection estimates for words that had been anagrammed than for words that had been read. Amnesic patients' recollection scores were not different for words that had been generated or that had been read, and the recollection estimate for words that had been generated was significantly reduced as compared to the group of healthy controls. For familiarity, both healthy controls and amnesic patients recognized as familiar more words that had been generated than words that had been read, and there was no difference between the two groups. These data support the hypothesis of a specific role of the hippocampus in recollection processes and suggest that other components of the MTL (e.g., perirhinal cortex) may be more involved in the process of familiarity.
18306299	Two patients with large lesions of the medial temporal lobe were given four tests of semantic knowledge that could only have been acquired after the onset of their amnesia. In contrast to previous studies of postmorbid semantic learning, correct answers could be based on a simple, nonspecific sense of familiarity about single words, faces, or objects. According to recent computational models (for example, Norman and O'Reilly (2003) Psychol Rev 110:611-646), this characteristic should be optimal for detecting the kind of semantic learning that might be supported directly by the neocortex. Both patients exhibited some capacity for new learning, albeit at a level substantially below control performances. Notably, the correct answers appeared to reflect declarative memory. It was not the case that the correct answers simply popped out in some automatic way in the absence of any additional knowledge about the items. Rather, the few correct choices made by the patients tended to be accompanied by additional information about the chosen items, and the available knowledge appeared to be similar qualitatively to the kind of factual knowledge that healthy individuals gradually acquire over the years. The results are consistent with the idea that neocortical structures outside the medial temporal lobe are able to support some semantic learning, albeit to a very limited extent. Alternatively, the small amount of learning detected in the present study could depend on tissue within the posterior medial temporal lobe that remains intact in both patients.
18286420	Declarative and non-declarative memories are thought be supported by two distinct memory systems that are often posited not to interact. However, Wagner, Maril, and Schacter (2000a) reported that at the time priming was assessed, greater behavioural and neural priming was associated with lower levels of subsequent recognition memory, demonstrating an interaction between declarative and non-declarative memory. We examined this finding using a similar paradigm, in which participants made the same or different semantic word judgements following a short or long lag and subsequent memory test. We found a similar overall pattern of results, with greater behavioural priming associated with a decrease in recognition and recall performance. However, neither various within-participant nor various between-participant analyses revealed significant correlations between priming and subsequent memory performance. These data suggest that both lag and task have effects on priming and declarative memory performance, but that they are largely independent and occur in parallel.
18285414	Our objective was to determine whether subclinical thyrotoxicosis alters health status, mood, and/or cognitive function.This was a double-blinded, randomized, cross-over study of usual dose l-T(4) (euthyroid arm) vs. higher dose l-T(4) (subclinical thyrotoxicosis arm) in hypothyroid subjects.	A total of 33 hypothyroid subjects receiving l-T(4) were included in the study.	Subjects underwent measurements of health status, mood, and cognition: Short Form 36 (SF-36); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, and Digit Span Backwards), and motor learning (Pursuit Rotor). These were repeated after 12 wk on each of the study arms.	Mean TSH levels decreased from 2.15 to 0.17 mU/liter on the subclinical thyrotoxicosis arm (P < 0.0001), with normal mean free T(4) and free T(3) levels. The SF-36 physical component summary and general health subscale were slightly worse during the subclinical thyrotoxicosis arm, whereas the mental health subscale was marginally improved. The POMS confusion, depression, and tension subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did not change. This improvement was related to changes in the SF-36 physical component summary and POMS tension subscales and free T(3) levels.	We found slightly impaired physical health status but improvements in measures of mental health and mood in l-T(4) treated hypothyroid subjects when subclinical thyrotoxicosis was induced in a blinded, randomized fashion. Motor learning was also improved. These findings suggest that thyroid hormone directly affects brain areas responsible for affect and motor function.	
18276116	Present evidence suggests that schizophrenia is associated with explicit memory deficits, whereas implicit memory seems to be largely preserved. Virtual reality studies on declarative allocentric memory in schizophrenia are rare, and studies on implicit egocentric memory in schizophrenia are lacking. However, virtual realities have a major advantage for the assessment of spatial navigation and memory formation, as computer-simulated first-person environments can simulate navigation in a large-scale space. Twenty-five subjects with recent-onset schizophrenia were compared with 25 healthy matched control subjects on two virtual reality tasks affording the navigation and learning of a virtual park (allocentric memory) and a virtual maze (egocentric memory). Compared with control subjects, schizophrenia subjects were significantly impaired in learning the virtual park. However, schizophrenia subjects were as able as control subjects to learn the virtual maze. Stronger disorganized symptoms of schizophrenia subjects were significantly related to more errors on the virtual maze. It is concluded that egocentric spatial learning adds to the many other implicit cognitive skills being largely preserved in schizophrenia. Possibly, the more global neural network supporting egocentric spatial learning is less affected than the declarative hippocampal memory system in early stages of schizophrenia and may offer opportunities for compensation in the presence of focal deficits.
18275549	Various studies have demonstrated that a night of sleep has a beneficial effect on the retention of previously acquired declarative material. In two experiments, we addressed the question of whether this effect extends to daytime naps. In the first experiment we assessed free recall of a list of 30 words after a 60 min retention interval that was either filled with daytime napping or waking activity. Memory performance was significantly enhanced after napping as opposed to waking but was not correlated with time spent in slow wave sleep or total sleep time within the napping condition. The second experiment was designed to clarify the role of total sleep time and therefore included an additional third group, which was allowed to nap for no longer than 6 min on average. In comparing word recall after conditions of no napping (waking), short napping, and long napping, we found superior recall for both nap conditions in contrast to waking as well as for long naps in contrast to short naps. These results demonstrate that even an ultra short period of sleep is sufficient to enhance memory processing. We suggest that the mere onset of sleep may initiate active processes of consolidation which - once triggered - remain effective even if sleep is terminated shortly thereafter.
18274266	In this study we examined the benefit of a daytime nap containing only NREM sleep on the performance of three declarative memory tasks: unrelated paired associates, maze learning, and the Rey-Osterrieth complex figure. Additionally, we explored the impact of factors related to task acquisition on sleep-related memory processing. To this end, we examined whether testing of paired associates during training leads to sleep-related enhancement of memory compared to simply learning the word pairs without test. We also examined whether strength of task acquisition modulates sleep-related processing for each of the three tasks. SUBJECTS AND PROCEDURE: Subjects (11 male, 22 female) arrived at 11:30, were trained on each of the declarative memory tasks at 12:15, and at 13:00 either took a nap or remained awake in the sleep lab. After the nap period, all subjects remained in the lab until retest at 16:00.Compared to subjects who stayed awake during the training-retest interval, subjects who took a NREM nap demonstrated enhanced performance for word pairs that were tested during training, but not for untested word pairs. For each of the three declarative memory tasks, we observed a sleep-dependent performance benefit only for subjects that most strongly acquired the tasks during the training session.	NREM sleep obtained during a daytime nap benefits declarative memory performance, with these benefits being intimately tied to how well subjects acquire the tasks and the way in which the information is acquired.	
18265960	The comparative effects of a newly described specific alpha7 nAChR partial agonist, S 24795, and a cholinesterase inhibitor, donepezil, currently used as a symptomatic Alzheimer's disease treatment were studied in two mouse models of aging-related memory deficits.We employed radial arm-maze paradigms assessing short-term working memory (STWM, experiment A) and mnemonic flexibility, a cardinal property of long-term declarative (LTDM, experiment B). Both compounds were administered daily at 0.3 and 1 mg/kg subcutaneously (~3 weeks).	In the STWM experiment, vehicle-treated aged mice displayed a severe and persistent deficit in the retention of successive arm visits in comparison to younger controls. S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at 0.3 mg/kg (but not 1 mg/kg) exerted beneficial effects on this deficit: The performance of aged mice treated with these drugs remarkably increased across the testing days and almost reached young adult performance level. In the critical test trials of memory flexibility (i.e., LTDM), in experiment B, S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at the dose of 1 mg/kg (but not 0.3 mg/kg) improved aged mice performance.	This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to recent literature in highlighting the potential interest of an alpha7 nAChR drug as a symptomatic AD therapeutic.	
18263624	The basal ganglia (BG) are thought to play a key role in learning from feedback, with mesencephalic dopamine neurons coding errors in reward prediction, thereby mediating information processing in the BG and the prefrontal cortex. In the present study, reward-based learning was assessed in patients with focal BG lesions, by studying outcome-based acquisition and reversal of stimulus-stimulus associations with different reward magnitudes in two probabilistic learning tasks. Eleven patients with selective BG lesions (three females) and 18 healthy control subjects (six females) participated in this study. Two cognitive transfer tasks provided a measure of declarative learning strategy application. On the group level, BG patients showed deficits in reversal learning, with dorsal striatum lesion patients being most severely affected. While basic mechanisms of learning from feedback such as the processing of different reward magnitudes appeared to be intact, patients needed more trials than controls to learn a second reward-based task, suggesting reduced carry-over effects in learning. A patient with a bilateral BG lesion showed better performance than controls on most learning tasks, applying a compensatory declarative learning strategy. The results are discussed in terms of the implication of different BG subregions in different aspects of learning from feedback.
18242064	The effect of phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, was examined in the water maze, a spatial learning and memory task dependent on hippocampal functions. Male adult C57Bl/6J mice received daily (s.c.) injections of either saline or PCP (0.25-4.0 mg/kg) for 12 days. During the last 5 days, the injections were followed by water maze training. Repeated PCP treatments disrupted spatial learning and memory in the 0.5-4.0 mg/kg dose range. Severe sensorimotor disturbances, observed at the 2.0 and 4.0 mg/kg doses of PCP, precluded further swim maze testing. The 0.5 mg/kg but not the 1.0 mg/kg dose of PCP impaired spatial learning and memory without any apparent sensorimotor deficits. PCP, at 1.0 mg/kg, produced impairment in non-spatial learning in the swim maze task and motor disturbances in the rotarod test. Repeated daily treatment with either the "atypical" antipsychotic drug clozapine (0.5 mg/kg i.p.) or the "typical" antipsychotic drug haloperidol (0.05 mg/kg i.p.) failed to influence spatial performances. The spatial impairment caused by the 0.5 mg/kg dose of PCP was blocked by concomitant treatment with clozapine (0.5 mg/kg), but not with haloperidol (0.05 mg/kg). The results suggest that it is possible, at low doses of PCP, to dissociate the spatial learning impairment in the water maze from the adverse behavioral effects of NMDA receptor blockade. This model may provide a basis for the analysis of the mechanisms underlying declarative memory disturbances in schizophrenia and the differences in mechanisms between typical and atypical antipsychotic drugs.
18239953	Contemporary dance-movement deliberately and systematically cultivated for its own sake-is examined in the light of the procedural and declarative view of long-term knowledge. We begin with a description of two settings in which new works of contemporary dance are created and performed. Although non-verbal, contemporary dance can be a language declared through movement and stillness of the body. Ideas for new movement material come from objects, events or imaginings that are spoken, seen, heard, imagined, or felt. Declared through movement, the idea becomes visible. Communication in dance involves general psychological processes such as direct visual perception of motion and force, motor simulation via mirror neurons, and implicit learning of movement vocabularies and grammars. Creating and performing dance appear to involve both procedural and declarative knowledge. The latter includes the role of episodic memory in performance and occasional labelling of movement phrases and sections in rehearsal. Procedural knowledge in dance is augmented by expressive nuance, feeling and communicative intent that is not characteristic of other movement-based procedural tasks. Having delineated lexical and grammatical components in dance, neural mechanisms are identified based on Ullman's (Ullman in Cognition 92:231-270, 2004) alignment of lexical knowledge with declarative memory and mental grammar with procedural memory. We conclude with suggestions for experiments to test these assumptions that concern thought in action in composition, performance and appreciation of contemporary dance.
18211155	Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.
18171945	An increasing body of evidence indicates that the vitamin A metabolite retinoic acid (RA) plays a role in adult brain plasticity by activating gene transcription through nuclear receptors. Our previous studies in mice have shown that a moderate downregulation of retinoid-mediated transcription contributed to aging-related deficits in hippocampal long-term potentiation and long-term declarative memory (LTDM). Here, knock-out, pharmacological, and nutritional approaches were used in a series of radial-arm maze experiments with mice to further assess the hypothesis that retinoid-mediated nuclear events are causally involved in preferential degradation of hippocampal function in aging. Molecular and behavioral findings confirmed our hypothesis. First, a lifelong vitamin A supplementation, like short-term RA administration, was shown to counteract the aging-related hippocampal (but not striatal) hypoexpression of a plasticity-related retinoid target-gene, GAP43 (reverse transcription-PCR analyses, experiment 1), as well as short-term/working memory (STWM) deterioration seen particularly in organization demanding trials (STWM task, experiment 2). Second, using a two-stage paradigm of LTDM, we demonstrated that the vitamin A supplementation normalized memory encoding-induced recruitment of (hippocampo-prefrontal) declarative memory circuits, without affecting (striatal) procedural memory system activity in aged mice (Fos neuroimaging, experiment 3A) and alleviated their LTDM impairment (experiment 3B). Finally, we showed that (knock-out, experiment 4) RA receptor beta and retinoid X receptor gamma, known to be involved in STWM (Wietrzych et al., 2005), are also required for LTDM. Hence, aging-related retinoid signaling hypoexpression disrupts hippocampal cellular properties critically required for STWM organization and LTDM formation, and nutritional vitamin A supplementation represents a preventive strategy. These findings are discussed within current neurobiological perspectives questioning the historical consensus on STWM and LTDM system partition.
18167422	Patients with depression show cognitive impairment, including executive function deficit, impairments in attention, declarative memory and psychomotor performance. In addition to classic, widely studied cognitive functions, in depression implicit learning and the interpretation of feedback and its impact on performance can also be impaired compared to healthy individuals. While cognitive functions have been widely studied, much less is known about implicit learning in depression.The two-phased Kilroy sequence association test examines the basal ganglia-mediated and the temporal lobe and hippocampus-mediated learning processes within one test. We compared the performance of 22 depressed patients (according to DSM-IV) and 20 healthy control subjects using the Kilroy test. In the depressed group, we also compared the performance on each step of the test with the symptom severity measured by the Hamilton D symptom scale.	Depressed patients showed impaired performance compared to healthy subjects on the first, learning phase of the test. The degree of deficit on the learning phase correlated with symptom severity. We found no difference between the two groups on the second, context-dependent phase of the test.	Our results confirm the presence of a striatal deficit in depressed patients. Results indicate that parallel memory systems are not equally affected in depression, and the character of deficit in depression may be specific to the illness.	
18162554	Episodic memories allow us to remember not only that we have seen an item before but also where and when we have seen it (context). Sometimes, we can confidently report that we have seen something (familiarity) but cannot recollect where or when it was seen. Thus, the two components of episodic recall, familiarity and recollection, can be behaviorally dissociated. It is not clear, however, whether these two components of memory are represented separately by distinct brain structures or different populations of neurons in a single anatomical structure. Here, we report that the spiking activity of single neurons in the human hippocampus and amygdala [the medial temporal lobe (MTL)] contain information about both components of memory. We analyzed a class of neurons that changed its firing rate to the second presentation of a previously novel stimulus. We found that the neuronal activity evoked by the presentation of a familiar stimulus (during retrieval) distinguishes stimuli that will be successfully recollected from stimuli that will not be recollected. Importantly, the ability to predict whether a stimulus is familiar is not influenced by whether the stimulus will later be recollected. We thus conclude that human MTL neurons contain information about both components of memory. These data support a continuous strength of memory model of MTL function: the stronger the neuronal response, the better the memory.
18162329	Steroid hormones modulate memory in animals and human adults. Little is known on the developmental effects of these hormones on the neural networks underlying memory. Using Congenital adrenal hyperplasia (CAH) as a naturalistic model of early steroid abnormalities, this study examines the consequences of CAH on memory and its neural correlates for emotionally arousing and neutral material in children. Seventeen patients with CAH and 17 age- and sex-matched healthy children (ages 12-14 years) completed the study. Subjects were presented positive, negative and neutral pictures. Memory recall occurred about 30min after viewing the pictures. Children with CAH showed memory deficits for negative pictures compared to healthy children (p<0.01). There were no group differences on memory performance for either positive or neutral pictures (p>0.1). In patients, 24h urinary-free cortisol levels (reflecting glucocorticoid replacement therapy) and testosterone levels were not associated with memory performance. These findings suggest that early steroid imbalances affect memory for negative material in children with CAH. Such memory impairments may result from abnormal brain organization and function following hormonal dysfunction during critical periods of development.
18155255	Item recognition for unfamiliar faces and scenes was tested in Jon, who has developmental amnesia resulting from bilateral hippocampal pathology. Performance and confidence judgements in healthy adults showed that both tests were equated for difficulty and had similar receiver operating characteristics (ROCs). Jon's performance on the faces test was indistinguishable from the controls, in both sensitivity and the shape of the ROC curve. In contrast his performance on the scenes test was markedly poor, and his ROC was inconsistent with both a standard dual process (DP; recollection and familiarity) model and an unequal variance signal detection model of recognition memory. Jon's data were as well fitted as controls' data by a DP model that included two recollection parameters, but required counter-intuitive parameter values corresponding to normal recollection and impaired familiarity, which likely reflect an idiosyncratic use of confidence judgements when his memory for the material is weak. The results highlight a limitation in using ROCs to estimate recollection and familiarity in patients who may have developed compensatory strategies for material that they have difficulty remembering (scenes, but not faces in this case). Overall, these data are difficult to reconcile with domain-general accounts of the hippocampal role in memory, including dual process models and the declarative model. Instead, the data indicate that the hippocampus plays a preferential role in the processing of topographical memoranda over faces memoranda.
18097800	Few methods exist to measure declarative (explicit) memory in children during the toddler and preschool stages of development. We report the development and psychometric properties of a new measure of declarative memory for this age group, the Color Object Association Test (COAT). In pilot testing and large scale application of the test, the COAT was demonstrated to be a reliable and a valid measure of declarative memory for healthy children ages 18-36 months, living in a disadvantaged community. The test shows a linear developmental trajectory, which allows longitudinal examination of the development of declarative memory in children.
18085555	The study of the biological bases of memory has a long history. Based on research with patients with specific lesions and disease, animal models, and neuroimaging studies, the neural substrate that supports declarative memory in adults has been relatively well articulated. By contrast, studies of the neural bases of memory in development is in its infancy. Yet joint consideration of the processes involved in building a memory trace, and of the time course of development of the neural structures involved, has contributed to the generation of specific predictions regarding the sources of age-related change. Specifically, there are suggestions that in infancy and very early childhood, encoding and consolidation processes account for substantial age-related variance in long-term declarative memory. With development, the locus of age-related variability in the vulnerability of memory traces shifts to the later-stage processes of memory storage and retrieval. These insights are afforded by consideration of multiple levels of analysis, from the biological to the behavioral.
18077800	We sought cognitive event-related potential (ERP) biomarkers of disease progression and subsequent conversion to dementia in mild cognitive impairment (MCI).Two ERP components, the P600 and N400, are sensitive to abnormal episodic/declarative memory and semantic processing. When congruous category-exemplars are repeated, smaller P600s (relative to initial presentation) are normally elicited. Repetitions of semantically incongruous words yield smaller N400 amplitude. In mild Alzheimer disease (AD), abnormalities of both the N400 and P600 repetition effects are present, suggesting a widespread failure of synaptic plasticity.	Patients with amnestic MCI (n = 32) were longitudinally studied annually with an ERP paradigm in which semantically congruous (50%) and incongruous target words are repeated 10 to 140 seconds after initial presentation. ERP data were analyzed to contrast MCI-to-AD converters (within 3 years) vs nonconverters, using split-plot analyses of variance.	A statistically significant P600 congruous word repetition effect was found only in the nonconverter group (F = 9.9, p = 0.005 vs MCI converters). This effect correlated with verbal memory measures. Repetition of incongruous words produced a significant N400 amplitude attenuation (across right-hemisphere sites) in nonconverters, but not in converters. Patients with MCI with abnormal/reduced N400 or P600 word repetition effects had an 87 to 88% likelihood of dementia within 3 years while those with normal/spared N400 and P600 repetition effects had only an 11 to 27% likelihood.	Abnormalities of the P600 or N400 in mild cognitive impairment are associated with an increased risk of subsequent conversion to Alzheimer disease (AD). These event-related potential components may offer useful biomarkers for the detection and staging of very early AD.	
18065153	The hippocampal formation is a key structure in memory formation and consolidation. The hippocampus receives information from different cortical and subcortical sources. Cortical information is mostly funneled to the hippocampus through the entorhinal cortex (EC) in a bi-directional way that ultimately ends in the cortex. Retrograde tracing studies in the nonhuman primate indicate that more than two-thirds of the cortical afferents to the EC come from polymodal sensory association areas. Although some evidence for the projection from visual unimodal cortex to the EC exists, inputs from other visual and auditory unimodal association areas, and the possibility of their convergence with polymodal input in the EC remains largely undisclosed. We studied 10 Macaca fascicularis monkeys in which cortical deposits of the anterograde tracer biotinylated dextran-amine were made into different portions of visual and auditory unimodal association cortices in the temporal lobe, and in polymodal association cortex at the upper bank of the superior temporal sulcus. Visual and auditory unimodal as well as polymodal cortical areas projected to the EC. Both visual unimodal and polymodal association cortices presented dense projections, while those from unimodal auditory association cortex were more patchy and less dense. In all instances, the projection distributed in both the superficial and deep layers of the EC. However, while polymodal cortex projected to all layers (including layer I), visual unimodal cortex did not project to layer I, and auditory unimodal cortex projected less densely, scattered through all layers. Topographically, convergence from the three cortical areas studied can be observed in the lateral rostral and lateral caudal subfields. The present study suggests that unimodal and polymodal association cortical inputs converge in the lateral EC, thereby providing the possibility for the integration of complex stimuli for internal representations in declarative memory elaboration.
18064549	The hypothesis that a pervasive impairment of declarative memory contributes to language impairment in low functioning autism (LFA) was tested. Participants with LFA, high functioning autism (HFA), intellectual disability (ID) without autism, and typical development (TD) were given two recognition tests and four tests of lexical understanding. It was predicted that recognition would be impaired in the LFA group relative to the HFA and TD groups but not the ID group, and that recognition would correlate with lexical knowledge in the LFA group but none of the other groups. These predictions were supported except that the HFA group performed more similarly to the LFA group than expected, a finding interpreted in terms of selectively impaired episodic memory.
18058388	JL, a 25-year-old physiotherapist, became densely amnesic following herpes simplex viral encephalitis (HSVE), causing bilateral damage to medial and ventral areas of her frontal and temporal lobes and their associated circuitry. Three years post-onset, her WAIS-R full scale IQ (Verbal 74, Performance 102) showed an estimated loss of +/- 50 points. She displayed severe global amnesia and markedly impaired social cognition. However, her immediate memory, perceptual priming, and cognitive problem-solving abilities were relatively spared. Her retention of professional skills was assessed using simulated physiotherapy scenarios. JL was able to demonstrate some procedural skills spontaneously, but was unable to apply them precisely and flexibly to individual patient needs. She showed no memory of theoretical or propositional physiotherapy knowledge, and could neither plan treatment nor reason clinically. Her performance was well below that of four other physiotherapists who had also not practised for 4 years. Thus, despite the relative sparing of her implicit memory, JL's performance lacked the co-ordinated operation of declarative and implicit long-term memory and the links to working memory that are necessary for the flexible performance of complex professional procedures.
18055361	According to WHO data more than 180 million people suffer from diabetes mellitus worldwide and this number could double within 15 years. Normal function of the brain is dependent on continuous supply of glucose. In hypoglycemia, production of counterregulatory hormones (glucagon, epinephrine, growth hormone, and cortisol) increases, the sympathetic system becomes stimulated, and features of neuroglycopenia appear in order to save the homeostasis. Hypoglycemia is an alarming, actually life threatening condition, but the exposure to chronic hyperglycemia has a more detrimental effect on the brain than recurrent exposure to severe hypoglycemia. The active neural response to hyperglycemia induces changes in gene expression and function. The first steps against hyperosmolality are initially adaptive, but later hyperactivation of the hypothalamic magnocellular neurosecretory cells leads to their structural damage. Changes in hippocampal gene transcription are partially implicated in the deterioration of declarative memory. Neurologically passive shunting of excess glucose through alternative cellular metabolic pathways induces atherogenic, vascular lesions, free radicals, leukoencephalopathy and atrophy of the brain and thus leading to cognitive deficits. In physiological conditions insulin has neuroprotective effect. However, insulin resistance in the central nervous system correlates with insulin resistance in the periphery. Loss of responsiveness to insulin could render neurons more susceptible to neurotoxic insults, the protective effect of insulin diminishes, and apoptosis, neurodegeneration and the resultant cognitive decline are all increased in insulin-resistant patients. Some unclear relations appear between diabetes mellitus and Alzheimer's disease. Diabetic patients with APOE-4 gene have an increased risk for Alzheimer's disease. Prevalence of depression is higher in patients with diabetes mellitus and in turn, depression is a risk factor for diabetes mellitus. Simultaneous presence of depression and diabetes mellitus tends to worsen the course of both.
18047597	In temporal lobe epilepsy, long-term memory disturbance starts early in life mainly affecting declarative memory. Primary impairment of episodic memory often results in reduced semantic and autobiographic memory. Neuropsychological performance predicts academic achievement and everyday life functioning while subjective memory complaints are highly correlated with depression. Memory impairment is also influenced by initial brain damage, developmental retardation and dynamic factors (e.g., seizure frequency, medication). Damage of functional tissue, low mental reserve capacity, and poor seizure outcome increase the risk for postsurgical memory impairment whereas functional release due to seizure freedom counteracts negative impact. Preliminary findings indicate that postsurgical training improves memory deficits and encourage further research.
18033621	The acquisition and flexible expression of complex relations is often attributed to declarative memory processes. The extent to which such tasks may be done implicitly has not been sufficiently explored. We report that analogical or transfer processes may be accomplished implicitly. Our analogy task requires acquisition of a transverse patterning set, and then tests for transfer on an unrelated set. Participants learn the relations A>B (given a choice between A and B choose A) and B>C and the unrelated set X>Y and Y>Z. Only the experimental group was trained on the transverse pair C>A. At test all trials are unreinforced: A?B, B?C, A?C, X?Y, Y?Z, X?Z. Analogy was observed when the experimental group chose Z>X at greater frequency than controls who uniformly chose X>Z. Analogy occurred with or without awareness of the transfer. The capacity to transfer relations to an analogous set demonstrates a level of flexibility and abstraction not generally thought to be possible for implicit processes.
18031992	This study sought to objectify the distinction between schizophrenia and schizoaffective disorder in terms of standard tasks measuring verbal and non-verbal cognitive ability, auditory working memory, verbal declarative memory and visual processing speed. Research participants included 103 outpatients with a diagnosis of schizophrenia, 48 with schizoaffective disorder, and 72 non-patients from the community. Schizophrenia patients were impaired on all cognitive measures relative to schizoaffective patients and non-psychiatric participants. Regression-based prediction models revealed that cognitive measures classified schizophrenia patients accurately (91%), but not patients with schizoaffective disorder (35%). In addition, there was no statistical evidence for the unique predictive validity of any specific cognitive task. Patients with schizophrenia were significantly more symptomatic and had greater community support requirements than those with schizoaffective disorder. However, group differences in cognitive performance are insufficient to separate these syndromes of psychotic illness.
18025960	Two major memory and learning systems operate in the brain: one for facts and ideas (ie, the declarative or explicit system), one for habits and behaviors (ie, the procedural or implicit system). Broadly speaking these two memory systems can operate either in concert or entirely independently of one another during the performance and learning of skilled motor behaviors. This Special Issue article has two parts. In the first, we present a review of implicit motor skill learning that is largely centered on the interactions between declarative and procedural learning and memory. Because distinct neuroanatomical substrates support unique aspects of learning and memory and thus focal injury can cause impairments that are dependent on lesion location, we also broadly consider which brain regions mediate implicit and explicit learning and memory. In the second part of this article, the interactive nature of these two memory systems is illustrated by the presentation of new data that reveal that both learning implicitly and acquiring explicit knowledge through physical practice lead to motor sequence learning. In our new data, we discovered that for healthy individuals use of the implicit versus explicit memory system differently affected variability of performance during acquisition practice; variability was higher early in practice for the implicit group and later in practice for the acquired explicit group. Despite the difference in performance variability, by retention both groups demonstrated comparable change in tracking accuracy and thus, motor sequence learning. Clinicians should be aware of the potential effects of implicit and explicit interactions when designing rehabilitation interventions, particularly when delivering explicit instructions before task practice, working with individuals with focal brain damage, and/or adjusting therapeutic parameters based on acquisition performance variability.
18025959	The question of whether memory is important to human existence is simple to answer: life without memory would be devoid of any meaning. The question of what memory is, however, is much more difficult to answer. The main purpose of this article is to provide an overview of memory function, by drawing distinctions between different memory systems, specifically declarative (ie, conscious) versus nondeclarative (ie, nonconscious) memory systems. To distinguish between these larger systems and their various components, we include discussion of deficits in memory that occur as a consequence of brain injury and normative aging processes. Included in these descriptions is discussion of the neuroanatomical correlates of each memory component described to illustrate the importance of particular brain regions to different aspects of memory function.
18023459	The medial temporal lobe (MTL) has long been considered essential for declarative long-term memory, whereas the fronto-parietal cortex is generally seen as the anatomical substrate of short-term memory. This traditional dichotomy is questioned by recent studies suggesting a possible role of the MTL for short-term memory. In addition, there is no consensus on a possible specialization of MTL sub-regions for memory of associative information. Here, we investigated short-term memory for single features and feature associations in three humans with post-surgical lesions affecting the right hippocampal formation and in 10 healthy controls. We used three delayed-match-to-sample tasks with two delays (900/5000 ms) and three set sizes (2/4/6 items). Subjects were instructed to remember either colours, locations or colour-location associations. In colour-only and location-only conditions, performance of patients did not differ from controls. By contrast, a significant group difference was found in the association condition at 5000 ms delay. This difference was largely independent of set size, thus suggesting that it cannot be explained by the increased complexity of the association condition. These findings show that the hippocampal formation plays a significant role for short-term memory of simple visuo-spatial associations, and suggest a specialization of MTL sub-regions for associative memory.
18004283	An extensive animal literature suggests that excessive corticosteroid exposure is associated with changes in memory and the hippocampus. Agents that decrease glutamate attenuate corticosteroid effects on the hippocampus. Minimal data are available on preventing or reversing corticosteroid effects on the human hippocampus. We previously reported that open-label lamotrigine was associated with significant improvement in declarative memory in corticosteroid-treated patients. We now examine the impact of 24 weeks of randomized, placebo-controlled lamotrigine therapy on declarative memory (primary aim) and hippocampal volume (secondary aim) in 28 patients (n=16 for lamotrigine, n=12 for placebo) taking prescription corticosteroids. All participants with data from at least one postbaseline assessment (n=9 for lamotrigine, n=11 for placebo) were included in the analysis. Declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and weeks 12 and 24. Hippocampal and total brain volumes were manually traced from MRI scans obtained at baseline and week 24. On the basis of an ANCOVA analysis, total words learned on the RAVLT at exit were significantly greater in the lamotrigine group (n=8, missing data or dropouts n=8) compared to the placebo group (n=11, dropout n=1). RAVLT scores in the lamotrigine group increased from mildly impaired to average range. Hippocampal volume changes were small in both lamotrigine (n=7) and placebo (n=7) groups during the 24-week assessment period and between-group differences were not significant. Results suggest that lamotrigine may improve declarative memory in patients taking prescription corticosteroids although differential dropout rate in the two groups is a concern.
18003068	The role of the hippocampus in associative memory is the establishment of long-term, declarative memories. For example, memories for facts, name and life experiences. Damage to the hippocampus leads to loss of ability to convert short-term memory to new long-term memories. This can happen due to epilepsy, stroke, dementia or head injuries. One of the possibilities of providing a solution to this problem is by prosthesis. The first step towards this is building of biomimetic model of the region. A system modeling approach is used to build the biomimetic model of the CA3 by the use of biological repetitive firing neurons of R.J.Macgregor. The output of the neuron model is a spiking output so there is no need for a separate spike producing circuitry. The electronic model is also presented with a possible circuit for realization of the plasticity. The weights of the network are updated by the synaptic activity plasticity rule (SAPR), which has weight updation depending on the value of the post synaptic potential of the spiking neurons. The various paths of the flow of information in and out of the hippocampus and the possible connections for the prosthesis are presented. The project takes into consideration the various experimental finding and the advances in synaptic plasticity published so far for building this biomimetic model.
18000060	After encoding, memory traces are initially fragile and have to be reinforced to become permanent. The initial steps of this process occur at a cellular level within minutes or hours. Besides this rapid synaptic consolidation, systems consolidation occurs within a time frame of days to years. For declarative memory, the latter is presumed to rely on an interaction between different brain regions, in particular the hippocampus and the medial prefrontal cortex (mPFC). Specifically, sleep has been proposed to provide a setting that supports such systems consolidation processes, leading to a transfer and perhaps transformation of memories. Using functional MRI, we show that postlearning sleep enhances hippocampal responses during recall of word pairs 48 h after learning, indicating intrahippocampal memory processing during sleep. At the same time, sleep induces a memory-related functional connectivity between the hippocampus and the mPFC. Six months after learning, memories activated the mPFC more strongly when they were encoded before sleep, showing that sleep leads to long-lasting changes in the representation of memories on a systems level.
17996334	The present study examined the influence of genetic polymorphisms in the apolipoprotein (APOE) and the butyrylcholinesterase (BCHE) gene on GC secretion, cognition and personality in 66 healthy older adults. These particular variables were chosen given that they have been shown to be associated with human stress (i.e.stress markers). Measures included basal serum GC levels and cognitive scores on declarative memory obtained annually over 3 years. Also, self-esteem, neuroticism and depression were evaluated. Results showed that participants with the APOE E4-BCHE K variant (E4-K group) present increased basal levels of GCs and poorer cognitive performance when compared to non-carriers of these variants. In addition, the E4-K group reported lower self-esteem and higher levels of depression. These findings may indicate a genotype effect on markers of stress and cognitive integrity years before symptoms of dementia are apparent.
17995908	Previous studies have suggested that memory is dependent on the occurrence of REM sleep. Research has mainly focused on two distinct types of memory function, declarative and procedural, and it seems that the latter may more directly depend on REM sleep. Memory consolidation has been more investigated than acquisition, maintenance, and recall, despite the fact that sleep may affect flow of information into/from storage. Moreover, tests have often been limited to stimuli within only one modality (usually visual or verbal). This study aimed to clarify the role of REM sleep in memory by investigating aspects of memory function, processing, and modality in the same experimental setting. Tests of acquisition and consolidation of multiple aspects of memory function within the visual and verbal modalities were administrated to subjects before and after REM sleep deprivation. Results show that test performance was not affected by REM sleep deprivation.
17986092	To verify whether the long-term retention of an emotionally arousing story is stronger than the retention of a neutral story, and the enhancing effects of emotional arousal on declarative memory in Alzheimer's disease (AD) patients.Twenty subjects (10 with AD and 10 controls matched for age and educational level) were studied. After the audiovisual presentation (neutral story), the subjects rated the narrative's emotionality. Later, they answered a multiple-choice questionnaire about the stories. Two weeks later, they watched the emotionally arousing story.	Subjects who watched the emotionally arousing story assigned a score of emotionality higher than the subjects in the neutral group (P = 0.023). In addition, the participants remembered more details of the arousing story, and had a higher score in the questionnaire (P < 0.001).	We demonstrated that an emotionally arousing content enhances long-term declarative memory in AD. Furthermore, present finding supports the use of this instrument for clinical and research purposes.	
17981265	Hippocampal volume reduction and declarative memory deficits are reported in humans and animals exposed to exogenous corticosteroids. The amygdala is another brain structure involved in the stress response that has important interactions with the hypothalamic-pituitary-adrenal axis. To our knowledge, no studies in animals or humans have examined the impact of exogenous corticosteroid administration on the amygdala. We assessed amygdala volume in patients receiving chronic prescription corticosteroid therapy and control subjects with similar medical histories not receiving corticosteroids.Fifteen patients on long-term prednisone therapy and 13 control subjects of similar age, gender, ethnicity, education, height, and medical history were assessed with magnetic resonance imaging. Amygdala volume was manually traced and compared between groups using a two-way analysis of variance (ANOVA). Correlations between amygdala volume, age, and corticosteroid dose/duration were assessed using Pearson's correlation coefficient.	Compared with control subjects, corticosteroid-treated patients had significantly smaller amygdala volumes. Right amygdala volume correlated significantly with age in control subjects and with duration of corticosteroid therapy in patients.	Patients receiving chronic corticosteroid therapy had smaller amygdala volumes than control subjects that correlated with duration of corticosteroid therapy. These findings suggest that corticosteroid exposure may be associated with changes in the amygdala as well as hippocampus.	
17972276	N-methyl-D-aspartate (NMDA) receptors play an important role in learning and memory. Targeting the glycine modulatory site of the NMDA receptor has been suggested as a therapeutic strategy to improve cognition, although findings have not been convincing. We used the Cognitive Drug Research computerised assessment system to examine the effects of high-dose glycine on a number of cognitive processes in healthy young subjects. The study was a randomised placebo controlled repeated measures design in which each subject received acute placebo or glycine (0.8 g/kg) orally, with treatment conditions separated by a 5-day washout period. No significant effects of glycine were found on measures of working memory, declarative memory, attention or perceptual processing. These findings, together with those of previous studies, cast doubt over the ability of acute high-dose glycine to improve cognitive function in healthy subjects and suggest that the optimum dose of glycine for improving cognition may vary between different populations, possibly due to differences in endogenous glycine levels and the functional status of NMDA receptors.
17959788	Humans devote much time to the exchange of memories within the context of shared general and personal semantic knowledge. Our hypothesis was that functional imaging in normal subjects would demonstrate the convergence of speech comprehension and production on high-order heteromodal and amodal cortical areas implicated in declarative memory functions. Activity independent of speech phase (that is, comprehension and production) was most evident in the left and right lateral anterior temporal cortex. Significant activity was also observed in the posterior cortex, ventral to the angular gyri. The left and right hippocampus and adjacent inferior temporal cortex were active during speech comprehension, compatible with mnemonic encoding of narrative information, but activity was significantly less during the overt memory retrieval associated with speech production. Therefore, although clinical studies suggest that hippocampal function is necessary for the retrieval as well as the encoding of memories, the former appears to depend on much less net synaptic activity. In contrast, the retrosplenial/posterior cingulate cortex and the parahippocampal area, which are closely associated anatomically with the hippocampus, were equally active during both speech comprehension and production. The results demonstrate why a severe and persistent inability both to understand and produce meaningful speech in the absence of an impairment to process linguistic forms is usually only observed after bilateral, and particularly anterior, destruction of the temporal lobes, and emphasize the importance of retrosplenial/posterior cingulate cortex, an area known to be affected early in the course of Alzheimer's disease, in the processing of memories during communication.
17959355	Inflammatory cytokines and the cholinergic system have been implicated in the effects of stressors on mood and memory; however, the underlying mechanisms involved and the potential interrelationships between these pathways remain unclear. To address these questions, we administered neuropsychological tests to 33 generally healthy surgery patients who donated blood samples several days prior to undergoing moderate surgery (baseline), on the morning of the surgery (i.e., a psychological stressor), and one day after surgery. Eighteen control subjects were similarly tested. Serum levels of inflammatory cytokines, acetylcholinesterase (AChE) activity, and the stressor-inducible AChE-R variant were measured. An elevation in anxiety levels, an increase in depressed mood, and a decline in declarative memory were observed on the morning of the surgery, prior to any medical intervention, and were exacerbated one day after surgery. The surgical stressor-induced elevated IL-1 beta levels, which contributed to the increased depressed mood and to the post-surgery increase in AChE-R expression. The latter increase, which was also predicted by pre-surgery AChE-R and post-surgery mood disturbances, was associated with exacerbated memory impairments induced by surgery. In addition, elevated levels of AChE-R on the morning of the surgery predicted the post-surgery elevation in IL-6 levels, which was associated with amelioration of the memory impairments induced by surgery. Taken together, these findings suggest that exposure to a surgical stressor induces a reciprocal up-regulation of AChE-R and pro-inflammatory cytokines, which are involved in regulating the surgery-induced mood and memory disturbances.
17958471	Emotional events are usually better remembered than neutral ones. This effect is mediated in part by a modulation of the hippocampus by the amygdala. Sleep plays a role in the consolidation of declarative memory. We examined the impact of sleep and lack of sleep on the consolidation of emotional (negative and positive) memories at the macroscopic systems level. Using functional MRI (fMRI), we compared the neural correlates of successful recollection by humans of emotional and neutral stimuli, 72 h after encoding, with or without total sleep deprivation during the first post-encoding night. In contrast to recollection of neutral and positive stimuli, which was deteriorated by sleep deprivation, similar recollection levels were achieved for negative stimuli in both groups. Successful recollection of emotional stimuli elicited larger responses in the hippocampus and various cortical areas, including the medial prefrontal cortex, in the sleep group than in the sleep deprived group. This effect was consistent across subjects for negative items but depended linearly on individual memory performance for positive items. In addition, the hippocampus and medial prefrontal cortex were functionally more connected during recollection of either negative or positive than neutral items, and more so in sleeping than in sleep-deprived subjects. In the sleep-deprived group, recollection of negative items elicited larger responses in the amygdala and an occipital area than in the sleep group. In contrast, no such difference in brain responses between groups was associated with recollection of positive stimuli. The results suggest that the emotional significance of memories influences their sleep-dependent systems-level consolidation. The recruitment of hippocampo-neocortical networks during recollection is enhanced after sleep and is hindered by sleep deprivation. After sleep deprivation, recollection of negative, potentially dangerous, memories recruits an alternate amygdalo-cortical network, which would keep track of emotional information despite sleep deprivation.
17950473	Ts65Dn mice, like individuals with Down syndrome (DS), demonstrate a functional dissociation between explicit and implicit forms of memory, showing selective impairment in explicit or declarative learning tasks. Here, we explored Ts65Dn explicit memory deficits further by evaluating the ability of these mice to assimilate the temporal and spatial contexts under which previously novel objects had been encountered. We found that Ts65Dn mice could in fact form contextual representations of objects over the course of a few hours, contrary to their inability to discriminate object novelty over a more prolonged period of 24h. These results suggest that Ts65Dn mice might have particular difficulties in declarative tasks requiring long-term memory, presenting an especially important putative therapeutic target for pre-clinical and clinical DS research.
17941343	Memory impairment is a prominent defining feature of Alzheimer's disease (AD), yet the degree to which the profile of memory impairment is uniform across patients is not fully resolved. The study examined patterns of memory impairment in a large cohort of AD patients, with particular attention to the relationship between working and long-term declarative memory. Tests of working memory, visual and verbal recall and recognition, and recent personal memory were administered to 67 AD patients in the early to moderate stages of disease and to 30 age-matched controls. Performance on all measures was significantly poorer in patients than in controls. Factor analysis of test scores delineated five factors representing the domains of working memory, visual recall, verbal recall, recognition, and personal memory, indicating that these aspects of memory can break down separately. Cluster analysis revealed distinct memory profiles. Some patients showed predominant problems in working memory, with relatively superior long term retention, whereas other patients showed the reverse pattern. Qualitatively distinct profiles arose at comparable levels of severity. Problems in working memory, but not long term memory were associated with the presence of language and perceptuospatial deficits. The results reinforce previous findings that both working and long term memory failure contribute to the memory symptoms of AD patients, and demonstrate dissociations in memory breakdown across the cohort. The link between working memory and language performance, together with findings of posterior hemisphere abnormalities on neuroimaging, lead us to reassess the nature of working memory deficits in AD.
17924524	Using Long-Evans rats tested in a water maze, this study assessed the role of 5-HT1A/5-HT7 receptors of the medial septum in encoding, consolidation, and retrieval of spatial information. The testing protocol (acquisition: daily four-trial sessions over three consecutive days; retention: probe trial on day 4) was first validated by showing that intraseptal infusions of lidocaine (LIDO; 40 microg/0.5 microL) disrupted acquisition and retrieval of the task. 8-OH-DPAT (4 microg/0.5 microL) infused before each acquisition session prevented learning/retention of the platform location, an effect attenuated by pretreatment with the 5-HT1A receptor antagonist WAY 100635. With the 5-HT7 antagonist SB 269970, the 8-OH-DPAT-induced acquisition deficit seemed attenuated, but there was no subsequent retention. When infused immediately, 1, 4, or 6 h after each acquisition session, 8-OH-DPAT did not hinder consolidation. When the infusions were performed 2 h postacquisition, however, consolidation was disrupted. Finally, when infused before a probe trial after drug-free acquisition, 8-OH-DPAT had no effect, suggesting no interference with retrieval processes. We also established that 8-OH-DPAT had no effects when the platform was visible, and altered neither home-cage activity nor anxiety-related behavior (elevated plus-maze). Altogether, these results show that 5-HT1A receptors in the septal region contribute both to declarative-like information encoding and subsequently, within a given postacquisition time window, to its consolidation. They do not participate in the retrieval of recently learned declarative-like information. These observations suggest that 5-HT1A receptors of the medial septum contribute to a serotonin-mediated mechanism involved in the encoding and consolidation, not the retrieval of spatial hippocampal-dependent knowledge. These results might have some relevance to approaches aimed at modifying serotonergic functions in the brain for the treatment of disorders such as depression, anxiety, post-traumatic stress, and amnesia.
17921875	Using functional magnetic resonance imaging during a verbal memory task, we investigated correlations of signal fluctuations within the hippocampus and ipsilateral frontal as well as temporal areas in temporal lobe epilepsy patients. Declarative memory abilities were additionally examined before and after temporal lobe epilepsy surgery. A significant difference exists in functional connectivity between patients whose mnemonic functions deteriorated and those who remained stable or improved. Univariate analyses showed significantly higher preoperative coupling between the hippocampus and Brodmann area 22 for the group that decreased in verbal learning. We suggest greater coupling to reflect higher functional network integrity. Postoperatively reduced learning ability in patients with higher preoperative coupling underlines the importance of hippocampal interaction with cortical areas for successful memory formation.
17917157	Animal experiments and cell biology studies have provided evidence that both estrogens and androgens can play a protective role against Alzheimer's disease (AD) related neurodegeneration. Males who become hypogonadal in later life often report problems with their memory. Lower than normal testosterone levels have also been detected in patients prior to the onset of AD, as well as in younger late-onset male AD patients, when compared to appropriate controls. The results of some small clinical trials suggest that testosterone can improve cognitive function in andropause. Although such improvement in cognitive function is subtle, patients on testosterone replacement therapy have reported memory improvements in both declarative and procedural domains. In contrast, there is no clinical evidence to date which suggest that the hormone dihydroepiandrosterone (DHEA) can improve cognitive function. Rises in the levels of the gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), have been associated with AD, but the clinical effects of reducing their levels remain to be determined. We hypothesize that androgens, gonadotropin modulators, or perhaps selective androgen receptor modulators may be useful components of therapy aimed at preventing the onset or delaying the progression of AD in male patients.
17911036	While there is mounting evidence for the importance of sleep for declarative memory consolidation in adults, so far this issue has not been investigated in children despite considerable differences in sleep duration and sleep architecture between children and adults. Here, 27 children (aged between 9 and 12yr) were examined on two conditions: on the Sleep-Wake condition, subjects learned word pairs in the evening and delayed recall was tested first in the next morning after sleep and then again in the following evening after daytime wakefulness. On the Wake-Sleep condition, learning took place in the morning and delayed recall was tested in the evening of the same day and again in the next morning after sleep. In both conditions retention of declarative memory was significantly increased only after an interval of sleep that either followed immediately after learning (as in the Sleep-Wake condition) or that followed after daytime wakefulness (as in the Wake-Sleep condition), respectively. The results support the hypothesis that sleep plays an active role in declarative memory consolidation even if delayed and further show for the first time the importance of sleep for declarative memory consolidation during childhood.
17905642	There is now compelling evidence that sleep promotes the long-term consolidation of declarative and procedural memories. Behavioral studies suggest that sleep preferentially consolidates explicit aspects of these memories, which during encoding are possibly associated with activation in prefrontal-hippocampal circuitry. Hippocampus-dependent declarative memory benefits particularly from slow-wave sleep (SWS), whereas rapid-eye-movement (REM) sleep seems to benefit procedural aspects of memory. Consolidation of hippocampus-dependent memories relies on a dialog between the neocortex and hippocampus. Crucial features of this dialog are the neuronal reactivation of new memories in the hippocampus during SWS, which stimulates the redistribution of memory representations to neocortical networks; and the neocortical slow (<1Hz) oscillation that synchronizes hippocampal-to-neocortical information transfer to activity in other brain structures.
17905567	Neurogenesis, the formation of new neurons from stem/progenitor cells, occurs in the hippocampal dentate gyrus throughout life. Although the exact function of adult hippocampal neurogenesis is currently unknown, recent studies suggest that the newly formed neuronal population plays an important role in hippocampal-dependent cognitive abilities, including declarative memory. The process of adult neurogenesis is greatly influenced by the interaction between cells of the adaptive immune system and CNS-resident immune cells. Our laboratory has recently demonstrated that immune cells contribute to maintaining life-long hippocampal neurogenesis. The regulation of such immune-cell activity is crucial: too little immune activity (as in immune deficiency syndromes) or too much immune activity (as in severe inflammatory diseases) can lead to impaired hippocampal neurogenesis, which could then result in impaired hippocampal-dependent cognitive abilities. From these converging discoveries arise a mechanism that can explain one route by which our body affects our mind.
17904876	Cocaine addiction is associated with long-term cognitive alterations including deficits on tests of declarative/spatial learning and memory. To determine the extent to which cocaine exposure plays a causative role in these deficits, adult male Long-Evans rats were given daily injections of cocaine (30 mg/kg/day x 14 days) or saline vehicle. Three months later, rats were trained for 6 sessions on a Morris water maze protocol adapted from Gallagher, Burwell, and Burchinal [Gallagher, M., Burwell, R., & Burchinal, M. (1993). Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behavioral Neuroscience, 107, 618-626]. Rats given prior cocaine exposure performed similarly to controls on training trials, but searched farther from the platform location on probe trials interpolated throughout the training sessions and showed increased thigmotaxis. The results demonstrate that a regimen of cocaine exposure can impair Morris water maze performance as long as 3 months after exposure. Although the impairments were not consistent with major deficits in spatial learning and memory, they may have resulted from cocaine-induced increases in stress responsiveness and/or anxiety. Increased stress and anxiety would be expected to increase thigmotaxis as well as cause impairments in searching for the platform location, possibly through actions on ventral striatal dopamine signaling.
17900050	Electroconvulsive therapy (ECT) is the most effective treatment in a variety of psychiatric syndromes (especially mood disorders). However one of its adverse effects is neurocognitive dysfunction. Declarative memory impairment after ECT is unquestionable and well investigated. There are only few ambiguous studies focused on nondeclarative and immediate memory changes during ECT.A study of immediate (working) memory changes in depressed patients treated with ECT (n=10; bitemporal ECT 3 times a week) or imipramine or desipramine (150-250 mg/day; n=10) was conducted in patients who fulfilled DSM-IV criteria for major unipolar depression. Hamilton Depression Rating Scale (HDRS) and Beck's Depression Inventory (BDI) were used to assess the efficacy of antidepressant therapy. Cognitive functions were assessed with neuropsychological tests: Stroop A and B, TMT (Trial Making) A and B. The patients' status was evaluated 1 day before the treatment and 1 day, 2 weeks, 1 month and 6 months after the first ECT procedure.	1 day after first ECT treatment, patient's working memory was slightly impaired, but this was not statistically significant. Both groups showed statistically significant improvement in working memory I month after start of treatment. However there were statistically significant differences between ECT and pharmacologically treated groups at the first month of therapy.	ECT treatment only temporally affects working memory function. The improvement of function may be a result of clinical recovery from depressant symptomatology.	
17898218	The acquisition of declarative (i.e., facts) and procedural (i.e., skills) memories may be supported by independent systems. This same organization may exist, after memory acquisition, when memories are processed off-line during consolidation. Alternatively, memory consolidation may be supported by interactive systems. This latter interactive organization predicts interference between declarative and procedural memories. Here, we show that procedural consolidation, expressed as an off-line motor skill improvement, can be blocked by declarative learning over wake, but not over a night of sleep. The extent of the blockade on procedural consolidation was correlated to participants' declarative word recall. Similarly, in another experiment, the reciprocal relationship was found: declarative consolidation was blocked by procedural learning over wake, but not over a night of sleep. The decrease in declarative recall was correlated to participants' procedural learning. These results challenge the concept of fixed independent memory systems; instead, they suggest a dynamic relationship, modulated by when consolidation takes place, allowing at times for a reciprocal interaction between memory systems.
17892595	 Recent advances have led to an understanding that the hippocampus is involved more broadly than explicit or declarative memory alone. Tasks which involve the acquisition of complex associations involve the hippocampus whether the learning is explicit or implicit. One hippocampal-dependent implicit task is transitive inference (TI). Recently it was suggested that implicit transitive inference does not depend upon the hippocampus (Frank, M. J., O'Reilly, R. C., & Curran, T. 2006. When memory fails, intuition reigns: midazolam enhances implicit inference in humans. Psychological Science, 17, 700-707). The authors demonstrated that intravenous midazolam, which is thought to inactivate the hippocampus, may enhance TI performance. Three critical assumptions are required but not met: 1) that deactivations of other regions could not account for the effect 2) that intravenous midazolam does indeed deactivate the hippocampus and 3) that midazolam influences explicit but not implicit memory. Each of these assumptions is seriously flawed. Consequently, the suggestion that implicit TI does not depend upon the hippocampus is unfounded.
17874597	Considerable interest in the hypothesis that different cognitive tasks recruit qualitatively distinct processing systems has led to the proposal of separate explicit (declarative) and implicit (procedural) systems. A popular probabilistic category learning task known as the weather prediction task is said to be ideally suited to examine this distinction because its two versions, "observation" and "feedback," are claimed to recruit the declarative and procedural systems, respectively. In two experiments, we found results that were inconsistent with this interpretation. In Experiment 1, a concurrent memory task had a detrimental effect on the implicit (feedback) version of the task. In Experiment 2, participants displayed comparable and accurate insight into the task and their judgment processes in the feedback and observation versions. These findings have important implications for the study of probabilistic category learning in both normal and patient populations.
17873684	Bipolar disorder is associated with the highest rates of substance abuse of any psychiatric disorder. Cocaine use is particularly common in patients with bipolar disorder. Both cocaine use and bipolar disorder are associated with mood symptoms and cognitive impairment. Therefore, treatments that stabilize mood, improve cognition, and reduce cocaine use would be useful. Citicoline modulates phospholipids metabolism and neurotransmitter levels and appears to improve cognition in some central nervous system disorders. A 12-week, randomized, placebo-controlled, parallel-group, add-on, proof-of-concept trial of citicoline was conducted in 44 outpatients with a history of mania or hypomania and cocaine dependence. The primary aim was to examine memory, but mood and cocaine use were also assessed.Participants were evaluated with a structured diagnostic interview; Inventory of Depressive Symptomatology-Self-Report, Young Mania Rating Scale, and Rey Auditory Verbal Learning Test. Cocaine use was assessed with urine drug screens. Data were analyzed using mixed-model analysis of covariance, generalized estimating equations, and logistic regression analyses that used all of the available data.	A significant group effect (P = 0.006) favoring citicoline was observed on the Rey Auditory Verbal Learning Test alternative word list. No significant between-group differences were found on the Inventory of Depressive Symptomatology-Self-Report or Young Mania Rating Scale. The citicoline group had a significantly lower probability of a cocaine-positive urine at exit (P = 0.026). The covariate-adjusted odds ratio estimate was 6.41, suggesting that those who took placebo had 6.41-times higher odds of testing positive for cocaine at exit than those who took citicoline. Citicoline was well tolerated, with no participants to our knowledge discontinuing because of medication side effects.	The use of citicoline was associated with improvement relative to placebo in some aspects of declarative memory and cocaine use, but not mood. The findings are promising and suggest that larger trials of citicoline are warranted.	
17872393	The orbitofrontal cortex is strongly connected with limbic areas of the medial temporal lobe that are critically involved in the establishment of declarative memories (entorhinal and perirhinal cortex and the hippocampal region) as well as the amygdala and the hypothalamus that are involved in emotional and motivational states. The present article reviews evidence regarding the role of the orbitofrontal cortex in the processing of novel information, breaches of expectation, and memory. Functional neuroimaging evidence is provided that there is a difference between the anterior and posterior orbitofrontal cortex in such processing. Exposure to novel information gives rise to a selective increase of activity in the granular anterior part of the orbitofrontal cortex (area 11) and this activity increases when subjects attempt to encode this information in memory. If the stimuli violate expectations (e.g., inspection of graffiti-like stimuli in the context of other regular stimuli) or are unpleasant (i.e., exposure to the sounds of car crashes), there is increased response in the posteromedial agranular/dysgranular area 13 of the orbitofrontal region. The anatomic data provide a framework within which to understand these functional neuroimaging findings.
17872388	It has been proposed that long-term declarative memories are ultimately stored through interactions between the hippocampal memory system and the neocortical association areas that initially processed the to-be-stored information. One association neocortex, the orbitofrontal cortex (OFC) is strongly and reciprocally connected with the hippocampal memory system and plays an important role in odor recognition memory in rats. We will report data from two studies: one that examined the firing of neurons in a task dependent on the parahippocampal region (PHR; including the perirhinal, postrhinal, and entrorhinal cortices), and one examined the firing of OFC neurons performing a task that is presumably dependent on the hippocampus. In the first study, we examined the role of OFC neurons in the continuous odor-guided nonmatching to sample task. While the firing of neurons in the PHR and OFC are similar in this task, there are several notable differences that are consistent with the idea that OFC is a high-order association cortex which interacts extensively with the PHR to store declarative memories. In the second study, we characterized the firing patterns of neurons in the OFC rats performing a passive, 8-odor-sequence memory task. Most interesting were neurons that fired selectively in anticipation of specific odors. We found that hippocampal lesions abolished the anticipatory firing in OFC, suggesting that these anticipatory responses (memory) were in fact dependent on the hippocampus, further supporting the view that the OFC interacts with the hippocampal memory system to store long-term, declarative memories.
17869339	A substantial and growing body of evidence from cognitive neuroscience supports the concept of multiple memory systems (MMS). However, the existence of multiple systems has been questioned by theorists who instead propose that dissociations can be accounted for within a single memory system. We present convergent evidence from neuroimaging and neuropsychological studies of category learning in favor of the existence of MMS for category learning and declarative knowledge. Whereas single-system theorists have argued that their approach is more parsimonious because it only postulates a single form of memory representation, we show that the MMS approach is superior in its ability to account for a broad range of data from psychology and neuroscience.
17855374	Functional neuroimaging research has repeatedly implicated the striatum in motor procedural learning, but attempts to explore this relation in patients with Parkinson's disease (PD) have yielded inconsistent results. Furthermore, the functional impact of procedural learning impairment is unknown. The present study sought to examine the effects of PD on procedural learning and to determine whether impaired procedural learning affects functional status. The performance of 95 non-demented PD patients on the serial reaction time task (SRTT) was compared with that of 44 demographically matched control subjects. The SRTT is a four-choice reaction time task in which visual stimuli are presented in six blocks of 100 trials either in a repeating sequence of 10 stimuli or randomly. Learning was inferred from the reduction of response times over five successive blocks of repeating sequence trials and from the increase in response times in the sixth random block. In addition, neuropsychological tests of declarative memory, executive and visuospatial functions were administered to all participants. Patients also received quantitative ratings of functional outcome. The two groups did not differ in the learning rate across blocks of repeating sequence trials. However, PD patients were significantly less efficient than controls in acquiring sequence-specific knowledge, although this impairment was relatively small (d = 0.38). Patients with more advanced clinical symptoms tended to show worse performance. Separate analyses of a subgroup of 24 non-medicated patients in the early stages of PD revealed no differences in SRTT performance relative to controls. Neuropsychological testing showed impairments in attention and executive functions, immediate and delayed explicit memory and visuospatial skills in the PD group, but none of the cognitive measures were related to procedural learning. Reduced motor sequence learning in PD patients did not influence their functional status. These findings indicate that procedural learning impairment is not an early feature of PD, but is likely to emerge with progression of the disease, independently of cognitive dysfunction or dopaminergic medication.
17854895	Schizophrenia is a devastating mental disorder with multiple facets, including the impairment of learning and memory. Recent evidence suggests that information is processed and represented by multiple interacting memory systems in the brain, including prefrontal cortex, basal ganglia, and medial temporal lobe. These structures are critical in the pathophysiology of schizophrenia. Whereas executive and declarative memory dysfunctions are well known in schizophrenia, habit learning deficits related to the basal ganglia are less clear, despite the fact that dopaminergic and other neurochemical processes in the basal ganglia may play a crucial role in the pathophysiology and pharmacology of schizophrenia. In this article, I propose that the investigation of different classification learning functions, including reward- and feedback-guided learning and acquired equivalence learning, may shed light on the neuropsychology, pathophysiology, pharmacology, and behavioral genetics of schizophrenia.
17854893	Previous research suggests that early performance of amnesic individuals in a probabilistic category learning task is relatively unimpaired. When combined with impaired declarative knowledge, this is taken as evidence for the existence of separate implicit and explicit memory systems. The present study contains a more fine-grained analysis of learning than earlier studies. Using a dynamic lens model approach with plausible learning models, we found that the learning process is indeed indistinguishable between an amnesic and control group. However, in contrast to earlier findings, we found that explicit knowledge of the task structure is also good in both the amnesic and the control group. This is inconsistent with a crucial prediction from the multiple-systems account. The results can be explained from a single system account and previously found differences in later categorization performance can be accounted for by a difference in learning rate.
17854846	The role of sub-cortical structures such as the striatum in language remains a controversial issue. Based on linguistic claims that language processing implies both recovery of lexical information and application of combinatorial rules it has been shown that striatal damaged patients have difficulties applying conjugation rules while lexical recovery of irregular forms is broadly spared (e.g., Ullman, M. T., Corkin, S., Coppola, M., Hickok, G., Growdon, J. H., Koroshetz, W. J., et al. (1997). A neural dissociation within language: Evidence that the mental dictionary is part of declarative memory, and that grammatical rules are processed by the procedural system. Journal of Cognitive Neuroscience, 9(2), 266-276). Here we bolstered the striatum-rule hypothesis by investigating lexical abilities and rule application at the phrasal level. Both processing aspects were assessed in a model of striatal dysfunction, namely Huntington's disease (HD). Using a semantic priming task we compared idiomatic prime sentences involving lexical access to whole phrases (e.g., "Paul has kicked the bucket") with idiom-derived sentences that contained passivation changes involving syntactic movement rules (e.g., "Paul was kicked by the bucket"), word changes (e.g., "Paul has crushed the bucket") or either. Target words that were either idiom-related (e.g., "death") reflecting lexical access to idiom meanings, word-related (e.g., "bail") reflecting lexical access to single words, or unrelated (e.g., "table"). HD patients displayed selective abnormalities with passivated sentences whereas priming was normal with idioms and sentences containing only word changes. We argue that the role of the striatum in sentence processing specifically pertains to the application of syntactic movement rules whereas it is not involved in canonical rules required for active structures or in lexical processing aspects. Our findings support the striatum-rule hypothesis but suggest that it should be refined by tracking the particular kind of language rules depending on striatal computations.
17854242	Antipsychotic medications differ in their sedative potential, which can affect cognitive performance. The primary objective of this double-blind study was to compare the effects of treatment initiation with risperidone and quetiapine on cognitive function in subjects with stable bipolar disorder.Subjects had a DSM-IV diagnosis of bipolar I disorder in partial or full remission and a Young Mania Rating Scale score <or= 8 at screening. Subjects were randomly assigned to 1 of 2 treatment sequences: risperidone-quetiapine or quetiapine-risperidone. Subjects in the risperidone-quetiapine sequence received 2 mg of risperidone with dinner and placebo with breakfast during period 1 and 100 mg of quetiapine with dinner and 100 mg with breakfast during period 2. Subjects in the quetiapine-risperidone sequence received the same treatments in reverse order. The 2 treatment periods were separated by a 6- to 14-day washout period. Cognitive function, including attention, working memory, declarative memory, processing speed, and executive functions, was measured before and after dosing. The Visual Analog Scale for Fatigue was also completed. The primary endpoint was a neurocognitive composite score (NCS). The study was conducted from November 2004 through August 2005.	Thirty subjects were randomly assigned; 28 took all doses of study medication and completed a baseline and at least 1 postbase-line assessment in each treatment. On the NCS, significantly better overall cognitive function was seen after risperidone than after quetiapine at each time point after dosing. Subjects performed significantly better after risperidone than after quetiapine (p < .05) on 9 of the 18 individual cognitive outcome measures and significantly better after quetiapine than after risperidone on 1 measure. Sleeping or the need for sleep during the test days was reported in significantly more patients after receiving quetiapine than risperidone.	The results indicate that initiation of quetiapine treatment was associated with more immediate adverse cognitive effects and increased somnolence than risperidone treatment.	
17853075	Sleep is critically involved in the consolidation of previously acquired memory traces. However, nocturnal sleep is not uniform but is subject to distinct changes in electrophysiological and neuroendocrine activity. Specifically, the first half of the night is dominated by slow wave sleep (SWS), whereas rapid eye movement (REM) sleep prevails in the second half. Concomitantly, hypothalamo-pituitary-adrenal (HPA) activity as indicated by cortisol release is suppressed to a minimum during early sleep, while drastically increasing during late sleep. We have shown that the different sleep stages and the concomitant glucocorticoid release are interactively involved in the consolidation of different types of memories. SWS-rich early sleep has been demonstrated to benefit mainly the consolidation of hippocampus-dependent declarative memories (i.e. facts and episodes). In contrast, REM sleep-rich late sleep was shown to improve in particular emotional memories involving amygdalar function, as well as procedural memories (for skills) not depending on hippocampal or amygdalar function. Enhancing plasma glucocorticoid concentrations during SWS-rich early sleep counteracted hippocampus-dependent declarative memory consolidation, but did not affect hippocampus-independent procedural memory. Preventing the increase in cortisol during late REM sleep-rich sleep by administration of metyrapone impaired hippocampus-dependent declarative memory but enhanced amygdala-dependent emotional aspects of memory. The data underscore the importance of pituitary-adrenal inhibition during early SWS-rich sleep for efficient consolidation of declarative memory. The increase in cortisol release during late REM sleep-rich sleep may counteract an overshooting consolidation of emotional memories.
17850223	The impact of alcohol on implicit, emotional learning is not well understood, partly because family history, drug use, and task demands influence these processes. The conditioned pattern preference (CPP) task provides a more ecologically valid means to investigate implicit cognition in the lab because it has low demand awareness and relies on learning to associate nonverbal cues with reward.This study examined the effects of acute alcohol intoxication on implicit learning using the CPP task in 83 intoxicated and 69 sober young adults. Information on individual drug use, family history, impulsivity, and alcohol expectancies was also collected.	Alcohol intoxication affected explicit, but not implicit learning on the CPP task. In addition, participants who reported a positive family history of addiction (FH+) or individual recreational drug use did not exhibit a preference for cues previously paired with reward.	Preference formation on the CPP task recruits motivational neurocircuitry, an effect that is unaltered by alcohol. Group differences in implicit emotional learning on this task may represent neurocognitive differences in individuals at risk for addiction.	
17848998	There is compelling evidence indicating that sleep plays a crucial role in the consolidation of new declarative, hippocampus-dependent memories. Given the increasing interest in the spatiotemporal relationships between cortical and hippocampal activity during sleep, this study aimed to shed more light on the basic features of human sleep in the hippocampus.We recorded intracerebral stereo-EEG directly from the hippocampus and neocortical sites in five epileptic patients undergoing presurgical evaluations. The time course of classical EEG frequency bands during the first three NREM-REM sleep cycles of the night was evaluated. We found that delta power shows, also in the hippocampus, the progressive decrease across sleep cycles, indicating that a form of homeostatic regulation of delta activity is present also in this subcortical structure. Hippocampal sleep was also characterized by: i) a lower relative power in the slow oscillation range during NREM sleep compared to the scalp EEG; ii) a flattening of the time course of the very low frequencies (up to 1 Hz) across sleep cycles, with relatively high levels of power even during REM sleep; iii) a decrease of power in the beta band during REM sleep, at odds with the typical increase of power in the cortical recordings.	Our data imply that cortical slow oscillation is attenuated in the hippocampal structures during NREM sleep. The most peculiar feature of hippocampal sleep is the increased synchronization of the EEG rhythms during REM periods. This state of resonance may have a supportive role for the processing/consolidation of memory.	
17848936	Insulin acts in the brain to reduce food intake and body weight and is considered a major adiposity signal in energy homeostasis. In normal-weight men, intranasal insulin administration reduces body fat and improves declarative memory. The present experiments aimed to generalize these findings to obese patients, with a view to evaluate the therapeutic potential of the compound.Insulin and placebo, respectively, were intranasally administered four times a day (amounting to 160 IU day(-1)) over 8 weeks to two groups of 15 obese men each.	Contrasting with the catabolic effects in normal-weight men, insulin treatment did not induce any significant reduction of body weight (P>0.50) and body fat (P>0.44) in the obese subjects. However, in accordance with the effects in normal-weight men, declarative memory and mood were improved (P<0.05) and hypothalamic-pituitary-adrenal axis activity as assessed by circulating ACTH (P<0.01) and cortisol levels (P<0.04) was reduced.	Our results indicate that in obese men, intranasal insulin is functionally active in the central nervous system but fails to affect the neuronal networks critically involved in body weight regulation. We conclude that obesity in men is associated with central nervous resistance to the adiposity signal insulin. This defect likely contributes to the persistence of obesity in spite of elevated levels of circulating insulin in obese patients.	
17848502	The medial temporal lobe (MTL) supports the formation and retrieval of long-term declarative memories, or memories for facts and everyday events. One challenge posed for this type of memory stems from the highly overlapping nature of common episodes. Within cognitive psychology, it is widely accepted that interference between information learned at different times is a major limitation on memory. In spite of several decades of intense research in the fields of interference theory and the neurobiological underpinnings of declarative memory, there is little direct evidence bearing on how the MTL resolves this interference to form accurate memories of everyday facts and events. Computational models of MTL function have proposed a mechanism in which the MTL, specifically the hippocampus, performs pattern separation, whereby overlapping representations are made less similar. However, there is little evidence bearing on how this process is carried out in the intact human MTL. Using high-resolution fMRI, we conducted a set of experiments that taxed behavioral pattern separation by using highly similar, interfering stimuli in a modified continuous recognition task. Regions within the parahippocampal gyrus demonstrated activity consistent with a "recall to reject" strategy. In contrast and critical to performing the task, activity within the hippocampus distinguished between correctly identified true stimulus repetitions, correctly rejected presentations of similar lure stimuli, and false alarms to similar lures. These data support the computational models' assertion that the hippocampus plays a key role in pattern separation.
17767149	Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD(67)), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5' flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5' untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.
17766093	Corticosteroid excess is associated with impairment in declarative memory and hippocampal changes. In animals, phenytoin blocks the effects of stress on memory and hippocampal histology. Levetiracetam also shows neuroprotective properties in some animal models. This report examines whether levetiracetam prevents mood or cognitive changes secondary to prescription corticosteroids.Thirty outpatients given systemic corticosteroid therapy for asthma were randomized to either levetiracetam (1500 mg/day) or placebo given concurrently with the corticosteroids. Mood was assessed with the Hamilton rating scale for depression (HRSD), Young mania rating scale (YMRS) and activation (ACT) subscale of the internal state scale, declarative memory with the Rey auditory verbal learning test (RAVLT), and attention and executive functioning with the Stroop color and word test at baseline and after approximately 7 days of corticosteroid plus levetiracetam or placebo therapy.	Levetiracetam and placebo groups showed significant improvement from baseline to exit on RAVLT total words recalled with a non-significant change on other outcomes. No significant between-group differences were found. Initial prednisone dose showed a significant correlation with change in some cognitive domains.	Levetiracetam was well tolerated when combined with prednisone. Significant between-group differences in mood and cognition were not found.	
17765272	Dopamine (DA) modulates working memory. However, the relation between DA systems and episodic (declarative) memory is less established. Frontal lobe DA function may be involved. We were interested in assessing whether apomorphine (Apo), a drug used extensively in clinical research as a probe of DA function, has an effect on episodic memory test performance in healthy volunteers.To investigate the effect of a presynaptic dose of Apo on episodic memory tests and on other tests thought to be sensitive to frontal lobe functions.	Twenty healthy subjects were treated with Apo HCl (5 microg/kg sc) or placebo (10 subjects/group) in a randomized, double blind parallel group design and performance on a battery of cognitive tests was assessed.	Apomorphine significantly impaired performance on tests of source recognition (d.f.=19, p=0.05) and item recognition memory (d.f.=19, p<0.05), and memory interference (d.f.=19, p<0.010). No significant change was found on other tests (Go/no-Go Test, Categorized Words, Stroop, Trail Making Test, and verbal fluency).	Findings in this small sample of subjects suggest that dopaminergic transmission affects episodic memory functions.	
17764396	In response to Meyer and Kurtz's (2006) recommended discontinuation of the terms "objective" and "projective" as descriptors of personality tests, a new classification system for personality measures is sketched out that is based on memory research. Adopting a widely used model of the organization of human memory systems (e.g., Squire, Knowlton, & Musen, 1993), a distinction between declarative and nondeclarative personality tests is proposed based on whether tests assess facets of personality represented in consciously accessible memory systems or in nonconscious memory systems whose operation is reflected in performance. The declarative/nondeclarative classification can be further refined by specifying separable memory systems within each domain of memory (e.g., episodic, semantic, priming, skill learning). It is proposed that such a new classification would be conceptually meaningful, because it links personality tests to highly refined accounts of human cognition, and heuristically fruitful, because it provides new insights into the properties and limits of existing tests and helps identify hitherto largely untapped sources for the assessment of personality.
17762510	Bipolar disorder (BD) is thought to be associated with abnormalities within discrete brain regions associated with emotional regulation, particularly in fronto-limbic-subcortical circuits. Several reviews have addressed the involvement of the prefrontal cortex in the pathophysiology of BD, whereas little attention has been given to the role of the hippocampus. This study critically reviews data from brain imaging, postmortem, neuropsychological, and preclinical studies, which suggested hippocampal abnormalities in BD. Most of the structural brain imaging studies did not find changes in hippocampal volume in BD, although a few studies suggested that anatomical changes might be restricted to the psychotic, pediatric, or unmedicated BD subgroups. Functional imaging studies showed abnormal brain activation in the hippocampus and its closely related regions during emotional, attentional, and memory tasks. This is consistent with neuropsychological findings that revealed a wide range of cognitive disturbances during acute mood episodes and a significant impairment in declarative memory during remission. Postmortem studies indicate abnormal glutamate and GABA transmission in the hippocampus of BD patients, whereas data from preclinical studies suggest that the regulation of hippocampal plasticity and survival might be associated with the therapeutic effects of mood stabilizers. In conclusion, the available evidence suggests that the hippocampus plays an important role in the pathophysiology of BD.
17714013	This study sought to explore the neural correlates that underlie autobiographical, episodic, and semantic memory. Autobiographical memory was defined as the conscious recollection of personally relevant events, episodic memory as the recall of stimuli presented in the laboratory, and semantic memory as the retrieval of factual information and general knowledge about the world. Our objective was to delineate common neural activations, reflecting a functional overlap, and unique neural activations, reflecting functional dissociation of these memory processes. We conducted an event-related functional magnetic resonance imaging study in which we utilized the same pictorial stimuli but manipulated retrieval demands to extract autobiographical, episodic, or semantic memories. The results show a functional overlap of the three types of memory retrieval in the inferior frontal gyrus, the middle frontal gyrus, the caudate nucleus, the thalamus, and the lingual gyrus. All memory conditions yielded activation of the left medial-temporal lobe; however, we found a functional dissociation within this region. The anterior and superior areas were active in episodic and semantic retrieval, whereas more posterior and inferior areas were active in autobiographical retrieval. Unique activations for each memory type were also delineated, including medial frontal increases for autobiographical, right middle frontal increases for episodic, and right inferior temporal increases for semantic retrieval. These findings suggest a common neural network underlying all declarative memory retrieval, as well as unique neural contributions reflecting the specific properties of retrieved memories.
17711573	Many human neuroimaging investigations on recognition memory employ verbal instructions to direct subject's attention to a stimulus attribute. But do the same or a similar neurophysiological process occur during nonverbal experiences, such as those involving contingency-shaped responses? Establishing the spatially distributed neural network underlying recognition memory for instructed stimuli and operant, contingency-shaped (i.e., discriminative) stimuli would extend the generality of contemporary domain-general views of recognition memory and clarify the involvement of declarative memory processes in human operant behavior.Fifteen healthy adults received equivalent amounts of exposure to three different stimulus sets prior to neuroimaging. Encoding of one stimulus set was prompted using instructions that emphasized memorizing stimuli (Instructed). In contrast, encoding of two additional stimulus sets was prompted using a GO/NO-GO operant task, in which contingencies shaped appropriate GO and NO-GO responding. During BOLD functional MRI, subjects completed two recognition tasks. One required passive viewing of stimuli. The second task required recognizing whether a presented stimulus was a GO/NO-GO stimulus, an Instructed stimulus, or novel (NEW) stimulus. Retrieval success related to recognition memory was isolated by contrasting activation from each stimulus set to a novel stimulus (i.e., an OLD > NEW contrast). To explore differences potentially related to source memory, separate contrasts were performed between stimulus sets.	No regions reached supralevel thresholds during the passive viewing task. However, a relatively similar set of regions was activated during active recognition regardless of the methods and included dorsolateral and ventrolateral prefrontal cortex, right inferior and posterior parietal regions and the occipitoparietal region, precuneus, lingual, fusiform gyri and cerebellum. Results also showed the magnitude of the functional response in the occipitoparietal region was inversely correlated with reaction times (RTs), such that the largest functional response and slowest RTs occurred to Instructed stimuli and the smallest functional response and fastest RTs occurred to GO stimuli, with effects to NO-GO stimuli intermediate. The inverse relation was also present bilaterally in the parahippocampus and hippocampus. Comparisons between stimulus sets also revealed regional differences potentially related to source memory.	Recognition of stimuli previously associated with instructions and operant contingencies (i.e., discriminative stimuli) generally recruited similar inferior frontal and occipitoparietal regions and right posterior parietal cortex, with the right occipitoparietal region showing the largest effect. These findings suggest domain-general views of recognition memory may be applicable to understanding the neural correlates of control exerted by discriminative stimuli and suggest declarative memory processes are involved in human operant behavior.	
17706671	Borderline personality disorder (BPD) is characterized by changes in subjective and objective measures of sleep quality. As recent findings point to the importance of sleep in memory consolidation, sleep-related memory consolidation was investigated in 15 female BPD patients (mean age 26.1+/-6.1 years) and 15 female healthy controls (mean age 25.6+/-6.8 years). Before and after the study night, declarative and procedural memory performance was tested by a paired associate list and a mirror tracing task. Subjective sleep quality was assessed by a sleep questionnaire, objective sleep quality was measured by a portable sleep recording device. During the study night the restorative value of sleep was significantly reduced in BPD patients (p<0.001), while objective sleep quality showed a trend for longer REM sleep duration (p=0.054). No significant differences were found regarding overnight performance improvement in the declarative and procedural memory tasks. Present findings suggest that declarative and procedural memory consolidation during sleep is intact in BPD patients.
17703897	The human ability to perform transitive inference (TI) is an area of debate from a neurocognitive standpoint. Some studies emphasize a stimulus driven medial-temporal lobe process [Preston, A.R., Shrager, Y., Dudukovic, N.M., Gabrieli, J.D., 2004. Hippocampal contribution to the novel use of relational information in declarative memory. Hippocampus 14, 148-152; Titone, D., Ditman, T., Holzman, P., Eichenbaum, H., Levy, D., 2004. A transitive inference test of relational memory in schizophrenia. Schizophr. Res. 68, 235-247; Van Elzakker, M., O'Reilley, R., Rudy, J., 2003. Transivity, flexibility, conjenctive representation and the hippocampus: an empirical analysis. Hippocampus 13, 334-340] while others emphasize a higher-level frontal lobe strategy that requires the flexible maintenance of information in working memory [Waltz, J., Knowlton, B., Holyoak, K., Boone, K., Mishkin, F., de Menedezes Santos, M., Thomas, C., Miller, B., 1999. A system for relational reasoning in human prefrontal cortex. Psychol. Sci. 10, 119-125]. In two experiments we investigated when and how adults employ different cognitive strategies during TI by evaluating the interaction between task instructions and individual differences in working memory capacity. Participants engaged in a paired discrimination task involving a 6-unit TI hierarchy and were either prior aware, prior unaware or serendipitously aware of the hierarchical relationship among stimulus items. Both prior aware participants and serendipitously aware participants were more likely to engage in a logic-based strategy compared to unaware participants who relied upon stimulus-driven strategies. Individual differences in working memory were associated with the acquisition of awareness in the serendipitously aware group and with the maintenance of awareness in the prior aware group. These findings suggest that the capacity for TI may be supported by multiple neurocognitive strategies, and that the specific strategy employed is dependent upon both task- and participant-related factors.
17692934	Neurobiologists are becoming increasingly interested in how complex cognitive representations are formed by the integration of sensory stimuli. To this end, discrimination tasks are frequently used to assess perceptual and cognitive processes in animals, because they are easy to administer and score, and the ability of an animal to make a particular discrimination establishes beyond doubt that the necessary perceptual/cognitive processes are present. It does not, however, follow that absence of discrimination means the animal cannot make a particular perceptual judgement; it may simply mean that the animal did not manage to discover the relevant discriminative stimulus when trying to learn the task. Here, it is shown that rats did not learn a cross-modal object discrimination (requiring association of each object's visual appearance with its odour) when trained on the complete task from the beginning. However, they could eventually make the discrimination when trained on the component parts step by step, showing that they were able to do the necessary cross-modal integration in the right circumstances. This finding adds to growing evidence that discrimination tasks tend to encourage feature-based discrimination, perhaps by engaging automatic, habit-based brain systems. Thus, they may not be the best way to assess the formation of multi-dimensional stimulus representations of the kind needed in more complex cognitive processes such as declarative memory. Instead, more natural tasks such as spontaneous exploration may be preferable.
17689852	Studies on how acute stress affects learning and memory have yielded inconsistent findings, with some studies reporting enhancing effects while others report impairing effects. Recently, Joëls et al. [Joëls, M., Pu, Z., Wiegert, O., Oitzl, M.S., Krugers, H.J., 2006. Learning under stress: how does it work? Trends in Cognitive Sciences, 10, 152-158] argued that stress will enhance memory only when the memory acquisition phase and stressor share the same spatiotemporal context (i.e., context-congruency). The current study tested this hypothesis by looking at whether context-congruent stress enhances declarative memory performance. Undergraduates were assigned to a personality stress group (n=16), a memory stress group (n=18), or a no-stress control group (n=18). While being exposed to the acute stressor or a control task, participants encoded personality- and memory-related words and were tested for free recall 24h later. Relative to controls, stress significantly enhanced recall of context-congruent words, but only for personality words. This suggests that acute stress may strengthen the consolidation of memory material when the stressor matches the to-be-remembered information in place and time.
17687266	Declarative memory impairments are common in patients with bipolar illness, suggesting underlying hippocampal pathology. However, hippocampal volume deficits are rarely observed in bipolar disorder. Here we used surface-based anatomic mapping to examine hippocampal anatomy in bipolar patients treated with lithium relative to matched control subjects and unmedicated patients with bipolar disorder. High-resolution brain magnetic resonance images were acquired from 33 patients with bipolar disorder (21 treated with lithium and 12 unmedicated), and 62 demographically matched healthy control subjects. Three-dimensional parametric mesh models were created from manual tracings of the hippocampal formation. Total hippocampal volume was significantly larger in lithium-treated bipolar patients compared with healthy controls (by 10.3%; p=0.001) and unmedicated bipolar patients (by 13.9%; p=0.003). Statistical mapping results, confirmed by permutation testing, revealed localized deficits in the right hippocampus, in regions corresponding primarily to cornu ammonis 1 subfields, in unmedicated bipolar patients, as compared to both normal controls (p=0.01), and in lithium-treated bipolar patients (p=0.03). These findings demonstrate the sensitivity of these anatomic mapping methods for detecting subtle alterations in hippocampal structure in bipolar disorder. The observed reduction in subregions of the hippocampus in unmedicated bipolar patients suggests a possible neural correlate for memory deficits frequently reported in this illness. Moreover, increased hippocampal volume in lithium-treated bipolar patients may reflect postulated neurotrophic effects of this agent, a possibility warranting further study in longitudinal investigations.
17680369	Since elderly people suffering from dementia want to go on living independently for as long as possible, they need to be able to maintain familiar and learn new practical skills. Although explicit or declarative learning methods are mostly used to train new skills, it is hypothesized that implicit or procedural techniques may be more effective in this population. The present review discusses 23 experimental studies on implicit motor-skill learning in patients with Alzheimer's disease (AD). All studies found intact implicit motor-learning capacities. Subsequently, it is elaborated how these intact learning abilities can be exploited in the patients' rehabilitation with respect to the variables 'practice' and 'feedback.' Recommendations for future research are provided, and it is concluded that if training programs are adjusted to specific needs and abilities, older people with AD are well able to (re)learn practical motor skills, which may enhance their autonomy.
17676534	A number of memory rehabilitation techniques have targeted people with various degrees of memory impairments. However, few studies have shown the contribution of preserved non-declarative memory capacity and errorless learning in the treatment of amnesic patients. The current case report describes the memory rehabilitation of a 44-year-old man with amnesia following viral encephalitis. The patient's procedural memory capacity had an important role in the use of a motor imagery strategy to remember people's names. It was further demonstrated that the application of a verbal learning technique was helpful in recalling new verbal information. These different memory rehabilitation techniques are discussed in terms of alternative possibilities in the rehabilitation of amnesic patients.
17676059	Brain regions that are involved in memory formation, particularly medial temporal lobe (MTL) structures and lateral prefrontal cortex (PFC), have been identified in adults, but not in children. We investigated the development of brain regions involved in memory formation in 49 children and adults (ages 8-24), who studied scenes during functional magnetic resonance imaging. Recognition memory for vividly recollected scenes improved with age. There was greater activation for subsequently remembered scenes than there was for forgotten scenes in MTL and PFC regions. These activations increased with age in specific PFC, but not in MTL, regions. PFC, but not MTL, activations correlated with developmental gains in memory for details of experiences. Voxel-based morphometry indicated that gray matter volume in PFC, but not in MTL, regions reduced with age. These results suggest that PFC regions that are important for the formation of detailed memories for experiences have a prolonged maturational trajectory.
17644222	Autobiographical episodic memory represents a subsystem of declarative long-term memory and largely depends on combining information from multiple sources. The purpose of this study was to assess neural correlates of declarative long-term memory in patients with amnestic mild cognitive impairment (MCI) and controls using fMRI and a task requiring autobiographical and semantic memory retrieval. Comparison of the network supporting episodic autobiographical and semantic memory irrespective of remoteness (recent and remote) revealed significant activations in right parietal cortex and precuneus bilaterally in the patients. Autobiographical episodic versus semantic memory retrieval in the controls led to significant bilateral activations of the parietal-temporal junction, left temporal pole, anterior cingulate, retrosplenial cortex and cerebellum. In contrast, MCI patients activated left supplementary motor area, left premotor and superior temporal cortex. In MCI patients compared to controls a dysfunction of the retrosplenial cortex during memory retrieval was revealed by a lack of differential activation in relation to recency of memories and memory type. Our data suggest that MCI leads to a loss of specificity in the neural network supporting declarative long-term memory.
17643054	Compelling evidence indicates that central nervous insulin enhances learning and memory and in particular benefits hippocampus-dependent (i.e., declarative) memory. Intranasal administration of insulin provides an effective way of delivering the compound to the central nervous system, bypassing the blood-brain barrier and avoiding systemic side effects.Here we review a series of recent studies on the effects of intranasally administered insulin on memory functions in humans. In accordance with the beneficial effects of intravenously administered insulin on hippocampus-dependent declarative memory observed in hyperinsulinemic-euglycemic clamp studies, intranasal insulin administration similarly improves this type of memory, but in the absence of adverse peripheral side effects.	Considering that cerebrospinal fluid insulin levels are reduced in patients suffering from Alzheimer's disease, these results may be of considerable relevance for future clinical applications of insulin in the treatment of memory disorders.	
17636546	The prevailing paradigm in cognitive neuroscience assumes that the brain can be best understood as consisting of modules specialised for different psychological functions. Within the field of memory, we assume modules for different kinds of memory. The most influential version of this view posits a module called the "medial temporal lobe memory system" which operates in the service of "declarative memory." This system can be contrasted with a separate "perceptual representation system" in the ventral visual stream, which is critical for perceptual learning and memory, an example of nondeclarative function. Here we question this modular memory systems view and suggest that a better way to understand the ventral visual-perirhinal-hippocampal stream is as a hierarchically organised representational continuum. We suggest that in general, rather than trying to map psychological functions onto brain modules, we could benefit by instead attempting to understand the functions of brain regions in terms of the representations they contain, and the computations they perform.
17627484	Previous research suggests separate neural networks for implicit (non-declarative) and explicit (declarative) memory processes. A core cognitive impairment in mild to moderate Alzheimer's disease (AD) is a pronounced declarative memory and learning deficit with relative preservation of non-declarative memory. Cholinesterase inhibitors has been purported to enhance cognitive function, and previous clinical trials consistently showed that donepezil, a reversible inhibitor of acetylcholinesterase (AChE), led to statistically significant improvements in cognition and patient function. This prospective pilot study is a randomized, double blind, placebo-controlled clinical trial investigating 10 patients with AD. Our purpose was to examine the relationship between declarative and non-declarative capability with particular emphasis on implicit sequence learning. Patients were assessed at baseline and again at 4-weeks. After participants' baseline data were obtained, each was double-blindly randomized to one of two groups: donepezil or placebo. At baseline participants were tested with two outcome measures (Serial Reaction Time Task, Alzheimer's Disease Assessment Scale-Cognitive Subscale). Participants were given either 5 mg donepezil or an identically appearing placebo to be taken nightly for 4 weeks (28 tablets), and then retested. The donepezil group demonstrated a greater likelihood of increases in both non-declarative and declarative processes. The placebo group was mixed without clearly definable trends or patterns. When the data were examined for coincidental changes in the two outcome measures together they are suggestive of a benefit from donepezil treatment for non-declarative and declarative processes.
17615247	Impairments in visual discrimination beyond long-term declarative memory have been found in amnesic individuals, with hippocampal lesions resulting in deficits in scene discrimination and perirhinal cortex damage affecting object discrimination. To complement these findings, the present functional magnetic resonance imaging study found that in healthy participants oddity judgment for novel trial-unique scenes, compared with face or size oddity, was associated with increased posterior hippocampus and parahippocampal cortex activity. In contrast, perirhinal and anterior hippocampus activity was observed during unfamiliar trial-unique face oddity judgment, when contrasted with scene or size oddity tasks. Activity in all of these regions decreased as the stimuli were repeated across trials, reflecting the participants' increasing familiarity with the stimuli. This change was significant in all areas, with the exception of the perirhinal cortex, right anterior hippocampus, and to a lesser extent the left anterior hippocampus during face oddity judgment. One possibility is that the activity in these regions may not reflect entirely episodic memory encoding but, in part, processes beyond the mnemonic domain. Thus, the perirhinal cortex, and possibly anterior hippocampus, may play a more generic role in the discrimination and processing of objects.
17606328	Increased levels of circulating glucocorticoids (GCs) due to stress have been shown to result in enhanced consolidation and impaired retrieval of memory in humans. Several studies have shown that participants may be categorized as high and low responders with regard to GC levels elicited by stress. In the current study, we studied the differential effects of acute psychosocial stress on declarative memory processes in high and low responders. Twenty male participants were exposed to the Trier Social Stress Test (TSST) and a rest condition, and they completed the Rey Auditory Verbal Learning Test (RAVLT). Results show that there was no general effect of psychosocial stress on declarative memory processes. However, high cortisol responders displayed better immediate free recall after being exposed to stress. Findings are discussed in the context of possible positive relations of stress and declarative memory performance.
17581780	Sleep contributes to processes of memory, but many questions still remain open. The aim of this study was to test the role of different aspects of sleep for memory performance in a group of patients with chronic non-restorative sleep.Forty-two consecutive patients (mean age 40.3 years; 31 women) with non-restorative sleep were included. All subjects underwent polysomnography for diagnostic reasons and obtained the following diagnoses (International Classification of Sleep Disorders, ICSD): psychophysiological or idiopathic insomnia (N=18), paradoxical insomnia (N=13), mild hypersomnia (N=6), and dysthymic disorder (N=5). Patients with sleep-related breathing disorders or restless legs were not included. Prior to polysomnography on the second night and the next morning, neuropsychological tests were performed. Declarative memory was tested by the Rey-Osterrieth Complex Figure Test and a paired associative word list. Procedural learning was assessed by a mirror-tracing skill.	Visual declarative memory performance was significantly associated with total sleep time, sleep efficiency, duration of non-rapid eye movement (NREM) sleep and number of NREM-REM sleep cycles, but not with specific measures of REM sleep or slow wave sleep.	Further indications of a role of sleep, and in particular of NREM sleep and sleep organization, for visual declarative memory were found.	
17573370	Two step theories of memory formation assume that an initial learning phase is followed by a consolidation stage. Memory consolidation has been suggested to occur predominantly during sleep. Very recent findings, however, suggest that important steps in memory consolidation occur also during waking state but may become saturated after some time awake. Sleep, in this model, specifically favors restoration of synaptic plasticity and accelerated memory consolidation while asleep and briefly afterwards. To distinguish between these different views, we recorded intracranial electroencephalograms from the hippocampus and rhinal cortex of human subjects while they retrieved information acquired either before or after a "nap" in the afternoon or on a control day without nap. Reaction times, hippocampal event-related potentials, and oscillatory gamma activity indicated a temporal gradient of hippocampal involvement in information retrieval on the control day, suggesting hippocampal-neocortical information transfer during waking state. On the day with nap, retrieval of recent items that were encoded briefly after the nap did not involve the hippocampus to a higher degree than retrieval of items encoded before the nap. These results suggest that sleep facilitates rapid processing through the hippocampus but is not necessary for information transfer into the neocortex per se.
17566942	According to Consolidation Theory (Squire, 1992, Psychological Review, 99, 195; Squire & Alvarez, 1995, Current Opinion in Neurobiology, 5, 169), the mesial temporal lobes have a time-limited role in the maintenance, storage and retrieval of retrograde declarative memories, such that they are not necessary for recalling remote memories. In contrast, proponents of the Multiple Trace Theory (Fuji, Moscovitch, & Nadel, 2000, Handbook of neuropsychology, 2nd ed., p 223, Amsterdam, New York: Elsevier; Nadel & Moscovitch, 1999, Current Opinion in Neurobiology, 7, 217) posit that the mesial temporal lobe (MTL) is necessary for remembering detailed autobiographical and topographical material from all time periods. A third theory of hippocampal function, the Cognitive Map Theory (O'Keefe & Nadel, 1978, The hippocampus as a cognitive map. Oxford: Clarendon), states that the hippocampus is involved in the processing of allocentric spatial representations. The precise role of the MTL in remote memory has been difficult to elucidate, as the majority of studies present cases with widespread brain damage that often occurred many years prior to testing. We investigated retrograde autobiographical, semantic and topographical memories in a subject (SG) who had recently sustained infarctions confined to the MTL and retrosplenial region bilaterally. Inconsistent with the predictions of Cognitive Map Theory, memory for spatial maps that were learned in the past was preserved. Additional testing indicated that SG suffered from a landmark agnosia, which affected remotely and recently acquired information equally. SG was also poor at imagining which direction he would have to turn his body to move from one landmark to another. In accordance with Consolidation Theory, SG performed similarly to control subjects for remote time periods on various measures of retrograde autobiographical memory and demonstrated intact knowledge regarding famous faces and vocabulary terms that were acquired in the past. In contrast, memory for remote public events was impaired. The current findings indicate that the mesial temporal and/or retrosplenial regions have little role to play in memory for remotely acquired spatial maps, autobiographical memories, famous faces or vocabulary terms. However, the findings for landmark naming, directional calculations between landmarks and knowledge of public events suggest that the MTL and/or retrosplenial cortices remain important for accessing these types of memories indefinitely.
17566769	Population transmembrane currents and neuronal firing in different layers of the human entorhinal cortex (ER) were recorded during semantic and episodic memory processes using a linear array of 24 laminar microelectrodes. Both measures, as well as local broadband spectral power, increased during retrieval of newly-learned characteristics, especially in superficial layers. No differences were observed in the activity evoked by remembering people as compared to places. Semantic retrieval evoked similar activity. In contrast, intentional encoding of declarative memory evoked relatively little activity. A double-dissociation of these responses with simultaneously recorded lateral inferotemporal recordings suggests that entorhinal cortex may be specifically engaged during retrieval, across multiple memory types and materials.
17566652	Ts1Cje and Ts65Dn are genetic mouse models of Down syndrome (DS). Like individuals with DS, these mice exhibit various hallmarks of hippocampal pathology, and deficits in hippocampal-based, declarative learning and memory tasks. Both spatial navigation and novel object recognition, two prototypical domains of declarative memory function, have been strongly characterized in the Ts65Dn DS model. Indeed, Ts65Dn mice show navigation problems in the Morris water maze, impaired alternation in a T-maze, and deficient working and reference memory in the radial arm maze task. They, likewise, show an inability to detect object novelty over time. In contrast to the Ts65Dn model, hippocampal-dependent cognition has been less well characterized in Ts1Cje. Although Ts1Cje mice have been found to exhibit spatial difficulties in the Morris water maze and reduced spontaneous alternation, their ability to process object-based information has never been examined. Here, we report that Ts1Cje mice perform normally in short-term and long-term novel object recognition tasks. The ability of Ts1Cje mice to detect object novelty, unlike Ts65Dn, may point to differences in the extent of hippocampal pathology in the two DS mouse models.
17558286	We set out to investigate the extent to which semantic integration processes during language comprehension indexed by the N400 component affect subsequent declarative memory processes as revealed by the putative event-related potential correlates of familiarity and recollection. To this end we designed an incidental recognition memory test whose study material was composed of sentences that were either correct or contained a semantic or syntactic violation. By this means it was possible to examine the mnemonic consequences of the N400 amplitude at study. We found a significant correlation between the amplitude of the N400 at encoding and the magnitude of the familiarity-related early old/new effect at test. It is argued that the processes that contributed to N400 generation increase the likelihood of familiarity-based recognition memory.
17556851	Earlier findings suggest both a link between sleep and memory consolidation and a relationship between abnormal sleep at baseline and poor treatment outcome in major depression after interpersonal psychotherapy (IPT).Pre-treatment polysomnography was examined in 32 patients with a major depressive episode (mean age = 39.5 years, 20 women). Declarative memory was tested by the Rey-Osterrieth Complex Figure Test and a paired associative word list and procedural learning was assessed by a mirror tracing skill. All patients were treated with IPT according to the manual and did not receive any antidepressant medication. Twenty-three patients took part in a minimum of 12 sessions of IPT. Remission was defined as 2 consecutive weeks with a score <8 on the Hamilton Rating Scale of Depression.	Declarative visual memory performance was associated with total sleep time and total amount of rapid eye movement sleep. In IPT remitters (n = 14), there was a trend towards a decrease in rapid eye movement density (first period) and a significant decrease in delta power in pre-treatment sleep in comparison to non-remitters (n = 9). Treatment outcome after IPT was also associated with declarative memory performance at baseline (as a trend).	Further indications of a role of sleep in memory processes and of the importance of specific sleep parameters as markers for a positive treatment response to psychotherapy were found.	
17554824	One of the fundamental principles of cortical brain regions, including the hippocampus, is that information is represented in the ensemble firing of populations of neurons, i.e., spatio-temporal patterns of electrophysiological activity. The hippocampus has long been known to be responsible for the formation of declarative, or fact-based, memories. Damage to the hippocampus disrupts the propagation of spatio-temporal patterns of activity through hippocampal internal circuitry, resulting in a severe anterograde amnesia. Developing a neural prosthesis for the damaged hippocampus requires restoring this multiple-input, multiple-output transformation of spatio-temporal patterns of activity. Because the mechanisms underlying synaptic transmission and generation of electrical activity in neurons are inherently nonlinear, any such prosthesis must be based on a nonlinear multiple-input, multiple-output model. In this paper, we have formulated the transformational process of multi-site propagation of spike activity between two subregions of the hippocampus (CA3 and CA1) as the identification of a multiple-input, multiple-output (MIMO) system, and proposed that it can be decomposed into a series of multiple-input, single-output (MISO) systems. Each MISO system is modeled as a physiologically plausible structure that consists of 1) linear/nonlinear feedforward Volterra kernels modeling synaptic transmission and dendritic integration, 2) a linear feedback Volterra kernel modeling spike-triggered after-potentials, 3) a threshold for spike generation, 4) a summation process for somatic integration, and 5) a noise term representing intrinsic neuronal noise and the contributions of unobserved inputs. Input and output spike trains were recorded from hippocampal CA3 and CA1 regions of rats performing a spatial delayed-nonmatch-to-sample memory task that requires normal hippocampal function. Kernels were expanded with Laguerre basis functions and estimated using a maximum-likelihood method. Complexity of the feedforward kernel was progressively increased to capture higher-order system nonlinear dynamics. Results showed higher prediction accuracies as kernel complexity increased. Self-kernels describe the nonlinearities within each input. Cross-kernels capture the nonlinear interaction between inputs. Second- and third-order nonlinear models were found to successfully predict the CA1 output spike distribution based on CA3 input spike trains. First-order, linear models were shown to be insufficient.
17546683	Recording the activity of neurons is a mainstay of animal memory research, while human recordings are generally limited to the activity of large ensembles of cells. The relationship between ensemble activity and neural firing rate during declarative memory processes, however, remains unclear. We recorded neurons and local field potentials (LFPs) simultaneously from the same sites in the human hippocampus and entorhinal cortex (ERC) in patients with implanted intracranial electrodes during a virtual taxi-driver task that also included a memory retrieval component. Neurons increased their firing rate in response to specific passengers or landmarks both during navigation and retrieval. Although we did not find item specificity in the broadband LFP, both theta- and gamma-band LFPs increased power to specific items on a small but significant percent of channels. These responses, however, did not correlate with item-specific neural responses. To contrast item-specific responses with process-specific responses during memory, we compared neural and LFP responses during encoding (navigation) and retrieval (associative and item-specific recognition). A subset of neurons also altered firing rates nonspecifically while subjects viewed items during encoding. Interestingly, LFPs in the hippocampus and ERC increased in power nonspecifically while subjects viewed items during retrieval, more often during associative than item-recognition. Furthermore, we found no correlation between neural firing rate and broadband, theta-band, and gamma-band LFPs during process-specific responses. Our findings suggest that neuronal firing and ensemble activity can be dissociated during encoding, item-maintenance, and retrieval in the human hippocampal area, likely relating to functional properties unique to this region.
19946603	Glucocorticoids (GCs, cortisol in human) are associated with impairments in declarative memory retrieval. Brain regions hypothesized to mediate these effects are the hippocampus and prefrontal cortex (PFC). Our aim was to use fMRI in localizing the effects of GCs during declarative memory retrieval. Therefore, we tested memory retrieval in 21 young healthy males in a randomized placebo-controlled crossover design. Participants encoded word lists containing neutral and emotional words 1 h prior to ingestion of 20 mg hydrocortisone. Memory retrieval was tested using an old/new recognition paradigm in a rapid event-related design. It was found that hydrocortisone decreased brain activity in both the hippocampus and PFC during successful retrieval of neutral words. These observations are consistent with previous animal and human studies suggesting that glucocorticoids modulate both hippocampal and prefrontal brain regions that are crucially involved in memory processing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11682-007-9003-2) contains supplementary material, which is available to authorized users.
17522024	Sleep architecture as well as memory function are strongly age dependent. Slow wave sleep (SWS), in particular, decreases dramatically with increasing age, starting already beyond the age of 30. SWS normally predominates during early nocturnal sleep and is implicated in declarative memory consolidation. However, the consequences of changes in sleep across the life span for sleep-associated memory consolidation have not been evaluated so far. Here, we compared declarative memory consolidation (for word-pair associates) during sleep in young and middle-aged healthy humans. The age groups (18-25 vs. 48-55 yr) did not differ with regard to learning performance before retention periods that covered, respectively, the first and second half of nocturnal sleep. However, after early retention sleep, where the younger subjects showed distinctly more SWS than the middle-aged (62.3 +/- 3.7 min vs. 18.4 +/- 7.2 min, P < 0.001), retrieval of the word pairs in the middle-aged was clearly worse than in the young (P < 0.001). In contrast, declarative memory retention did not differ between groups after late sleep, where retention was generally worse than after early sleep (P = 0.005). Retention of declarative memories was the same in both age groups when sleep periods containing equal amounts of SWS were compared, i.e., across late sleep in the young and across early sleep in the middle-aged. Our results indicate a decline in sleep-associated declarative memory consolidation that develops already during midlife and is associated with a decrease in early nocturnal SWS.
17522018	The reconsolidation hypothesis states that a consolidated memory could again become unstable and susceptible to facilitation or impairment for a discrete period of time after a reminder presentation. The phenomenon has been demonstrated in very diverse species and types of memory, including the human procedural memory of a motor skill task but not the human declarative one. Here we provide evidence for both consolidation and reconsolidation in a paired-associate learning (i.e., learning an association between a cue syllable and the respective response syllable). Subjects were given two training sessions with a 24-h interval on distinct verbal material, and afterward, they received at testing two successive retrievals corresponding to the first and second learning, respectively. Two main results are noted. First, the first acquired memory was impaired when a reminder was presented 5 min before the second training (reconsolidation), and also when the second training was given 5 min instead of 24 h after the first one (consolidation). Second, the first retrieval proved to influence negatively on the later one (the retrieval-induced forgetting [RIF] effect), and we used the absence of this RIF effect as a very indicator of the target memory impairment. We consider the demonstration of reconsolidation in human declarative memory as backing the universality of this phenomenon and having potential clinical relevance. On the other hand, we discuss the possibility of using the human declarative memory as a model to address several key topics of the reconsolidation hypothesis.
17507060	The hippocampus has been proposed to play a critical role in memory through its unique ability to bind together the disparate elements of an experience. This hypothesis has been widely examined in rodents using a class of tasks known as "configural" or "non-linear", where outcomes are determined by specific combinations of elements, rather than any single element alone. On the basis of equivocal evidence that hippocampal lesions impair performance on non-spatial configural tasks, it has been proposed that the hippocampus may only be critical for spatial configural learning. Surprisingly few studies in humans have examined the role of the hippocampus in solving configural problems. In particular, no previous study has directly assessed the human hippocampal contribution to non-spatial and spatial configural learning, the focus of the current study. Our results show that patients with primary damage to the hippocampus bilaterally were similarly impaired at configural learning within both spatial and non-spatial domains. Our data also provide evidence that residual configural learning can occur in the presence of significant hippocampal dysfunction. Moreover, evidence obtained from a post-experimental debriefing session suggested that patients acquired declarative knowledge of the underlying task contingencies that corresponded to the best-fit strategy identified by our strategy analysis. In summary, our findings support the notion that the hippocampus plays an important role in both spatial and non-spatial configural learning, and provide insights into the role of the medial temporal lobe (MTL) more generally in incremental reinforcement-driven learning.
17504777	Recognition of the need to treat cognitive deficits in schizophrenia is compelling and well established, with empirical findings and conceptual arguments related to cognitive enhancement appearing regularly in the literature. Cognitive enhancement itself, however, remains at an early stage. Biological approaches have centered on the development of antipsychotic medications that also improve cognition, but the results have so far remained modest. As a way to facilitate the development of cognitive enhancers in schizophrenia, this article focuses on adjunctive pharmacological approaches to antipsychotic medications and highlights the need for systematic explorations of relevant brain mechanisms. While numerous conceptual criteria might be employed to guide the search, we will focus on 4 points that are especially likely to be useful and which have not yet been considered together. First, the discussion will focus on deficits in a particular cognitive domain, verbal declarative memory. Second, we will review the current status of preclinical and clinical efforts to improve declarative memory using antipsychotic medications, which is the main, existing mode of treatment. Third, we will examine an example of an adjunctive intervention-glucose administration-that improves memory in animals and humans, modulates function in brain regions related to verbal declarative memory, and is highly amenable to translational research. Finally, a heuristic model will be outlined to explore how the intervention maps on to the underlying neurobiology of schizophrenia. More generally, the discussion underlines the promise of cognitive improvement in schizophrenia and the need to approach the issue in a programmatic manner.
17500644	Building on 2 previous studies (B. R. Ekstrand, 1967; B. R. Ekstrand, M. J. Sullivan, D. F. Parker, & J. N. West, 1971), the authors present 2 experiments that were aimed at characterizing the role of retroactive interference in sleep-associated declarative memory consolidation. Using an A-B, A-C paradigm with lists of word pairs in Experiment 1, the authors showed that sleep provides recovery from retroactive interference induced at encoding, whereas no such recovery was seen in several wake control conditions. Noninterfering word-pair lists were used in Experiment 2 (A-B, C-D). Sleeping after learning, in comparison with waking after learning, enhanced retention of both lists to a similar extent when encoding was less intense because of less list repetition and briefer word-pair presentations. With intense encoding, sleep-associated improvements were not seen for either list. In combination, the results indicate that the benefit of sleep for declarative memory consolidation is greater for weaker associations, regardless of whether weak associations result from retroactive interference or poor encoding.
17499318	Declarative memory allows an organism to discriminate between previously encountered and novel items, and to place past encounters in time. Numerous imaging studies have investigated the neural processes supporting item recognition, whereas few have examined retrieval of temporal information. In the present study, functional magnetic resonance imaging (fMRI) was conducted while subjects engaged in temporal recency and item novelty decisions. Subjects encountered three-alternative forced-choice retrieval trials, each consisting of two words from a preceding study phase and one novel word, and were instructed to either identify the novel item (Novelty trials) or the more recently presented study item (Recency trials). Relative to correct Novelty decisions, correct Recency decisions elicited greater activation in a network of left-lateralized regions, including frontopolar and dorsolateral prefrontal cortex and intraparietal sulcus. A conjunction analysis revealed that these left-lateralized regions overlapped with those previously observed to be engaged during source recollection versus novelty detection, suggesting that during Recency trials subjects attempted to recollect event details. Consistent with this interpretation, correct Recency decisions activated posterior hippocampus and parahippocampal cortex, whereas incorrect Recency decisions elicited greater anterior cingulate activation. The magnitude of this latter effect positively correlated with activation in right dorsolateral prefrontal cortex. Finally, correct Novelty decisions activated the anterior medial temporal lobe to a greater extent than did correct Recency decisions, suggesting that medial temporal novelty responses are not obligatory but rather can be modulated by the goal-directed allocation of attention. Collectively, these findings advance understanding of how subjects strategically engage frontal and parietal mechanisms in the service of attempting to remember the temporal order of events, and how retrieval goals impact novelty processing within the medial temporal lobe.
17496891	There are many causes for variation in the responses of the motor apparatus to neural commands. Fast-timescale disturbances occur when muscles fatigue. Slow-timescale disturbances occur when muscles are damaged or when limb dynamics change as a result of development. To maintain performance, motor commands need to adapt. Computing the best adaptation in response to any performance error results in a credit assignment problem: which timescale is responsible for this disturbance? Here we show that a Bayesian solution to this problem accounts for numerous behaviors of animals during both short- and long-term training. Our analysis focused on characteristics of the oculomotor system during learning, including the effects of time passage. However, we suggest that learning and memory in other paradigms, such as reach adaptation, adaptation of visual neurons and retrieval of declarative memories, largely follow similar rules.
17493643	Tourette's syndrome (TS) is a developmental disorder characterized by motor and verbal tics. The tics, which are fast and involuntary, result from frontal/basal-ganglia abnormalities that lead to unsuppressed behaviors. Language has not been carefully examined in TS. We tested the processing of two basic aspects of language: idiosyncratic and rule-governed linguistic knowledge. Evidence suggests that idiosyncratic knowledge (e.g., in irregular past tense formation; bring-brought) is stored in a mental lexicon that depends on the temporal-lobe-based declarative memory system that also underlies conceptual knowledge. In contrast, evidence suggests that rule-governed combination (e.g., in regular past tenses; walk+-ed) takes place in a mental grammar that relies on the frontal/basal-ganglia-based procedural memory system, which also underlies motor skills such as how to use a hammer. We found that TS children were significantly faster than typically developing control children in producing rule-governed past tenses (slip-slipped, plim-plimmed, bring-bringed) but not irregular and other unpredictable past tenses (bring-brought, splim-splam). They were also faster than controls in naming pictures of manipulated (hammer) but not non-manipulated (elephant) items. These data were not explained by a wide range of potentially confounding subject- and item-level factors. The results suggest that the processing of procedurally based knowledge, both of grammar and of manipulated objects, is particularly speeded in TS. The frontal/basal-ganglia abnormalities may thus lead not only to tics, but also to a wider range of rapid behaviors, including the cognitive processing of rule-governed forms in language and other types of procedural knowledge.
17493189	To determine whether circulating markers of activated inflammation and hemostasis are associated with cognitive decline in older people.Prospective cohort study (Edinburgh Artery Study).	Eleven general practices in Edinburgh, Scotland.	A sample of 452 men and women followed for 16 years.	Biomarker data were collected in 1987/88, and cognitive assessment was first conducted in 1998/99, when the mean age of the sample +/- standard deviation was 73.1+/-5.0), and subsequently in 2002/03. Information was obtained on verbal declarative memory (Wechsler Logical Memory Test (LMT)), nonverbal reasoning (Raven's Standard Progressive Matrices), verbal fluency (Verbal Fluency Test), information processing speed (Wechsler Digit Symbol Test), and a general cognitive factor representing the variance common to the individual test scores.	In age-adjusted analyses, plasma fibrinogen, interleukin-6 (IL-6), and intercellular adhesion molecule 1 (ICAM-1) were negatively associated with performance on all cognitive measures in 2002/03 except the LMT (correlation coefficients from -0.10 to -0.24). In multivariate analyses controlling for demographic characteristics, depression, and cardiovascular morbidity and risk factors, fibrinogen independently predicted 4-year decline in nonverbal reasoning (P<.05). Also, when cognitive change was estimated from peak prior level, IL-6 turned out to be inversely related to decline in information processing speed (P<.05). Similarly, ICAM-1 was associated with a greater decline in general cognitive ability (P<.05) and nonverbal ability (P<.05).	Systemic markers of inflammation and hemostasis are associated with a progressive decline in general and specific cognitive abilities in older people, independent of major vascular comorbidity.	
17483102	To test the influence of neurocognitive functioning on community functioning among formerly homeless persons with serious mental illness and to determine whether that influence varies with social context, independent of individual characteristics.In metropolitan Boston, 112 persons in Department of Mental Health shelters were administered a neuropsychological test battery and other measures and then randomly assigned to empowerment-oriented group homes or independent apartments, as part of a longitudinal study of the effects of housing on multiple outcomes. Subjects' case managers completed Rosen's 5-dimensional Life Skills Inventory at 3, 6, 12, and 18 months and subjects reported on their social contacts at baseline, 6, 12, and 18 months. Subject characteristics are controlled in the analysis.	Three dimensions of neurocognitive functioning--executive function, verbal declarative memory, and vigilance--each predicted community functioning. Better executive function predicted improved self-care and less turbulent behavior among persons living alone, better memory predicted more positive social contacts for those living in a group home, and higher levels of vigilance predicted improved communication in both housing types.	Neurocognition predicts community functioning among homeless persons with severe mental illness, but in a way that varies with the social context in which community functioning occurs.	
17473069	The objective of the study was to determine whether subclinical hypothyroidism causes decrements in health status, mood, and/or cognitive function.This was a double-blinded, randomized, crossover study of usual dose l-thyroxine (L-T4) (euthyroid arm) vs. lower dose L-T4 (subclinical hypothyroid arm) in hypothyroid subjects.	Nineteen subjects on L-T4 therapy for primary hypothyroidism participated in the study.	Subjects underwent measurements of health status, mood, and cognition using validated instruments: Short Form 36, Profile of Mood States, and tests of declarative memory (paragraph recall, complex figure), working memory (N-back, subject ordered pointing, digit span backward), and motor learning (pursuit rotor). The same measures were repeated after 12 wk on each of the study arms.	Mean TSH levels increased to 17 mU/liter on the subclinical hypothyroid arm (P < 0.0001). Mean free T4 and free T3 levels remained within the normal range. The Profile of Mood States fatigue subscale and Short Form 36 general health subscale were slightly worse during the subclinical hypothyroid arm. Measures of working memory (N-back, subject ordered pointing) were worse during the subclinical hypothyroid arm. These differences did not depend on mood or health status but were related to changes in free T4 or free T3 levels. There were no decrements in declarative memory or motor learning.	We found mild decrements in health status and mood in L-T4-treated hypothyroid subjects when subclinical hypothyroidism was induced in a blinded, randomized fashion. More importantly, there were independent decrements in working memory, which suggests that subclinical hypothyroidism specifically impacts brain areas responsible for working memory.	
17471077	We compared surface and intracranial electroencephalogram recordings of mediotemporal structures. These structures are critically involved in declarative memory formation and memory consolidation during sleep. As memory processing is suggested to involve the interplay between fast and slow oscillations, we hypothesized different correlations between frequency bands in surface versus mediotemporal electroencephalogram recordings. Polysomnographic recordings obtained in 10 patients with unilateral temporal lobe epilepsy were analyzed. In accordance with earlier studies, we observed that power density in surface electroencephalogram is organized reciprocally between delta/theta and fast frequencies above 16 Hz during non-rapid-eye-movement sleep (negative correlations). In contrast, we found that within the hippocampus delta/theta power alternated in parallel with fast oscillations above 16 Hz during non-rapid-eye-movement sleep (positive correlations).
17471074	It is unclear whether shorter wave latencies of middle-latency-auditory-evoked-potentials may be associated to cognitive function other than nondeclarative memory. We investigated the presence of declarative, nondeclarative and dreaming memory in propofol-anaesthetized patients and any relationship to intraoperatively registered middle-latency-auditory-evoked-potentials. An audiotape containing one of two stories was presented to patients during anaesthesia. Patients were interviewed on dream recall immediately upon emergence from anaesthesia. Declarative and nondeclarative memories for intraoperative listening were assessed 24 h after awakening without pointing out positive findings. Six patients who reported dream recall showed an intraoperative Pa latency less than that of patients who were unable to remember any dreams (P<0.001). A high responsiveness degree of primary cortex was associated to dream recall formation during anaesthesia.
17468346	Early nocturnal sleep enhances the consolidation of declarative memories acquired during prior wakefulness. Patients with type 1 diabetes frequently experience hypoglycemic episodes during sleep. We investigated whether short-lasting hypoglycemia during early nocturnal sleep affects the sleep-associated consolidation of declarative memories.Sixteen type 1 diabetic patients and 16 healthy subjects matched for age and BMI were tested. On one condition, a linear fall of plasma glucose to 2.2 mmol/l was induced within 60 min by infusing insulin during early sleep. On the control condition, euglycemia (>3.86 mmol/l) was maintained throughout the night. In the morning, subjects recalled word pairs learned in the preceding evening. To assess mood and attention, a symptom questionnaire, an adjective check list, and the Stroop test were applied. Also, auditory event-related brain potentials were recorded.	After euglycemia, subjects recalled 1.5 +/- 0.5 more word pairs than after hypoglycemia (P < 0.01), remembering 2.0 +/- 0.6 more word pairs than at immediate recall before sleep (P = 0.002). Across the hypoglycemic night, no such gain occurred (+0.5 +/- 0.6 words; P = 0.41). Hypoglycemia during sleep also impaired mood (P < 0.05) but did not affect attention. Effects compared well between type 1 diabetic patients and healthy control subjects.	Our findings indicate specific sensitivity of declarative memory consolidation during sleep to rather short episodes of mild hypoglycemia. This effect may disable memory processing in type 1 diabetic patients prone to nocturnal hypoglycemic episodes and underlines the importance of considering sleep as a critical period in the treatment of these patients.	
17455198	The hippocampus has been shown to be required for the acquisition of declarative or explicit memory. Whether all hippocampal-dependent forms of learning and memory are explicit is an open question. Controversy has emerged about the existence of implicit hippocampal-dependent tasks. Two implicit tasks that may involve the hippocampusare a relational eye tracking task (Ryan et al. (2000) Psychol Sci 11:454-461) and transitive inference (Greene et al. (2006) J Cognit Neurosci 18:1156-1173; Greene et al. (2001) Mem Cognit 29:893-902). Recently, it was shown that both of these tasks may depend upon task awareness (Smith et al. (2006) J Neurosci 26:11304-11312; Smith and Squire (2005) J Neurosci 25:10138-10146). It is argued that in both cases, distinct, explicit versions of the tasks were created, which do not disprove the implicit nature of the original tasks.
17454351	Modern symptom validity tests (SVTs) use empirical cutoffs for decision making. However, limits to the applicability of these cutoffs may arise when severe cognitive symptoms are present. The purpose of the studies presented here was to explore these limits of applicability. In Experiment 1, a group of 24 bona fide neurological patients without clinically obvious cognitive symptoms was compared to a group of 24 patients with rather severe symptoms. A comprehensive test battery was employed, which included four SVTs (the Test of Memory Malingering, TOMM, the Word Memory Test, WMT, the Bremer Symptomvalidierung, BSV, and the Amsterdam Short-Term Memory Test, ASTM). In Experiment 2, a group of 20 patients with mild Alzheimer's disease was compared to 14 healthy controls. Results of both studies showed that cognitive impairment may significantly interfere with SVT performance. Correlation analyses revealed dissimilar relationships between SVTs and neuropsychological test measures. Whereas TOMM and WMT correlated mainly with tests of declarative memory, the BSV correlated with tests of attention, and ASTM correlated with tests of working memory. Intercorrelations between symptom validity measures were relatively low. The published cutoffs of the TOMM would be suitable for estimating effort in patients with Mini-Mental State Examination scores of 24 or above. More research will be necessary to investigate how performance in SVTs is related to cognitive functioning in populations of severely impaired patients.
17440612	Temporal sequence represents the main principle underlying episodic memory. The storage of temporal sequence information is thought to involve hippocampus-dependent memory systems, preserving temporal structure possibly via chaining of sequence elements in heteroassociative networks. Converging evidence indicates that sleep enhances the consolidation of recently acquired representations in the hippocampus-dependent declarative memory system. Yet, it is unknown if this consolidation process comprises strengthening of the temporal sequence structure of the representation as well, or is restricted to sequence elements independent of their temporal order. To address this issue we tested the influence of sleep on the strength of forward and backward associations in word-triplets.Subjects learned a list of 32 triplets of unrelated words, presented successively (A-B-C) in the center of a screen, and either slept normally or stayed awake in the subsequent night. After two days, retrieval was assessed for the triplets sequentially either in a forward direction (cueing with A and B and asking for B and C, respectively) or in a backward direction (cueing with C and B and asking for B and A, respectively). Memory was better for forward than backward associations (p<0.01). Sleep did not affect backward associations, but enhanced forward associations, specifically for the first (AB) transitions (p<0.01), which were generally more difficult to retrieve than the second transitions.	Our data demonstrate that consolidation during sleep strengthens the original temporal sequence structure in memory, presumably as a result of a replay of new representations during sleep in forward direction. Our finding suggests that the temporally directed replay of memory during sleep, apart from strengthening those traces, could be the key mechanism that explains how temporal order is integrated and maintained in the trace of an episodic memory.	
17435595	The functional deficits associated with hippocampal sclerosis during declarative memory formation are largely unknown. In this study, we analyzed intracranial event-related potentials recorded from the medial temporal lobes of nine epilepsy patients performing a word memorization task. We used frequency-specific wavelet analysis to assess stimulus-related changes in power and intertrial phase coherence. Statistical analysis revealed a significant decrease of stimulus-induced power in the delta and theta range on the side of pathology. No significant differences in phase locking were observed. Findings indicate a reduced availability of recruitable neural assemblies not only in the hippocampus but also in the rhinal cortex during memory formation. Network functions related to the timing of neural responses to the stimulus appear to be preserved.
17432197	The human capacity for acquiring speech and language must derive, at least in part, from the genome. Recent advance in the field of molecular genetics finally discovered 'Language Gene'. Disruption of FOXP2 gene, the firstly identified 'language gene' causes severe speech and language disorder. To elucidate the anatomical basis of language processing in the brain, we examined the expression pattern of FOXP2/Foxp2 genes in the monkey and rat brains through development. We found the preferential expression of FOXP2/Foxp2 in the striosomal compartment of the developing striatum. Thus, we suggest the striatum, particularly striosomal system may participate in neural information processing for language and speech. Our suggestion is consistent with the declarative/ procedural model of language proposed by Ullman (1997, 2001), which the procedural memory-dependent mental grammar is rooted in the basal ganglia and the frontal cortex, and the declarative memory-dependent mental lexicon is rooted in the temporal lobe.
17426095	There is evidence of both hypothalamic-pituitary-adrenocortical (HPA) axis and cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the exact nature and the associations between these abnormalities remain unclear.The aim of the study was to characterize the nature of the HPA dysregulation in T2DM and ascertain whether impaired cognition in T2DM could be attributed to these abnormalities.	A cross-sectional study was performed, contrasting matched groups on HPA axis function and cognition by using the combined dexamethasone (DEX)/CRH test and a neuropsychological battery assessing declarative and working memory, attention, and executive function.	The study was conducted in a research clinic in an academic medical center.	Participants were volunteers functioning in the cognitively normal range. We studied 30 middle-aged individuals with T2DM, on average 7.5 yr since diabetes diagnosis, and 30 age-, gender-, and education-matched controls.	Basal cortisol levels, cortisol levels during the DEX/CRH test, and performance on neuropsychological tests were measured.	Individuals with T2DM had elevated basal plasma cortisol levels, higher levels after DEX suppression, and a larger response to CRH (all P <or= 0.005). Among individuals with T2DM, cortisol levels during the DEX/CRH test were positively associated with glycosylated hemoglobin (P = 0.05), independent of age, body mass index, hypertension, and dyslipidemia. Diabetic subjects showed cognitive impairments restricted to declarative memory. Across all subjects, declarative memory was inversely associated with cortisol levels; however, these associations were subsumed by glycemic control (glycosylated hemoglobin).	HPA hyperactivity and declarative memory deficits are present in T2DM. Both alterations may reflect the negative impact of poor glycemic control on the hippocampal formation.	
17417938	The prevailing view of medial temporal lobe (MTL) function has two principal elements: first, that the MTL subserves memory but not perception, and second, that the many anatomically distinctive parts of the MTL function together in the service of declarative memory. Recent neuropsychological studies have, however, challenged both opinions. First, studies in rodents, nonhuman primates, and humans suggest that the perirhinal cortex represents information about objects for both mnemonic and perceptual purposes. Second, the idea that MTL components contribute to declarative memory in similar ways has also been contradicted. Whereas the perirhinal cortex plays an essential role in familiarity-based object recognition, the hippocampus contributes little, if at all, to this function. In both primates and rodents, the hippocampus contributes to the memory and perception of places and paths, whereas the perirhinal cortex does so for objects and the contents of scenes.
17412711	In the last decade, there has been an increasing interest in cognitive alterations during the early course of schizophrenia. From a clinical perspective, a better understanding of cognitive functioning in putative at-risk states for schizophrenia is essential for developing optimal early intervention models. Two approaches have more recently been combined to assess the entire course of the initial schizophrenia prodrome: the predictive "basic symptom at-risk" (BS) and the ultra high-risk (UHR) criteria. Basic symptoms are considered to be present during the entire disease progression, including the initial prodrome, while the onset of symptoms captured by the UHR criteria expresses further disease progression toward frank psychosis. The present study investigated the cognitive functioning in 93 subjects who met either BS or UHR criteria and thus were assumed to be at different points on the putative trajectory to psychosis. We compared them with 43 patients with a first episode of psychosis and to 49 help-seeking patient controls. All groups performed significantly below normative values. Both at-risk groups performed at intermediate levels between the first-episode (FE) group and normative values. The UHR group demonstrated intermediate performance between the FE and BS groups. Overall, auditory working memory, verbal fluency/processing speed, and declarative verbal memory were impaired the most. Our results suggest that cognitive impairments may still be modest in the early stages of the initial schizophrenia prodrome and thus support current efforts to intervene in the early course of impending schizophrenia because early intervention may prevent or delay the onset of frank psychosis and thus prevent further cognitive damage.
17404777	The aims of this study were to investigate the pattern of cortical atrophy and the relationships between memory performances and the brain regions in Alzheimer's Disease (AD). optimized voxel-based morphometry (VBM) was applied to the MRI brain images of 18 probable AD and 18 healthy subjects (HS). Patients performed verbal and visuo-spatial episodic and shortterm memory tests. Contrasting of AD group with HS, and anatomobehavioural correlations were carried out in order to identify regional atrophic changes and neuro-cognitive aspects in AD group. We found evidence of gray matter (GM) volume reduction in AD in the medial temporal, parietal and frontal areas bilaterally and in the left anterior thalamic nuclei. Performance on the episodic memory delayed recall tests co-varied with GM volume in the left entorhinal cortex. The pattern of cortical atrophy likely reflects the heterogeneous level of dementia severity in our AD group. The anatomical region affected in the left hemisphere indicates a sufferance at multiple levels of the Polysynaptic Hippocampal Pathway, which is involved in declarative memory. Findings on the entorhinal cortex and the delayed memory scores support the role of the entorhinal cortex in episodic memory. Damage to the entorhinal cortex, deafferenting the hippocampus from neocortical inputs, interferes with episodic memory consolidation in AD patients.
17401727	Evidence accumulated in the last decade indicating that psychoactive substances negatively influence neurogenesis in the adult hippocampus has provided new insights into the neurobiology of drug addiction. Using a variety of experimental approaches and treatments, drugs such as psychomotor stimulants, opioids, alcohol and psychedelic compounds have been shown to alter one or several aspects of adult neurogenesis, including the rate of progenitor proliferation, the survival of newly generated cells, and the maturation and acquisition of cellular phenotype. This evidence, though critical from a neurotoxicological standpoint, cannot be linked unambiguously to the process of drug dependence at this stage of research. Drug addiction is a complex recurrent process involving the acquisition and maintenance of drug taking, followed by detoxification, abstinence and eventual relapse to drug seeking. The specific contribution of adult hippocampal neurogenesis to each of these processes is yet to be determined. This notwithstanding, the suggested role of the hippocampus in the storage and retrieval of declarative and contextual memories on the one hand, and in the regulation of mood and affect on the other, provides a fertile ground for further exploring the mutual relationships between postnatal hippocampal neurogenesis and addictive behaviours.
17400305	Sleep spindles and rapid eye movements have been found to increase following an intense period of learning on a combination of procedural memory tasks. It is not clear whether these changes are task specific, or the result of learning in general. The current study investigated changes in spindles, rapid eye movements, K-complexes and EEG spectral power following learning in good sleepers randomly assigned to one of four learning conditions: Pursuit Rotor (n=9), Mirror Tracing (n=9), Paired Associates (n=9), and non-learning controls (n=9). Following Pursuit Rotor learning, there was an increase in the duration of Stage 2 sleep, spindle density (number of spindles/min), average spindle duration, and an increase in low frequency sigma power (12-14Hz) at occipital regions during SWS and at frontal regions during Stage 2 sleep in the second half of the night. These findings are consistent with previous findings that Pursuit Rotor learning is consolidated during Stage 2 sleep, and provide additional data to suggest that spindles across all non-REM stages may be a mechanism for brain plasticity. Following Paired Associates learning, theta power increased significantly at central regions during REM sleep. This study provides the first evidence that REM sleep theta activity is involved in declarative memory consolidation. Together, these findings support the hypothesis that brain plasticity during sleep does not involve a unitary process; that is, different types of learning have unique sleep-related memory consolidation mechanisms that act in dissociable brain regions at different times throughout the night.
17395434	In aged and pathological populations, reduced hippocampal volume is frequently described in association with impairment of hippocampus-dependent cognitive processes and chronically elevated cortisol levels. Recent studies in young healthy subjects show a negative association between hippocampal volume and memory. The aim of the present study was to investigate the associations among hippocampal volume, cortisol levels and memory performance in a group of healthy young men. Hippocampal volume was determined by manual segmentation of high-resolution 3D Magnetic Resonance Images from 13 subjects. Stress-induced cortisol levels in response to the "Trier Social Stress Test" (TSST) as well as the cortisol response to awakening (CRA) over four weeks were assessed. Declarative memory performance was tested before and after exposure to the TSST. The results show that larger hippocampal volume was associated with a significantly stronger cortisol increase in response to the TSST and a significantly greater CRA. Moreover, larger hippocampal volume was associated with significantly lower memory performance before the TSST. Our results challenge the direction of the frequently observed relationships among hippocampal volume, cortisol reactivity and memory performance and question the relevance of findings in clinical and aged subjects for young healthy populations.
17390317	Recent evidence from neuroscience indicates that the anticipation of external rewards may enhance declarative memory consolidation by increasing dopaminergic-modulated plasticity in the hippocampus. A number of studies in psychology, however, have shown that external rewards may have null, or even negative, effects on learning. To shed light on this issue, we developed a novel task, in which native Japanese speakers were rewarded to learn unknown English words inside a functional MRI scanner. Rewards had no effect on recall performance unless we used a rating of reward-induced anxiety as a covariate. In this case, for highly rewarded words, we found a negative correlation between recall performance and anxiety ratings. For those words, high recall performance and low anxiety ratings were associated with enhanced activity in the midbrain dopaminergic centers, the hippocampus, and the amygdala. On the other hand, low recall performance and high anxiety ratings were associated with enhanced activity in the anterior cingulate and middle frontal gyrus, brain regions that have been shown to be involved with anxiety and divided attention, respectively. A connectivity analysis indicated positive functional connectivity between the midbrain dopaminergic centers and both the hippocampus and the amygdala, as well as negative connectivity between the anterior cingulate and the amygdala. Thus, both our behavioral and imaging results suggest that the anticipation of rewards can, depending on the individual level of reward-induced anxiety, have either a beneficial effect or a negative effect on word learning.
17390120	REM or dreaming sleep is one of three states of consciousness. It is characterized by rapid eye movements, muscle atonia, desynchronized EEG, and autonomic dysregulation. A dysfunction of one of these four cardinal traits explains the primary disorders of REM sleep, including REM sleep behavior disorder and narcolepsy. Although seen in other stages, sleep apnea syndrome, coronary syndromes, and stroke are strongly triggered by the autonomic dysregulation of REM sleep. REM sleep has an antiepileptic effect, which has not yet been used in clinical practice. It favors procedural memory, but not declarative memory. While present neurophysiologic theories, backed up by new neuroimaging techniques, preferentially explore the genesis of REM sleep, psychodynamic theories have searched for its raison d'être by focusing on mentally stabilizing or purifying effects of dreaming. The exploding interest in dreaming sleep, images, and imaging may also yield a harvest for clinical medicine, and further perplexing findings, such as RBD as harbinger of parkinsonism should be expected.
17388705	Primary negative symptoms are intrinsic to the pathology of schizophrenia and are associated with significant deficits in motivation, verbal and nonverbal communication, affect, and cognitive and social functioning. Overall, atypical antipsychotic medications have been found to be more efficacious than conventional antipsychotics in the treatment of negative symptoms, based on studies with acute patients. Results have been confounded by concomitant improvements in positive, depressive, and extrapyramidal symptoms. This 12-week, double-blind, controlled study aimed to examine the effects of the atypical antipsychotic olanzapine versus haloperidol on persistent, primary negative symptoms and neurocognitive functions in stable schizophrenic patients with the deficit syndrome and low levels of concomitant positive, depressive, and extrapyramidal symptoms.Thirty-five patients with DSM-IV-TR schizophrenia and predominant negative symptoms were randomly assigned in a 12-week double-blind study to either olanzapine (15-20 mg/day) or haloperidol (15-20 mg/day). Patients taking haloperidol received additional blinded benztropine. Inclusion criteria were Positive and Negative Syndrome Scale (PANSS) negative score of >or=20, PANSS positive score < 20, and fulfilling the criteria for the Schedule for the Deficit Syndrome. The PANSS, Clinical Global Impressions, Hamilton Rating Scale for Depression (HAM-D), Simpson-Angus Scale, and Abnormal Involuntary Movement Scale were assessed at regular subsequent intervals. A neuropsychological battery examining declarative verbal learning memory, attention and processing speed, executive functioning, and simple motor functioning domains of cognition was assessed at baseline and endpoint. The study ran from September 1998 through May 2005.		There was a statistically significant difference for PANSS negative symptoms (F = 5.44, df = 1,15; p <or=.05), with an 8.63-point decrease in the olanzapine group (t = 5.66, df = 1,33; p <or=.05), and PANSS total score (t = 9.304, df = 1,33; p <or=.05). Linear mixed model for repeated measures indicated that the olanzapine group showed a statistically significant change in negative symptom scores (F = 9.70, df = 1,15; p <or=.05). There were no significant differences for change in PANSS positive score, PANSS general psychopathology score, and HAM-D score. Using a criterion of 40% decrease in the PANSS negative subscale score, 31.25% of patients were classified as responders in the olanzapine group, while only 10.53% were responders in the haloperidol group. There were no significant between-treatment differences in the incidence of extrapyramidal side effects. Olanzapine-treated patients experienced more weight gain than the haloperidol-treated group (F = 7.044, df = 1,33; p <or=.05). Neuropsychological Results: Significant differences in change from baseline to endpoint for the olanzapine-treated group were seen for declarative verbal learning memory (F = 11.499, df = 1,14; p = .021) and the motor functioning domain (F = 4.405, df = 1,31; p = .044).	The results of this study suggest that olanzapine treatment was associated with significant improvement in primary negative symptoms, overall symptomatic improvement as measured by the PANSS total score, and improvement in some areas of neurocognition as compared with haloperidol/benztropine mesylate treatment.	
17381359	Many hypothyroid subjects receiving L-thyroxine (L-T4) complain of psychological symptoms or cognitive dysfunction. However, there is limited validated information on these self-reports.Cross-sectional comparison of 20 euthyroid and 34 treated hypothyroid subjects, aged 20-45 years, with normal thyroid-stimulating hormone (TSH) levels. Subjects underwent the following validated measures: Short Form 36 (SF-36); Symptom Checklist 90-Revised (SCL-90-R); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, Digit Span Backwards), and motor learning (Pursuit Rotor).	L-T4-treated subjects had higher mean TSH and free T4 levels, but free triiodothyronine (T3) levels were comparable to controls. L-T4-treated subjects had decrements on SF-36 and SCL-90-R summary scales and subscales. These subjects performed slightly worse on N-Back and Pursuit Rotor tests. Neither TSH nor thyroid hormone levels were associated with performance on psychological or cognitive measures.	This group of L-T4-treated subjects had decrements in health status, psychological function, working memory, and motor learning compared to euthyroid controls. Higher mean TSH levels suggest this may be related to suboptimal treatment, although there were no correlations between TSH levels and outcomes. These findings are limited by potential selection bias, and randomized studies targeting different TSH levels and memory subdomains would clarify these issues.	
17368108	The medial temporal lobes (MTLs) are essential for both encoding and retrieval processes in declarative memory. In addition, they are a frequent seizure focus for medically refractory epilepsy. One of the major side effects of MTL resection is a decline in memory functions. Most functional imaging paradigms have been developed to find preoperative measures that, to obtain a prognosis of postoperative memory performance, employ explicit memory encoding strategies to elicit MTL activation, and require a great amount of cognitive effort. We applied three different implicit encoding tasks, which require less effort and time, to a group of healthy subjects. We found left-lateralized activation for verbal stimuli, bilateral activation for pictures, and right-lateralized activation for faces. The present study shows that even with an implicit memory-encoding paradigm, a lateralized activation of MTL structures can be achieved. This may lead to paradigms for routine clinical application that require less cognitive effort and time on the part of patients.
17351137	We explored the circumstances in which rats engage either declarative memory (and the hippocampus) or habit memory (and the dorsal striatum). Rats with damage to the hippocampus or dorsal striatum were given three different two-choice discrimination tasks (odor, object, and pattern). These tasks differed in the number of trials required for learning (approximately 10, 60, and 220 trials). Dorsal striatum lesions impaired discrimination performance to a greater extent than hippocampal lesions. Strikingly, performance on the task learned most rapidly (the odor discrimination) was severely impaired by dorsal striatum lesions and entirely spared by hippocampal lesions. These findings suggest that discrimination learning in the rat is primarily supported by the dorsal striatum (and habit memory) and that rats engage a habit-based memory system even for a task that takes only a few trials to acquire. Considered together with related studies of humans and nonhuman primates, the findings suggest that different species will approach the same task in different ways.
17347444	Sleep facilitates memory consolidation. A widely held model assumes that this is because newly encoded memories undergo covert reactivation during sleep. We cued new memories in humans during sleep by presenting an odor that had been presented as context during prior learning, and so showed that reactivation indeed causes memory consolidation during sleep. Re-exposure to the odor during slow-wave sleep (SWS) improved the retention of hippocampus-dependent declarative memories but not of hippocampus-independent procedural memories. Odor re-exposure was ineffective during rapid eye movement sleep or wakefulness or when the odor had been omitted during prior learning. Concurring with these findings, functional magnetic resonance imaging revealed significant hippocampal activation in response to odor re-exposure during SWS.
17344392	The perirhinal cortex (PRh) is widely accepted as having an important role in object recognition memory in humans and animals. Contrary to claims that PRh mediates declarative memory exclusively, previous evidence suggests that PRh has a role in the perceptual processing of complex objects. In the present study, we conducted an examination of the possible role of PRh in perceptual function in rats. We examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus postrhinal cortices) in the rat would cause deficits in a zero-delay object-recognition task and a simultaneous oddity discrimination task. Both of these tasks measured spontaneous (untrained, unrewarded) behavior, and the stimuli in these experiments were manipulated to produce varying levels of perceptual difficulty. As predicted by simulations using a computational model, rats with PPRh lesions were impaired in object recognition when the stimuli to be discriminated were manipulated to share many features in common. Furthermore, rats with PPRh and PRh lesions were impaired in a simultaneous oddity discrimination task when the stimuli to be discriminated were manipulated explicitly to be more perceptually similar. These findings provide support for the idea that PRh in the rat is important for the perceptual processing of complex objects, in addition to its well established role in memory.
17343944	Researchers have utilized the savings in relearning paradigm in a variety of settings since Ebbinghaus developed the tool over a century ago. In spite of its widespread use, we do not yet understand what type(s) of memory are measurable by savings. Specifically, can savings measure both declarative and non-declarative memories? The lack of conscious recollection of the encoded material in some studies indicates that non-declarative memories may show savings effects, but as all studies to date have used declarative tasks, we cannot be certain. Here, we administer a non-declarative task and then measure savings in relearning the material declaratively. Our results show that while material outside of awareness may show savings effects, non-declarative sequence memory does not. These data highlight the important distinction between memory without awareness and non-declarative memory.
17334205	Common activations in prefrontal cortex (PFC) during episodic and semantic long-term memory (LTM) tasks have been hypothesized to reflect functional overlap in terms of working memory (WM) and cognitive control. To evaluate a WM account of LTM-general activations, the present study took into consideration that cognitive task performance depends on the dynamic operation of multiple component processes, some of which are stimulus-synchronous and transient in nature; and some that are engaged throughout a task in a sustained fashion. PFC and WM may be implicated in both of these temporally independent components. To elucidate these possibilities we employed mixed blocked/event-related functional magnetic resonance imaging (fMRI) procedures to assess the extent to which sustained or transient activation patterns overlapped across tasks indexing episodic and semantic LTM, attention (ATT), and WM. Within PFC, ventrolateral and medial areas exhibited sustained activity across all tasks, whereas more anterior regions including right frontopolar cortex were commonly engaged in sustained processing during the three memory tasks. These findings do not support a WM account of sustained frontal responses during LTM tasks, but instead suggest that the pattern that was common to all tasks reflects general attentional set/vigilance, and that the shared WM-LTM pattern mediates control processes related to upholding task set. Transient responses during the three memory tasks were assessed relative to ATT to isolate item-specific mnemonic processes and were found to be largely distinct from sustained effects. Task-specific effects were observed for each memory task. In addition, a common item response for all memory tasks involved left dorsolateral PFC (DLPFC). The latter response might be seen as reflecting WM processes during LTM retrieval. Thus, our findings suggest that a WM account of shared PFC recruitment in LTM tasks holds for common transient item-related responses rather than sustained state-related responses that are better seen as reflecting more general attentional/control processes.
17306237	The medial temporal lobe (MTL) is crucial for declarative memory formation, but the function of its subcomponents in associative memory formation remains controversial. Most functional imaging studies on this topic are based on a stepwise approach comparing a condition with and one without associative encoding. Extending this approach we applied additionally a parametric analysis by varying the amount of associative memory formation. We found a hippocampal subsequent memory effect of almost similar magnitude regardless of the amount of associations formed. By contrast, subsequent memory effects in rhinal and parahippocampal cortices were parametrically and positively modulated by the amount of associations formed. Our results indicate that the parahippocampal region supports associative memory formation as tested here and the hippocampus adds a general mnemonic operation. This pattern of results might suggest a new interpretation. Instead of having either a fixed division of labor between the hippocampus (associative memory formation) and the rhinal cortex (non-associative memory formation) or a functionally unitary MTL system, in which all substructures are contributing to memory formation in a similar way, we propose that the location where associations are formed within the MTL depends on the kind of associations bound: If visual single-dimension associations, as used here, can already be integrated within the parahippocampal region, the hippocampus might add a general purpose mnemonic operation only. In contrast, if associations have to be formed across widely distributed neocortical representations, the hippocampus may provide a binding operation in order to establish a coherent memory.
17296931	The hippocampus and adjacent medial temporal lobe structures are known to support declarative memory, but there is not consensus about what memory functions the hippocampus might support that are distinct from the functions of the adjacent cortex. One idea is that the hippocampus is specifically important for allocentric spatial memory, e.g., the hippocampus is especially needed to remember object locations when there is a shift in viewpoint between study and test. We tested this proposal in two experiments. Patients with damage limited to the hippocampus were given memory tests for object locations in a virtual environment. In the first experiment, participants studied locations of a variable number of images (one to five) and tried to remember the image locations from either the same viewpoint as during study (shift of 0 degrees) or a different viewpoint (shift of 55 degrees, 85 degrees, or 140 degrees). In each viewpoint condition (shifts of 0 degrees, 55 degrees, 85 degrees, and 140 degrees), patients performed normally when remembering one or two image locations. Further, performance declined to a similar degree in each viewpoint condition as patients tried to remember increasing numbers of image locations. In the second experiment, participants tried to remember four images after viewpoint shifts of 0 degrees, 55 degrees, 85 degrees, or 140 degrees. Patients were mildly impaired at all conditions (shifts of 0 degrees, 55 degrees, 85 degrees, and 140 degrees), and the impairment was no greater when viewpoint shifted. We conclude that damage to the hippocampus does not selectively impair viewpoint-independent spatial memory. Rather, hippocampal damage impairs memory as the memory load increases.
17288648	Traumatic memory is a key symptom in psychological trauma victims and may remain vivid for several years. Psychotherapy has shown that neither the psychopathological signs of trauma nor the expression of traumatic memories are static over time. However, few studies have investigated the neural substrates of psychotherapy-related symptom changes.We studied 16 subthreshold post-traumatic stress disorder (PTSD) subjects by using a script-driven symptom provocation paradigm adapted for single photon emission computed tomography (SPECT) that was read aloud during traumatic memory retrieval both before and after exposure-based and cognitive restructuring therapy. Their neural activity levels were compared with a control group comprising 11 waiting-list subthreshold PTSD patients, who were age- and profile-matched with the psychotherapy group.	Significantly higher activity was observed in the parietal lobes, left hippocampus, thalamus and left prefrontal cortex during memory retrieval after psychotherapy. Positive correlations were found between activity changes in the left prefrontal cortex and left thalamus, and also between the left prefrontal cortex and left parietal lobe.	Neural mechanisms involved in subthreshold PTSD may share neural similarities with those underlying the fragmented and non-verbal nature of traumatic memories in full PTSD. Moreover, psychotherapy may influence the development of a narrative pattern overlaying the declarative memory neural substrates.	
17286888	The consequences of congenital brain disorders for adult cognitive function are poorly understood. We studied different forms of memory in 29 young adults with spina bifida meningomyelocele (SBM), a common and severely disabling neural tube defect. Nondeclarative and semantic memory functions were intact. Working memory was intact with low maintenance and manipulation requirements, but impaired on tasks demanding high information maintenance or manipulation load. Prospective memory for intentions to be executed in the future was impaired. Immediate and delayed episodic memory were poor. Memory deficits were exacerbated by an increased number of lifetime shunt revisions, a marker for unstable hydrocephalus. Memory status was positively correlated with functional independence, an important component of quality of life.
17267792	Individuals with panic disorder perceive panic attacks as unpredictable. Because predictability is fundamental to Pavlovian conditioning, failure to predict panic attacks could be due to a basic deficit in conditioning. The present study examined trace eyeblink conditioning in order to test the hypothesis that individuals with panic disorder are impaired in associative learning tasks that depend on declarative memory.Delay and trace eyeblink conditioning were tested in separate experimental sessions in 19 individuals meeting DSM-IV criteria for panic disorder and 19 sex- and age-matched healthy comparison subjects. In the delay paradigm, a mild puff was delivered to the eye at the end of a 500-msec tone; in the trace paradigm, the puff was delivered after a 700-msec empty "trace" interval that followed the end of the tone.	Patients and comparison subjects showed similar rates of conditioned responses in the delay paradigm, but patients showed reduced rates of conditioned responses in the trace paradigm.	These results suggest that individuals with panic disorder suffer from a deficit in declarative associative learning. Such a deficit points to impaired hippocampal function that may disrupt cognitive processing of internal and external cues predictive of a panic attack.	
17266638	One of the most remarkable features of the mammalian central nervous system is its ability to store large amounts of information for periods approaching a lifetime. However, during the aging process cognitive domains, such as long-term (declarative) memory and working memory decline in some, but by far not all individuals. It is essential to understand the physiological changes that cause memory decline and also to elucidate why preserved memory abilities vary so greatly across individuals and memory tasks. A generally accepted hypothesis has been that long-lasting activity-dependent changes in the efficacy of synaptic transmission in the mammalian brain are considered to be of fundamental importance for the storage of information. There is now a more detailed understanding of the changes in neuronal plasticity during aging at the molecular and systems levels. This review discusses recent findings on age-related changes in neuronal plasticity, which have opened up novel sites of action for therapeutic intervention.
17265459	The hypothesis that hippocampal activity at encoding is causally related to subsequent declarative memory expression is tested in the mouse, by using lidocaine inactivation of the hippocampus in combination with c-fos neuroimaging analysis. We employed a two-stage radial maze paradigm of spatial discrimination, which was previously shown to dissociate between declarative and nondeclarative expression of memory related to the same acquired material. In Stage 1 (encoding), mice learnt the constant location of food among a set of six arms (three baited, three unbaited) by being submitted repeatedly to discontiguous experiences with each arm separately ("go/no-go" discrimination). In Stage 2 (test-session), they are challenged with novel presentations of the arms, which are either combined into pairs of opposite valence ("two-choice" discrimination), or opened all six together ("six-choice" discrimination). Previous experiments have demonstrated that the "two-choice" situation is a critical test for declarative memory while "six-choice" discrimination may rely on procedural memory. We observed that (i) hippocampal activity measured by c-fos mRNA expression was increased by "go/no-go" learning, and this activation was blocked by pre-training local infusions of lidocaine; (ii) when performed just before each session of Stage 1, such inactivation spared the acquisition of "go/no-go" discrimination but produced, subsequently, a selective deficit in the "two-choice" test (not in the "six-choice" test). This study indicates that the hippocampus is "spontaneously" engaged in encoding processes necessary for long-term storage of discontiguous experiences under a form enabling flexible declarative memory expression.
17261685	To differentiate frontotemporal dementia (FTD) subtypes from each other and from probable Alzheimer disease (AD) using neuropsychological tests.Patients with FTD and AD (n = 109) were studied with a comprehensive neuropsychological protocol at first contact. Data were subjected to a principal components analysis (PCA) to extract core neuropsychological features. A five-factor solution accounted for 72.89% of the variance and yielded factors related to declarative memory, working memory/visuoconstruction, processing speed/mental flexibility, lexical retrieval, and semantic memory.	Between- and within-group analyses revealed that patients with AD obtain their lowest scores on tests of declarative memory while semantic dementia (SemD) patients are particularly disadvantaged on tests of semantic memory. On tests of processing speed/mental flexibility time to completion was faster for social comportment/dysexecutive (SOC/EXEC) patients, but these patients made more errors on some tests. Patients with corticobasal degeneration (CBD) and progressive nonfluent aphasia (PNFA) were impaired on tests of working memory. Logistic regression analyses using factor scores successfully assigned FTD subgroups and AD patients into their respective diagnostic categories.	Patients with differing frontotemporal dementia phenotypes can be distinguished from each other and from Alzheimer disease using neuropsychological tests.	
17254000	Duchenne muscular dystrophy (DMD) is a progressive pediatric disorder that affects both muscle and brain. Children with DMD have mean IQ scores that are about one standard deviation lower than population means, with lower Verbal IQ than Performance IQ scores. For the present study, verbal skills and verbal memory skills were examined in males with DMD with the Clinical Evaluation of Language Fundamentals, 3rd edition, and the California Verbal Learning Test for Children. Performance of 50 males with DMD (age range 6-14 y, mean 9 y 4 mo [SD 2 y 1 mo]) was compared to normative values. Two subsets of the probands were also compared with two comparison groups: unaffected siblings (n=24; DMD group age range 6-12 y, mean 9 y 1 mo [SD 1 y 8 mo]; sibling age range 6-15 y, mean 9 y 11 mo [SD 2 y 4 mo]) and males with cerebral palsy (CP); (n=23; DMD group age range 6-9 y, mean 7 y 8 mo [SD 1 y 2 mo]; CP age range 6-8 y, mean 6 y 8 mo [SD 0 y 8 mo]). Results demonstrated that although males with DMD performed slightly more poorly than normative values, they performed comparably to the controls on most measures. Consistent deficits were observed only on tests requiring immediate repetition for verbal material (Recalling Sentences, and Concepts and Directions). On other language tasks, including tests of understanding and use of grammar, and understanding of semantic relationships, the males with DMD performed well. Moreover, the males with DMD performed well on multiple indices of verbal recall, and there was no evidence of declarative memory deficits. DMD is a single-gene disorder that is selectively associated with decreased verbal span capacity, but not impaired recall.
17237776	During sequence learning, individuals show motor-skill acquisition and an ability to verbally describe items within the sequence. We disrupted this latter, declarative component by having participants learn a word list immediately after sequence learning. This induced off-line skill improvements. We conclude that off-line memory processing relies not only on the engagement of neuroplastic mechanisms but also on the disengagement of an interaction between declarative and procedural memory systems.
17234277	The neural mechanisms for the formation of declarative memory (memory for facts and events) are believed to be integrated from processes mediated by hippocampal long-term potentiation (LTP) and long-term depression (LTD). Traditionally, LTP has been designated as the main mediator of spatial memory storage in the hippocampus, whereas LTD has been assigned an auxiliary role in signal-to-noise regulation or in forgetting. It has recently become apparent, however, that LTD contributes directly to hippocampal information storage. In fact, LTD could dominate in the processing of precise spatial characteristics. Accumulating evidence supports the idea that LTP and LTD enable distinct and separate forms of information storage, which together facilitate the generation of a spatial cognitive map.
17229463	Acute tryptophan depletion (ATD) studies have shown that serotonin plays a role in learning and memory processes. In this study, we performed a pooled analysis of nine ATD studies in order to examine the nature of the memory-impairing effects of ATD and mediating factors, such as gender, age and vulnerability for disease in which disturbed serotonin was hypothesized to play a role. All studies that were used in this pooled analysis assessed declarative episodic memory using a verbal learning task paradigm. Immediate recall, delayed recall, and delayed recognition scores were examined. A total of 211 participants were included in the analysis. The analysis revealed that ATD impaired not only delayed recall, but also immediate recall. The ATD-induced impairments were larger in females than in males. Furthermore, ATD did not interact with any other serotonergic vulnerability and age. This suggests that the only factor that actually has the properties of a serotonergic vulnerability factor for declarative memory performance is female gender. The findings provide further support for a critical role of serotonin in declarative episodic memory.
17222533	The hippocampus participates in multiple functions, including spatial navigation, adaptive timing and declarative (notably, episodic) memory. How does it carry out these particular functions? The present article proposes that hippocampal spatial and temporal processing are carried out by parallel circuits within entorhinal cortex, dentate gyrus and CA3 that are variations of the same circuit design. In particular, interactions between these brain regions transform fine spatial and temporal scales into population codes that are capable of representing the much larger spatial and temporal scales that are needed to control adaptive behaviors. Previous models of adaptively timed learning propose how a spectrum of cells tuned to brief but different delays are combined and modulated by learning to create a population code for controlling goal-oriented behaviors that span hundreds of milliseconds or even seconds. Here it is proposed how projections from entorhinal grid cells can undergo a similar learning process to create hippocampal place cells that can cover a space of many meters that are needed to control navigational behaviors. The suggested homology between spatial and temporal processing may clarify how spatial and temporal information may be integrated into an episodic memory. The model proposes how a path integration process activates a spatial map of grid cells. Path integration has a limited spatial capacity, and must be reset periodically, leading to the observed grid cell periodicity. Integration-to-map transformations have been proposed to exist in other brain systems. These include cortical mechanisms for numerical representation in the parietal cortex. As in the grid-to-place cell spatial expansion, the analog representation of number is extended by additional mechanisms to represent much larger numbers. The model also suggests how visual landmarks may influence grid cell activities via feedback projections from hippocampal place cells to the entorhinal cortex.
17203585	The glycan chains of glycoconjugates play important roles in cell-cell and cell-matrix interactions. In the CNS, previous studies on learning and memory suggest the importance of oligosaccharides attached to glycoconjugates in the modulation of synaptic connections. We studied the hippocampal glycan distribution of rats subject to an inhibitory avoidance task. The expression of glycans was examined by lectin-histochemistry using Vicia villosa lectin (VVL) for terminal alpha/beta N-acetylgalactosamine (alpha/beta GalNAc); Galanthus nivalus lectin (GNL) for terminal mannose alpha-1,3 (Man alpha-1,3); Peanut agglutinin (PNA) for galactose beta-1,3N-acetylgalactosamine (Gal beta-1,3 GalNAc); Erythrina cristagalli lectin (ECL) for galactose beta-1,4 N-acetylglucosamine (Gal beta-1,4 GlcNAc); Sambucus nigra lectin (SNA) for sialic acid alpha-2.6 galactose (SA alpha-2,6 Gal); Maackia amurensis lectin II (MAL II) for sialic acid alpha-2,3 (SA alpha-2,3); Wheat germ agglutinin (WGA) for terminal N-acetylglucosamine with/ without sialic acid (GlcNAc wo SA); succynilated WGA (sWGA) for terminal N-acetylglucosamine without sialic acid (terminal GlcNAc without SA); Griffonia simplicifolia lectin II (GSL II) for terminal alpha/beta N-acetylglucosamine (alpha/beta GlcNAc terminal); and Lotus tetragonolobus lectin (LTL) alpha-fucose. Two groups of 10 animals were examined: non-trained (Control) and Trained rats. ECL, sWGA and GSL II were negative for both groups in all the hippocampal subfields studied. For both groups, VVL was negative in CA4 and granular cells of the Dentate Gyrus (DG) and LTL was negative in the CA4 subfield. Expression of alpha/beta GalNAc, alpha-fucose and GlcNAc in other hippocampal subflields was positive, with no differences between groups. However, expression of Man alpha-1,3 was significantly higher in the CA1, CA2, CA3, and CA4 subfields in the Trained group. On the other hand, expression of Gal beta-1,3 GalNAc was significantly low in CA4 and DG in the Trained group. In conclusion, the results here presented indicate that the exposure of rats to an associative behavioral paradigm related to declarative memory, involves some regulatory mechanism/s for the differential patterns of glycan expression.
17201473	The substantia nigra pars compacta (SNc) and the dorsal striatum are often considered to be necessary for stimulus-response (S-R) habit learning, whereas the dorsal hippocampus is considered to be necessary for relational (declarative) memory. Spatial learning is a kind of relational learning that occurs when a rat is released from different locations (variable start) in a water maze to find a submerged platform that is kept in a constant location. However, when the rat is always released from the same starting position (constant start), it can learn to find the platform oriented by a fixed configuration of cues, that is, by S-R learning. To test the critical role of the SNc in S-R and relational learning, the authors tested adult male Wistar rats, sham-operated or with a lesion in the SNc, in these 2 versions of the water maze task. The SNc lesion was induced by bilateral intranigral infusion of 0.5 micromol 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Although the SNc-lesioned rats learned the variable-start version as effectively as sham rats did, they were significantly impaired in learning the constant-start version of the task.
17201463	Research on the effect of acute stress and high levels of glucocorticoids on memory has largely focused on memory tasks involving the medial temporal lobe (e.g., declarative memory). Less is known, however, about the effects of stress and glucocorticoids on more strategic memory processes regulated by the prefrontal cortex (e.g., source monitoring). In the current study, the authors investigated whether exposure to acute psychosocial stress would result in altered source monitoring performance relative to the performance of a nonstressed control group. To this end, the authors assigned nonsmoking, healthy, young men to either a stress (n = 22) or a control (n = 18) condition, after which the men were given an internal source monitoring test. Results show that relative to control participants, stressed participants made fewer source monitoring errors. This study suggests that stress may have differential effects on memory, depending on whether the memory test is regulated by the prefrontal cortex or the medial temporal lobe.
17197370	Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-fos, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-fos expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia.
17182108	Multiple studies have documented deficits in verbal declarative memory function in depression that improve with resolution of symptoms; imaging studies show deficits in anterior cingulate function in depression, a brain area that mediates memory. No studies to date have examined neural correlates of emotionally valenced declarative memory using affectively negative (sad) verbal material that is clinically relevant to understanding depression. Also no studies have examined the effects of treatment on neural correlates of verbal declarative memory. The purpose of this study was to examine the effects of treatment with antidepressants on verbal declarative memory in patients with depression.Subjects with (N=18) and without (N=9) mid-life major depression underwent positron emission tomography (PET) imaging during verbal declarative memory tasks with both neutral paragraph encoding compared to a control condition, and emotional (sad) word pair retrieval compared to a control condition. Imaging was repeated in 13 subjects with depression after treatment with antidepressants.	Patients with untreated depression had a failure of anterior cingulate activation relative to controls during retrieval of emotional word pairs. Antidepressant treatment resulted in increased anterior cingulate function compared to the untreated baseline for both neutral and emotional declarative memory.	Limitations include a small sample size and variety of antidepressants used.	These results are consistent with alterations in anterior cingulate function that are reversible with treatment in patients with depression. These findings may have implications for understanding the mechanism of action of antidepressants in the treatment of depression.	
17179724	Whereas age-related declines in declarative memory have been demonstrated in multiple cross-sectional and longitudinal studies, the effect of age on non-declarative manifestations of memory, such as repetition priming and perceptual skill learning, are less clear. The common assumption, based on cross-sectional studies, is that these processes are only mildly (if at all) affected by age.To investigate long-term changes in repetition priming and age-related differences in identification of fragmented pictures in a 5-year longitudinal design.	Healthy adults (age 28-82 years) viewed drawings of objects presented in descending order of fragmentation. The identification threshold (IT) was the highest fragmentation level at which the object was correctly named. After a short interval, old pictures were presented again along with a set of similar but novel pictures. Five years later the participants repeated the experiment.	At baseline and 5-year follow-up alike, one repeated exposure improved IT for old (priming) and new (skill acquisition) pictures. However, long-term retention of priming gains was observed only in young adults. Working memory explained a significant proportion of variance in within-occasion priming, long-term priming, and skill learning.	Contrary to cross-sectional results, this longitudinal study suggests perceptual repetition priming is not an age-invariant phenomenon and advanced age and reduced availability of cognitive resources may contribute to its decline.	
17168159	While learning and memory are related, they are distinct processes each with different forms of expression and underlying molecular mechanisms. An invertebrate model system, Lymnaea stagnalis, is used to study memory formation of a non-declarative memory. We have done so because: (1) We have discovered the neural circuit that mediates an interesting and tractable behaviour; (2) This behaviour can be operantly conditioned and intermediate-term and long-term memory can be demonstrated; and (3) It is possible to demonstrate that a single neuron in the model system is a necessary site of memory formation. This article reviews how Lymnaea has been used in the study of behavioural and molecular mechanisms underlying consolidation, reconsolidation, extinction and forgetting.
17167082	Non-rapid eye movement sleep has been strongly implicated in consolidation of both declarative and procedural memory in humans. Elevated sleep-spindle density in slow-wave sleep after learning has been shown recently in humans. It has been proposed that sleep spindles, 12-15 Hz oscillations superimposed on slow waves (<1 Hz), in concert with high-frequency hippocampal sharp waves/ripples, promote neural plasticity underlying remote memory formation. The present study reports the first indication of learning-associated increase in spindle density in the rat, providing an animal model to study the role of brain oscillations in memory consolidation during sleep. An odor-reward association task, analogous in many respects to human paired-associate learning, is rapidly learned and leads to robust memory in rats. Rats learned the task over 10 massed trials within a single session, and EEG was monitored for 3 h after learning. Learning-induced increase in spindle density is reliably reproduced in rats in two different learning situations, differing primarily in the behavioral component of the task. This increase in spindle density is also present after reactivation of remote memory and in situations when memory update is required; it is not observed after noncontingent exposure to reward and training context. The latter results substantially extend findings in humans. The magnitude of increase (approximately 25%) and the time window of maximal effect (approximately 1 h after sleep onset) were remarkably similar to human data, making this a valid rodent model to study network interactions through the use of simultaneous unit recordings and local field potentials during postlearning sleep.
17162997	To verify that the classic "Old/New" memory effect can be detected after a long delay, and to investigate the differential influence of declarative memory processes after normal sleep and daytime wake.The protocol is a variation of a more traditional study-recognition test used in event-related potential (ERP) studies in which sleep or wake is inserted between the learning and recognition session in order to verify the existence of the Old/New effect (ie, positive shift that occurs when stimuli are repeated). ERPs were recorded during the recognition-test session. The protocol was based on early work that compared the effect of sleep on memory without recording sleep.	Data collection occurred in the outpatient sleep laboratory.	Results from 13 subjects (6 men) aged between 21 and 39 years.	The subjects performed the recognition memory test after sleep and daytime wake periods. More-accurate performance for the old (studied) stimuli occurred after the sleep session. Analysis of variance on correctly answered reaction times revealed a significant effect of condition (old/new) with no difference across session. A repeated-measure analysis revealed differences in "Old/New" effect, whereby the amplitude difference between the old and new items was larger after sleep than after wake.	This effect of sleep was found in early frontal and later posterior ERP components, processes that represent strategic, contextual processing and facilitation of episodic memory. Memory representation was not different across sessions. These findings suggest that sleep and wake facilitate 2 components of memory unequally, ie, episodic recognition and memory representation functioning.	
17148960	The hippocampal formation is a multicomponent region of the medial temporal lobe preferentially involved in declarative and relational memory processing. Behavioral studies have suggested a protracted functional maturation of these structures in primates, and postnatal developmental abnormalities in the hippocampal formation are thought to contribute to neurodevelopmental disorders, such as autism, schizophrenia, epilepsy and Down syndrome. Despite all that we know about the functional organization of the adult hippocampal formation, notably absent is a systematic study of its postnatal maturation in primates. In this article, we review current knowledge of the structural development of the primate hippocampal formation and present new data on its postnatal neuroanatomical development. We summarize what is known about the neurobiological processes, such as the addition of new neurons, the establishment and elaboration of connectivity, and the neurochemical changes, that underlie the structural development and functional maturation of the primate hippocampal formation. We conclude that there is yet insufficient information to identify distinct developmental windows during which different hippocampal regions undergo specific maturational processes. For this reason, it is currently impossible to determine the ages at which specific hippocampal circuits become structurally mature and potentially capable of supporting defined, age-specific functional processes. Together with work in rodents, systematic studies of the structural development and functional maturation of the monkey hippocampal formation will be necessary to gain insight not only into the types of information processing that it subserves, but also into the specific maturational processes that might be affected in human neurodevelopmental disorders.
17141741	Recent findings in young adults suggest that rapid eye movement (REM) sleep plays a role in procedural memory consolidation. The significance of REM sleep for memory consolidation in old age has not yet been investigated.Effects of REM sleep manipulation on declarative and procedural memory consolidation were investigated in 107 healthy older adults, ages 60-82 years. Rapid eye movement sleep deprivation was achieved by REM sleep awakenings and compared with non-REM sleep awakenings. Rapid eye movement sleep augmentation was realized physiologically by REM sleep rebound and pharmacologically by administering an acetylcholinesterase inhibitor in a double-blind, placebo-controlled design. Memory performance was tested by a paired associate list and a mirror tracing task at 9:30 pm and 7:30 am with sleep intervening between 11:00 pm and 7:00 am.	Although REM sleep deprivation led to a significant reduction in total and phasic REM sleep, memory consolidation remained unaffected. Both REM sleep augmentation groups showed a significant increase in phasic REM sleep, whereas only pharmacological cholinergic REM sleep manipulation exerted a significant positive effect on procedural memory consolidation.	Because only after cholinergic stimulation of phasic REM sleep procedural memory consolidation is improved, cholinergic activation seems to be a crucial component of REM sleep-related memory consolidation in old age.	
17138309	Two experimental methods, which have dominated the study of declarative memory in preverbal children with imitation tasks, namely the deferred imitation and elicited imitation paradigm, differ in the amount of physical contact with test stimuli afforded infants prior to a test for long-term recall. The current study assessed effects of pre- and post-demonstration contact with test stimuli on deferred imitation of novel, single-step unrelated actions with multiple objects by 8(1/2)- and 10(1/2)-month-old infants (N=50). The rate of target action completion after a delay remained consistent at both ages across different conditions of prior contact with test stimuli. This study shows that a within-subjects baseline appraisal is valid within certain experimental parameters and offers a more economical alternative. The results show furthermore that different experimental designs utilized to assess deferred imitation are highly comparable for the first year despite differences in determining baseline.
17138260	Declarative memory in infants is often assessed via deferred imitation. Not much is known about the information processing basis of the memory effect found in these experiments. While in the typical deferred imitation study the order of actions remains the same during demonstration and retrieval, in two experiments with n=30 respective n=25, 10- and 11-month-old infants, the order of novel unrelated actions in demonstration and retrieval was varied (same, reversed, mixed). This allowed a separation of item-specific from item-relational information processing. In both experiments best memory performance was found when the order of target actions remained the same during encoding and recall, demonstrating that infants seem to rely on item-specific as well as item-relational information which has to be ad hoc constructed while encoding.
17135379	Delta power in sleep is of increasing interest because of its association with waking performance in neuropsychological tests. In schizophrenia, this link might be impaired because of a decrease in delta power in sleep and pronounced cognitive deficits. The authors analyzed delta power in sleep and neuropsychological performance in 16 patients with schizophrenia on stable medication with amisulpride and 17 healthy subjects. In healthy subjects, the authors found significant positive correlations between morning performance in declarative memory, procedural learning, and attention and delta power, especially in frontal channels. The authors interpret these results in terms of dysfunctions of thalamocortical and prefrontal networks in schizophrenia.
21049376	We report on M.S., an 83-year-old patient with isolated pure progressive amnesia. This rare, recently identified, form of amnesia has been described in elderly patients. Neuropathological studies suggest that this syndrome is an atypical clinical presentation of Alzheimer's disease. The aim of our study was to characterize the neuropsychological pattern of pure progressive amnesia in comparison with other amnestic syndromes and memory dissociations reported in the literature. Our results indicate that pure progressive amnesia is characterized by a highly unusual dissociation in the realm of memory, with severe deficits on tests based on recognition and recall of verbal and visual single items, contrasting with relatively preserved anterograde autobiographical and spatial memory and normal recall of complex material such as stories. These findings suggest that memory for single items could depend on an independent system. One hypothesis is that M.S.'s unusual memory profile results from relative dysfunction of the ventral medial temporal lobe pathway. An alternative explanation implicates cognitive reserve. Further studies are required in order to progress on this matter. In any case, pure progressive amnesia is a clinical syndrome that may provide further insight into the organization of declarative memory.
17133381	The medial temporal lobe (MTL) is critical for declarative memory formation. Several theories of MTL function propose functional distinctions between the different structures of the MTL, namely the hippocampus and the surrounding cortical areas. Furthermore, computational models and electrophysiological studies in animals suggest distinctions between the subregions of the hippocampus itself. Standard fMRI resolution is not sufficiently fine to resolve activity on the scale of hippocampal subregions. Several approaches to scanning the MTL at high resolutions have been made, however there are limitations to these approaches, namely difficulty in conducting group-level analyses. We demonstrate here techniques for scanning the MTL at high resolution and analyzing the high-resolution fMRI data at the group level. To address the issue of cross-participant alignment, we employ the ROI-LDDMM alignment technique, which is demonstrated to result in smaller alignment errors when compared with several other common normalization techniques. Finally, we demonstrate that the pattern of activation obtained in the high-resolution functional data is similar to that obtained at lower resolution, although the spatial extent is smaller and the percent signal change is greater. This difference in the pattern of activation may be due to less partial volume sampling in the high-resolution data, resulting in more accentuated regions of activation.
17126861	The disproportionate impairment for the recognition of facial expressions of disgust in patients with Huntington's disease (HD) forms a double dissociation with the impaired recognition of fear that has been reported in amygdala patients. The dissociation has generated discussion regarding the potential existence of neural substrates dedicated to the recognition of facial signals of specific emotions. The aim of this study was to establish whether the impairment for disgust in HD was restricted solely to the domain of facial perception, or whether HD patients also demonstrate impairment in other kinds of disgust. Fourteen HD patients and fourteen age and education matched healthy controls participated in seven disparate emotion processing tasks. (1) A measure of knowledge for the situational determinants of distinct emotions; (2) recognition of emotion expressed in nonverbal vocalisations; (3) recognition of the emotional content of explicit lexical stimuli; (4) recognition of emotional content in pictures of emotion scenes; (5) a disgust experience questionnaire; (6) a measure of olfactory hedonic responsiveness; (7) a measure of gustatory perception. While verbal aspects of disgust processing were preserved, parallel impairments were revealed for olfactory disgust, vocal disgust expressions, the classification of disgusting pictures, and declarative knowledge of disgust elicitors. The finding of impaired perception of disgust signalled through different input domains suggests that the inability to recognise the facial expression in this population reflects a fundamental problem with disgust processing.
17122043	Object recognition is the canonical test of declarative memory, the type of memory putatively impaired after damage to the temporal lobes. Studies of object recognition memory have helped elucidate the anatomical structures involved in declarative memory, indicating a critical role for perirhinal cortex. We offer a mechanistic account of the effects of perirhinal cortex damage on object recognition memory, based on the assumption that perirhinal cortex stores representations of the conjunctions of visual features possessed by complex objects. Such representations are proposed to play an important role in memory when it is difficult to solve a task using representations of only individual visual features of stimuli, thought to be stored in regions of the ventral visual stream caudal to perirhinal cortex. The account is instantiated in a connectionist model, in which development of object representations with visual experience provides a mechanism for judgment of previous occurrence. We present simulations addressing the following empirical findings: (1) that impairments after damage to perirhinal cortex (modeled by removing the "perirhinal cortex" layer of the network) are exacerbated by lengthening the delay between presentation of to-be-remembered items and test, (2) that such impairments are also exacerbated by lengthening the list of to-be-remembered items, and (3) that impairments are revealed only when stimuli are trial unique rather than repeatedly presented. This study shows that it may be possible to account for object recognition impairments after damage to perirhinal cortex within a hierarchical, representational framework, in which complex conjunctive representations in perirhinal cortex play a critical role.
17108581	This article presents a computational model and a simulation of the decrease of activities of daily living performances due to Alzheimer's disease. The disease evolution is simulated thanks to the cognitive architecture ACT-R. Activities are represented according to the retrieval of semantic units in declarative memory and the trigger of rules in procedural memory. The simulation of Alzheimer's disease decrease is simulated thanks to the variation of subsymbolic parameters. The model is applied to a cooking activity. Simulation of 100 hundred subjects shows results similar to those realised in a standardized assessment with human subjects.
17107493	Competing models of declarative memory were tested with structural equation models to analyze whether a second-order latent variable structure for episodic and semantic memory was invariant across age groups and across noise exposure conditions. Data were taken from three previous experimental noise studies that were performed with the same design, procedure, and dependent measures, and with participants from four age groups (13-14, 18-20, 35-45, and 55-65 years). Two noise conditions, road traffic noise and meaningful irrelevant speech, were compared to a quiet control group. The structural models put to the test were taken from Nyberg et al. (2003), which employed several memory tests that were the same as ours and studied age-groups that partly overlapped with our groups. In addition we also varied noise exposure conditions. Our analyses replicated and supported the second-order semantic-episodic memory models in Nyberg et al. (2003). The latent variable structures were invariant across age groups, with the exception of our youngest group, which by itself showed a less clear latent structure. The obtained structures were also invariant across noise exposure conditions. We also noted that our text memory items, which did not have a counterpart in the study by Nyberg et al. (2003), tend to form a separate latent variable loading on episodic memory.
17101872	The most useful information about the anatomy of human memory comes from cases where there has been extensive neuropsychological testing followed by detailed post-mortem neurohistological analysis. To our knowledge, only eight such cases have been reported (four with medial temporal lobe damage and four with diencephalic damage). Here we present neuropsychological and post-mortem neurohistological findings for one patient (NC) with bilateral damage to the medial temporal lobe and two patients (MG, PN) with diencephalic damage due to bilateral thalamic infarction and Korsakoff's syndrome, respectively. All three patients exhibited a similar phenotype of amnesia with markedly impaired declarative memory (anterograde and retrograde) but normal performance on tests of nondeclarative memory (e.g., priming and adaptation-level effects) as well as on tests of other cognitive functions. Patient NC had damage to the hippocampus (dentate gyrus and the CA1 and CA3 fields) and layer III of the entorhinal cortex, but with relative sparing of the CA2 field and the subiculum. Patient MG had damage to the internal medullary lamina and mediodorsal thalamic nuclei. Patient PN had damage to the mammillary nuclei, mammillothalamic tracts, and the anterior thalamic nuclei. These findings illuminate several issues regarding the relation between diencephalic and medial temporal lobe amnesia, the status of recognition memory in amnesia, and the neuroanatomy of memory.
17100790	Both sleep and emotion are known to modulate processes of memory consolidation, yet their interaction is poorly understood. We examined the influence of sleep on consolidation of emotionally arousing and neutral declarative memory. Subjects completed an initial study session involving arousing and neutral pictures, either in the evening or in the morning. Twelve hours later, after sleeping or staying awake, subjects performed a recognition test requiring them to discriminate between these original pictures and novel pictures by responding "remember,""know" (familiar), or "new." Selective sleep effects were observed for consolidation of emotional memory: Recognition accuracy for know judgments of arousing stimuli improved by 42% after sleep relative to wake, and recognition bias for remember judgments of these stimuli increased by 58% after sleep relative to wake (resulting in more conservative responding). These findings hold important implications for understanding of human memory processing, suggesting that the facilitation of memory for emotionally salient information may preferentially develop during sleep.
17098374	Hippocampus is the brain structure, vital for episodic and declarative memory. Atrophy of the human hippocampus is seen in a variety of psychiatric and neurological disorders e.g. recurrent depression, schizophrenia, bipolar disorder, post-traumatic stress disorder, epilepsy, head injury, and Alzheimer's disease (AD). Importantly, aging hippocampus also undergoes atrophy. In many instances, for example, AD, the atrophy precedes the development of symptoms while in others, there is a temporal relationship between atrophy and symptomatology. The presence of atrophied hippocampus is one of the most consistent features of many common psychiatric disorders. Several factors contribute to this atrophy. Stress is one of the most profound factors implicated and the mechanisms involve glucocorticoids, serotonin, excitatory amino acids etc. Hippocampal formation as a whole can undergo atrophy or its individual structural components e.g. apical dendrities can exhibit atrophy. Several drugs of unrelated classes have been shown to prevent atrophy indicating heterogenous manner in which hippocampal atrophy is produced. These include, tianeptine (affects structural plasticity in hippocampus and is an effective antidepressant); phenytoin (antiseizure and neuroprotective); fluoxetine (downregulates neurodegenerative enzyme and increases neuroprotective hippocampal S100 beta); lithium (neuroprotective and antiapoptotic); tricyclic antidepressants (increase hippocampal neurogenesis); antipsychotics (reduce hippocampal neuronal suppression); sodium valproate (increases neurogenesis) and mifepristone (antioxidant, neuroprotective and anti-glucocorticoid). Now the most important question is: to what extent does the hippocampal atrophy play a role in the genesis of symptoms of diseases or their progression? And if it does, can we achieve the same degree of prevention or reversal seen in experimental animals, in humans also. An even more important question is: whether the prevention of atrophy would be clinically useful in affecting disease, viz slowing its progression, reducing morbidity, complications or positively affecting the outcome of one or more of its clinically important aspects. If the answer to this is yes, we would have to know at what stage of the disease we use the drugs, dose, duration, follow-up and efficacy. The use of these drugs in the above mentioned conditions can not only test the potential of atrophy as a future drug target, but could also help in learning more about the hippocampus in both health and diseases.
17086200	There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz--another frequency band that normally predominates during rapid-eye-movement sleep--decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.
17085038	Those inclined to relish in scientific controversy will not be disappointed by the literature on the effects of sleep on memory. Opinions abound. Yet refinements in the experimental study of these complex processes of sleep and memory are bringing this fascinating relationship into sharper focus. A longstanding position contends that sleep passively protects memories by temporarily sheltering them from interference, thus providing precious little benefit for memory. But recent evidence is unmasking a more substantial and long-lasting benefit of sleep for declarative memories. Although the precise causal mechanisms within sleep that result in memory consolidation remain elusive, recent evidence leads us to conclude that unique neurobiological processes within sleep actively enhance declarative memories.
17084573	The decline of cognitive capacities with age in mouse lemur primates (Microcebus murinus) was assessed. Eight young adults (2-4 years) and nine aged adults (7-11 years) were examined on tasks designed to measure executive functions, procedural and declarative memory. The mouse lemurs were tested on the go-no go successive discrimination task, set shifting tasks (including extra-dimensional shift and reversal discrimination) and a spatial rule-guided discrimination task. There were four major findings. First, the deficits observed were not global but only on specific tasks indicating that only specific cognitive abilities are impaired with aging. Second, there were variations among aged subjects suggesting different patterns of cognitive aging. Third, alterations in cognitive abilities with aging in mouse lemurs seemed to be comparable to those described in aged monkeys and humans. Indeed, executive functions and declarative memory were affected in subpopulations of aged subjects whereas procedural memory remained intact in all the tested aged subjects. Finally, two forms of executive dysfunctions were distinguished among the aged subjects. The ultimate goal is to correlate age-related cognitive deficit with brain alterations and this study has helped to select candidate regions to be thoroughly scrutinized in aged mouse lemurs.
17079658	We asked what kind of memory is operating when eye movements change as the result of experience. Participants viewed scenes that were either novel, repeated, or manipulated (i.e., a change was introduced in one region of the scene). Eye movements differed depending on the past viewing history of each scene. Participants made fewer fixations and sampled fewer regions when scenes were repeated than when scenes were novel. When scenes were altered, participants made more fixations in the altered region, spent more time looking at the altered region, and made more transitions into and out of the altered region than in unchanged (matched) regions in the repeated scenes. Importantly, these effects occurred only when individuals were aware that a change had occurred. Participants who were unaware that the scene had been altered looked at the changed scenes in the same way that they looked at repeated scenes. Thus, there was no indication that eye movements could reveal an unaware (unconscious) form of memory. Instead, eye movements reflected conscious memory of whether the scene was repeated or manipulated. The findings were the same when awareness was assessed after viewing all the scenes (experiment 1) and when awareness was assessed after each scene was presented (experiment 2). In experiment 3, memory-impaired patients with damage limited to the hippocampus were impaired at deciding whether scenes were novel, repeated, or manipulated. Thus, the ability to consciously recollect recent encounters with scenes reflects a form of hippocampus-dependent memory. The findings show that experience-dependent eye movements in response to altered scenes reflect conscious, declarative memory, and they support the link between aware memory, declarative memory, and hippocampus-dependent memory.
17074956	Patients with schizophrenia show deficits in several neurocognitive domains. However, the relationship between white matter integrity and performance in these domains is poorly understood. The authors conducted neurocognitive testing and diffusion tensor imaging in 25 patients with schizophrenia. Performance was examined for tests of verbal declarative memory, attention, and executive function. Relationships between fractional anisotropy and cognitive performance were examined by using voxelwise correlational analyses. In each case, better performance on these tasks was associated with higher levels of fractional anisotropy in task-relevant regions.
17074430	Memorizing new facts and events means that entering information produces specific physical changes within the brain. According to the commonly accepted view, traces of memory are stored through the structural modifications of synaptic connections, which result in changes of synaptic efficiency and, therefore, in formations of new patterns of neural activity (the hypothesis of synaptic plasticity). Most of the current knowledge on learning and initial stages of memory consolidation ("synaptic consolidation") is based on this hypothesis. However, the hypothesis of synaptic plasticity faces a number of conceptual and experimental difficulties when it deals with potentially permanent consolidation of declarative memory ("system consolidation"). These difficulties are rooted in the major intrinsic self-contradiction of the hypothesis: stable declarative memory is unlikely to be based on such a non-stable foundation as synaptic plasticity. Memory that can last throughout an entire lifespan should be "etched in stone." The only "stone-like" molecules within living cells are DNA molecules. Therefore, I advocate an alternative, genomic hypothesis of memory, which suggests that acquired information is persistently stored within individual neurons through modifications of DNA, and that these modifications serve as the carriers of elementary memory traces.
17073169	Intracranial recordings of cognitive potentials within the human hippocampal system have identified N400 potentials in the anterior mesial temporal lobe (AMTL-N400) that correlate with verbal memory performance and are associated with novelty detection. Their amplitudes to "new" but not "old" words in a verbal recognition task correlate with the neuronal density of the hippocampal CA1-region and can be reduced selectively by the NMDA-receptor blocker ketamine. Moreover, it could be shown that NMDA-receptor dependent long-term potentiation (LTP), a form of synaptic plasticity with Hebbian characteristics, can be readily induced in human hippocampal slices but not in patients with hippocampal sclerosis. In these latter patients, we also found a reduction of AMTL-N400 amplitudes similar to the one induced by ketamine. In addition, we could show that hippocampal novelty detection is associated with successful encoding for declarative memory. Together, our findings suggest that successful encoding for declarative memory is at least in part mediated by NMDA-receptor dependent novelty detection within the human hippocampal system.
17069471	Preclinical studies have implicated cholinergic neurotransmission, specifically M1 muscarinic acetylcholine receptor (mAChR) activation, in sleep-associated memory consolidation. In the present study, we investigated the effects of administering the direct M1 mAChR agonist RS-86 on pre-post sleep memory consolidation. Twenty healthy human participants were tested in a declarative word-list task and a procedural mirror-tracing task. RS-86 significantly reduced rapid eye movement (REM) sleep latency and slow wave sleep (SWS) duration in comparison with placebo. Presleep acquisition and postsleep recall rates were within the expected ranges. However, recall rates in both tasks were almost identical for the RS-86 and placebo conditions. These results indicate that selective M1 mAChR activation in healthy humans has no clinically relevant effect on pre-post sleep consolidation of declarative or procedural memories at a dose that reduces REM sleep latency and SWS duration.
17062373	Two major memory systems have been recognized over the years (Squire, in Memory and Brain, 1987): the declarative memory system, which is under the control of the hippocampus and related temporal lobe structures, and the procedural or habit memory system, which is under the control of the striatum and its connections (Mishkin et al., in Neurobiology of Learning by G Lynch et al., 1984; Knowlton et al., Science 273:1399, 1996). Most if not all learning tasks studied in animals, however, involve either the performance or the suppression of movement. Animals acquire connections between environmental or discrete sensory cues (conditioned stimuli, CSs) and emotionally or otherwise significant stimuli (unconditioned stimuli, USs). As a result, they learn to perform or to inhibit the performance of certain motor responses to the CS which, when learned well, become what can only be called habits (Mishkin et al., 1984): to regularly walk or swim to a place or away from a place, or to inhibit one or several forms of movement. These responses can be viewed as conditioned responses (CRs) and may sometimes be very complex. This is of course also seen in humans: people learn how to play on a keyboard in response to a mental or written script and perform the piano or write a text; with practice, the performance improves and eventually reaches a high criterion and becomes a habit, performed almost if not completely without awareness. Commuting to school in a big city in the shortest possible time and eschewing the dangers is a complex learning that children acquire to the point of near-perfection. It is agreed that the rules that connect the perception of the CS and the expression of the CR change from their first association to those that take place when the task is mastered. Does this change of rules involve a switch from one memory system to another? Are different brain systems used the first time one plays a sonata or goes to school as compared with the 100th time? Here we will comment on: 1) reversal learning in the Morris water maze (MWM), in which the declarative or spatial component of a task is changed but the procedural component (to swim) persists and needs to be re-linked with a different set of spatial cues; and 2) a series of observations on an inhibitory avoidance task that indicate that the brain systems involved change with further learning.
17060564	The hippocampal formation is essentially involved in the formation of conscious memories for facts and events and neurologic diseases affecting the hippocampus associate with severe memory deficits, i.e., temporal lobe epilepsies.We studied the degree of declarative memory dysfunction in 24 human subjects with unilateral mesial temporal lobe epilepsy, using the unique possibility to access memory performance of each isolated hippocampus by intracarotid amobarbital anesthesia. Subsequently, hippocampal specimens from the same patients were available for neuropathologic analysis following surgical treatment of intractable seizures.	Neuronal cell loss in the dentate gyrus and all hippocampal subfields correlated with memory performance with the exception of CA2. Moreover, multiple regression and partial correlation analyses identified neuronal cell loss within the internal limb of the dentate gyrus, a developmentally distinct subregion of the hippocampal formation known to generate new neurons throughout life, as highly significant predictor for the patient's ability to learn and recall memories.	In accordance with animal studies, the dentate gyrus may play a critical role in the neuronal network associated with memory formation.	
17060048	In populations of young and older adults, it has been shown that individuals may be categorized into one of three diurnal subgroups when salivary cortisol levels are assessed over a 2-day period and compared for their consistency across days: a typical subgroup, a flat subgroup, and an inconsistent subgroup. Interestingly, recent studies have reported that the typical subgroup represents the majority of the young and older adult population, a finding that is difficult to reconcile with previous studies showing increased cortisol levels in older adults with depression or cognitive impairments. In order to assess whether a typical diurnal cortisol profile is representative across different subgroups of older adults, we assessed diurnal cortisol cycle representation in a sample of older adults with subjective complaints of depression and/or memory problems. Furthermore, given the robust relationship between cortisol and cognitive function, the present study examined the association between the three diurnal subgroups and cognitive performance. Forty-two older individuals were recruited on the basis of reporting subjective complaints of either memory problems and/or depressive mood. Participants were asked to sample their saliva over a 2-day period and were then asked to undergo a neuropsychological evaluation that taps into short-term memory, declarative memory and language. The results showed that 69% of the sample presented a Flat cycle of salivary cortisol over a 2-day period while 19% presented an inconsistent pattern and 12% presented a typical pattern. Participants in the flat subgroup were significantly impaired on letter verbal fluency. Furthermore, a relationship was found between diurnal cortisol subgroup representation and subjective complaint profile. These findings show that older adults with complaints of memory problems and/or depressive symptoms do not present the typical profile of the diurnal cortisol cycle, and they provide a preliminary view of how diurnal cortisol profile relates to cognitive function during human aging.
17035163	Stress and cortisol are known to impair memory retrieval of well-consolidated declarative material. The effects of cortisol on memory retrieval may in particular be due to glucocorticoid (GC) receptors in the hippocampus and prefrontal cortex (PFC). Therefore, effects of stress and cortisol should be observable on both hippocampal-dependent declarative memory retrieval and PFC-dependent working memory (WM). In the present study, it was tested whether psychosocial stress would impair both WM and memory retrieval in 20 young healthy men. In addition, the association between cortisol levels and cognitive performance was assessed. It was found that stress impaired WM at high loads, but not at low loads in a Sternberg paradigm. High cortisol levels at the time of testing were associated with slow WM performance at high loads, and with impaired recall of moderately emotional, but not of highly emotional paragraphs. Furthermore, performance at high WM loads was associated with memory retrieval. These data extend previous results of pharmacological studies in finding WM impairments after acute stress at high workloads and cortisol-related retrieval impairments.
17019627	Discrete-trial training (DTT) relies critically on implementation by trained tutors. We report three experiments carried out in the development of "DTkid"--interactive computer simulation software that presents "SIMon", a realistic virtual child with whom novice tutors can learn and practise DTT techniques. Experiments 1 and 2 exposed groups of participants either to DTkid training or to a control task. Participants in the former groups demonstrated significantly greater procedural and declarative knowledge of DTT. Experiment 3 confirmed this finding, further demonstrating that observation of DTkid training trials alone was sufficient to enhance participants' declarative and procedural knowledge of DTT. Results indicate that DTkid offers the potential for an effective means of teaching DTT skills to novice tutors of children with autism.
17015860	Extensive evidence documents emotional modulation of hippocampus-dependent declarative memory in humans. However, little is known about the emotional modulation of striatum-dependent procedural memory. To address how emotional arousal influences declarative and procedural memory, the current study utilized (1) a picture recognition and (2) a weather prediction (WP) task (a probabilistic classification learning task), which have been shown to rely on hippocampal- and striatum-based memory systems, respectively. Observers viewed arousing or neutral pictures after (Experiment 1) or during (Experiment 2) WP training trials. A 1-wk delayed picture recognition memory test revealed enhanced declarative memory for arousing compared with neutral pictures. Arousal during encoding impaired initial WP acquisition but did not influence retention when tested after a 1-wk delay. Data from a subsequent 3-mo delayed test, however, suggested that arousal during acquisition may enhance remote WP retention. These results suggest a potential dissociation between how readily emotional arousal influences hippocampus-dependent and striatum-dependent memory systems in humans.
17014370	Different structures within the medial-temporal lobe likely make distinct contributions to declarative memory. In particular, several current psychological and computational models of memory predict that the hippocampus and parahippocampal regions play different roles in the formation and retrieval of declarative memories [e.g., Norman, K. A., & O'Reilly, R. C. Modeling hippocampal and neocortical contributions to recognition memory: A complementary-learning systems approach. Psychological Review, 110, 611-646, 2003]. Here, we examined the neuronal firing patterns in these two regions during recognition memory. Recording directly from neurons in humans, we find that cells in both regions respond to novel stimuli with an increase in firing (excitation). However, already on the second presentation of a stimulus, neurons in these regions show very different firing patterns. In the parahippocampal region there is dramatic decrease in the number of cells responding to the stimuli, whereas in the hippocampus there is recruitment of a large subset of neurons showing inhibitory (decrease from baseline firing) responses. These results suggest that inhibition is a mechanism used by cells in the human hippocampus to support sparse coding in mnemonic processing. The findings also provide further evidence for the division of labor in the medial-temporal lobe with respect to declarative memory processes.
16989555	On the assumption that linguistic faculties reflect both lexical storage in the temporal cortex and combinatorial rules in the striatal circuits, several authors have shown that striatal-damaged patients are impaired with conjugation rules while retaining lexical knowledge of irregular verbs [Teichmann, M., Dupoux, E., Kouider, S., Brugières, P., Boissé, M. F., Baudic, S., Cesaro, P., Peschanski, M., & Bachoud-Lévi, A. C. (2005). The role of the striatum in rule application. The model of Huntington's disease at early stage. Brain, 128, 1155-1167; Ullman, M. T., Corkin, S., Coppola, M., Hickok, G., Growdon, J. H., Koroshetz, W. J., & Pinker, S. (1997). A neural dissociation within language: Evidence that the mental dictionary is part of declarative memory, and that grammatical rules are processed by the procedural system. Journal of Cognitive Neuroscience, 9, 266-276]. Yet, such impairment was documented only with explicit conjugation tasks in the production domain. Little is known about whether it generalizes to other language modalities such as perception and whether it refers to implicit language processing or rather to intentional rule operations through executive functions. We investigated these issues by assessing perceptive processing of conjugated verb forms in a model of striatal dysfunction, namely, in Huntington's Disease (HD) at early stages. Rule application and lexical processes were evaluated in an explicit task (acceptability judgments on verb and nonword forms) and in an implicit task (lexical decision on frequency-manipulated verb forms). HD patients were also assessed in executive functions, and striatal atrophy was evaluated with magnetic resonance imaging (bicaudate ratio). Results from both tasks showed that HD patients were selectively impaired for rule application but lexical abilities were spared. Bicaudate ratios correlated with rule scores on both tasks, whereas executive parameters only correlated with scores on the explicit task. We argue that the striatum has a core function in linguistic rule application generalizing to perceptive aspects of morphological operations and pertaining to implicit language processes. In addition, we suggest that the striatum may enclose computational circuits that underpin explicit manipulation of regularities.
16971536	The cholinergic system has long been implicated in learning and memory, yet its specific function remains unclear. In the present study, we investigated the role of cortical acetylcholine in a rodent model of declarative memory by infusing the cholinergic muscarinic receptor antagonist scopolamine into the rat perirhinal cortex during different stages (encoding, storage/consolidation, and retrieval) of the spontaneous object recognition task. Presample infusions of scopolamine significantly impaired object recognition compared with performance of the same group of rats on saline trials; this result is consistent with previous reports supporting a role for perirhinal acetylcholine in object information acquisition. Scopolamine infusions directly before the retrieval stage had no discernible effect on object recognition. However, postsample infusions of scopolamine with sample-to-infusion delays of up to 20 h significantly facilitated performance relative to postsample saline infusion trials. Additional analysis suggested that the infusion episode could cause retroactive or proactive interference with the sample object trace and that scopolamine blocked the acquisition of this interfering information, thereby facilitating recognition memory. This is, to our knowledge, the first example of improved recognition memory after administration of scopolamine. The overall pattern of results is inconsistent with a direct role for cortical acetylcholine in declarative memory consolidation or retrieval. Rather, the cholinergic input to the perirhinal cortex may facilitate acquisition by enhancing the cortical processing of incoming stimulus information.
16964249	Emotions generally facilitate memory, an effect mediated by the basolateral amygdala (BLA). To study the underlying mechanisms, we recorded BLA, perirhinal and entorhinal neurons during an appetitive trace-conditioning task. We focused on the rhinal cortices because they constitute the interface between the hippocampus, a mediator of memory consolidation, and the neocortex, the storage site of declarative memories. We found that, after unexpected rewards, BLA activity increased impulse transmission from perirhinal to entorhinal neurons and that this effect decayed as the association between conditioned stimuli and rewards was learned. At this late phase of learning, the BLA effect occurred when the animals were anticipating the reward. By enhancing the processing of sensory cues, the BLA-mediated facilitation of rhinal interactions may explain how the amygdala promotes memory formation in emotional conditions.
16959417	Lesion and imaging studies have demonstrated that encoding and retrieval of declarative memories, i.e. consciously accessible events and facts, depend on operations within the rhinal cortex and the hippocampus, two substructures of the medial temporal lobe. Analysis of intracranially recorded EEG in presurgical epilepsy patients revealed that successful memory formation is accompanied within one second by a transient enhancement and later decrease of Rhinal-hippocampal phase synchronization in the gamma range, as well as enhanced connectivity in the low-frequency range. In these studies, words with a high frequency of occurrence were used as stimulus material. Here, we re-examined these effects in another group of 10 presurgical epilepsy patients, this time not only for high-frequency, but also for low-frequency words. For successfully memorized compared to later forgotten high-frequency words we again observed an early phase coupling and later decoupling within the gamma range, as well as enhanced coupling within the sub-gamma range. However, for remembered as compared to forgotten low-frequency words clear synchronization increases were only observed for the delta band, but not for the gamma band. Our data suggest, that broadband Rhinal-hippocampal coupling including the gamma range only occurs, when significant semantic associations are processed within rhinal cortex, as is the case for high-frequency words.
16957495	This is the first case report of a comprehensive neuropsychologic examination of an older man with the fragile X-associated tremor-ataxia syndrome (FXTAS).FXTAS, a newly identified phenotype affecting older male carriers of the fragile X premutation allele, is a progressive disorder marked by gait ataxia, action tremor, peripheral neuropathy, executive cognitive deficits, generalized brain atrophy, and neuronal and astrocytic intranuclear inclusion bodies throughout the brain. The patient previously had undergone neurologic evaluation, molecular analysis, and magnetic resonance imaging.	The patient was administered a neuropsychologic examination, assessing motor and somatosensory functioning, visual and spatial functioning, speech and language, attention, executive abilities, learning and memory, and reasoning.	The patient showed a pattern of cognitive impairment characterized by essentially normal speech and language, moderately impaired control of attention, and moderate to severe deficits in working memory, executive functioning, and both declarative and procedural learning. Visual and spatial abilities were relatively unimpaired, and verbal reasoning was only mildly deficient.	The findings suggest that a cognitive disorder, with especially marked executive cognitive function and memory deficits, accompanies FXTAS. The findings in FXTAS are compared with those in several other neurodegenerative disorders.	
16950222	Studies in humans and in animals have demonstrated that a network of brain regions is involved in performance of declarative and recognition memory tasks. This network includes the hippocampal formation (HF) as well as the ventrolateral prefrontal cortex (VLPFC). Studies in animals have suggested that the relationship between these brain regions is strongly modulated by dopamine.Using fMRI in healthy humans matched for a series of demographic and genetic variables, we studied the effect of the COMT val158met polymorphism on function of HF and VLPFC as well as on their functional coupling during recognition memory.	The COMT Val allele was associated with: relatively poorer performance at retrieval; reduced recruitment of neuronal resources in HF and increased recruitment in VLPFC during both encoding and retrieval; and unfavorable functional coupling between these two regions at retrieval. Moreover, functional coupling during retrieval was predictive of behavioral accuracy.	These results shed new light on individual differences in responsivity and connectivity between HF and VLPFC related to genetic modulation of dopamine, a mechanism accounting at least in part for individual differences in recognition memory performance.	
16949839	Previous fMRI studies have demonstrated preferential involvement of the perirhinal cortex and hippocampus in tasks of object and spatial memory, respectively. Here we investigated whether similar activity would also be present when object and spatial discrimination was assessed in the absence of explicit declarative memory demands. On each trial in the scanner, participants were presented simultaneously with two arrays of objects and were asked to indicate whether both arrays were identical, differed with respect to the identity of one object or differed with respect to the spatial arrangement of the objects. It was found that the detection of an object identity change was associated with significant right perirhinal cortex activity. We suggest that this perirhinal activity indicates a role of this structure in processes beyond declarative memory, for example, short-term visual working memory or higher order perception. Significantly greater hippocampal activity was not, however, observed during the spatial arrangement condition, perhaps due to the relatively low spatial processing demands of this task.
16943553	Learning-dependent increases in sleep spindle density have been reported during nocturnal sleep immediately after the learning session. Here, we investigated experience-dependent changes in daytime sleep EEG activity after declarative learning of unrelated word pairs. At weekly intervals, 13 young male volunteers spent three 24 h sessions in the laboratory under carefully controlled homeostatic and circadian conditions. At approximately midday, subjects performed either one of two word-pair learning tasks or a matched nonlearning control task, in a counterbalanced order. The two learning lists differed in the level of concreteness of the words used, resulting in an easier and a more difficult associative encoding condition, as confirmed by performance at immediate cued recall. Subjects were then allowed to sleep for 4 h; afterward, delayed cued recall was tested. Compared with the control condition, sleep EEG spectral activity in the low spindle frequency range and the density of low-frequency sleep spindles (11.25-13.75 Hz) were both significantly increased in the left frontal cortex after the difficult but not after the easy encoding condition. Furthermore, we found positive correlations between these EEG changes during sleep and changes in memory performance between pre-nap and post-nap recall sessions. These results indicate that, like during nocturnal sleep, daytime sleep EEG oscillations including spindle activity are modified after declarative learning of word pairs. Furthermore, we demonstrate here that the nature of the learning material is a determinant factor for sleep-related alterations after declarative learning.
16936940	Two major memory systems have been recognized over the years (Squire 1987): the declarative memory system, which is under the control of the hippocampus and related temporal lobe structures, and the procedural or habit memory system, which is under the control of the striatum and its connections. Most if not all learning tasks studied in animals, however, involve either the performance or the suppression of movement; this, if learned well, may be viewed as having become a habit. It is agreed that memory rules change from their first association to those that take place when the task is mastered. Does this change of rules involve a switch from one memory system to another? Here we will comment on: 1) reversal learning in the Morris water maze (MWM), in which the declarative or spatial component of a task is changed but the procedural component (to swim to safety) persists and needs to be re-linked with a different set of spatial cues; and 2) a series of observations on an inhibitory avoidance task that indicate that the brain systems involved change with further learning.
16936707	There is compelling evidence that intranasal administration of regular human insulin (RH-I) improves memory in humans. Owing to the reduced tendency of its molecules to form hexamers, the rapid-acting insulin analog insulin aspart (ASP-I) is more rapidly absorbed than RH-I after subcutaneous administration. Since after intranasal insulin administration, ASP-I may also be expected to access the brain, we examined whether intranasal ASP-I has stronger beneficial effects on declarative memory than RH-I in humans. Acute (40 IU) and long-term (4 x 40 IU/day over 8 weeks) effects of intranasally administered ASP-I, RH-I, and placebo on declarative memory (word lists) were assessed in 36 healthy men in a between-subject design. Plasma insulin and glucose levels were not affected. After 8 weeks of treatment, however, word list recall was improved compared to placebo in both the ASP-I (p<0.01) and the RH-I groups (p<0.05). ASP-I-treated subjects performed even better than those of the RH-I-treated group (p<0.05). Our results indicate that insulin-induced memory improvement can be enhanced by using ASP-I. This finding may be especially relevant for a potential clinical administration of intranasal insulin in the treatment of memory disorders like Alzheimer's disease.
16935408	Although the dualistic concept is unpopular among neuroscientists involved in experimental studies of the brain, neurophysiological literature is full of covert dualistic statements on the possibility of understanding neural mechanisms of human consciousness. Particularly, the covert dualistic attitude is exhibited in the unwillingness to discuss neural mechanisms of consciousness, leaving the problem of consciousness to psychologists and philosophers. This covert dualism seems to be rooted in the main paradigm of neuroscience that suggests that cognitive functions, such as language production and comprehension, face recognition, declarative memory, emotions, etc., are performed by neural networks consisting of simple elements. I argue that neural networks of any complexity consisting of neurons whose function is limited to the generation of electrical potentials and the transmission of signals to other neurons are hardly capable of producing human mental activity, including consciousness. Based on results obtained in physiological, morphological, clinical, and genetic studies of cognitive functions (mainly linguistic ones), I advocate the hypothesis that the performance of cognitive functions is based on complex cooperative activity of "complex" neurons that are carriers of "elementary cognition." The uniqueness of human cognitive functions, which has a genetic basis, is determined by the specificity of genes expressed by these "complex" neurons. The main goal of the review is to show that the identification of the genes implicated in cognitive functions and the understanding of a functional role of their products is a possible way to overcome covert dualism in neuroscience.
16934773	A recent increase in long-term sick leave (LTSL) in Sweden affects mostly women in the public sector. Depression-related diagnoses account for most of the increase, and work-related stress has been implicated.We examined dexamethasone/corticotropin-releasing hormone (dex/CRH) test responses, magnetic resonance imaging measures of prefrontocortical and hippocampal volumes, and cognitive performance in 29 female subjects fulfilling three core criteria: 1) LTSL > 90 days; 2) unipolar depression or maladaptive stress reaction with depressed mood; 3) job-related stress given as a reason for disability. This group was compared with 28 healthy matched controls.	The cortisol response to CRH differed markedly between the two groups (p = .002), with a dampened response in patients. This difference remained after removing subjects on antidepressant drugs (p = .006) or smokers (p = .003). Neither hippocampal nor prefrontocortical volumes differed. Performance on hippocampus-dependent declarative memory tests did not differ between groups, but the LTSL group had impaired working memory.	Our most salient finding is an attenuated dex-CRH response in patients on LTSL due to job-stress related depression. This is opposite to what has been described in major depression. It remains to be established whether this impairment is the end result of prolonged stress exposure, or a pre-existing susceptibility factor.	
16933659	The hallucinogenic "designer drug" known as Foxy or Methoxy Foxy and formally know as 5-Methoxy-N,N-di(iso)propyltryptamine hydrochloride (5-MeO-DIPT) is rapidly gaining popularity among recreational users. However, little is known about the consequences of its use on neuropsychological development or behavior. During one of two adolescent periods, the rats were given repeated injections of either saline or 5 mg/kg of 5-MeO-DIPT. Once the animals reached 80 days of age, they were trained and tested on a number of tasks designed to assess the effects of 5-MeO-DIPT, if any, on memory tasks with spatial components that presumably involve declarative memory systems and on a nonspatial task that is considered sensitive to disruptions in nondeclarative memory. With one exception, both the 5-MeO-DIPT- and saline-treated rats were able to master the spatial navigation tests at comparable rates. However, the performance of the drug-treated rats was markedly inferior to that of the control animals on a response-learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. This could indicate reductions in serotonin activity in the forebrain similar to the effects of studied drugs such as methylenedioxymethamphetamine (MDMA), suggesting 5-MeO-DIPT may act as a toxin compromising serotoninergic systems in the brain.
16931152	To investigate the impact of a short daytime nap on procedural and declarative memory consolidation.Following a normal night's sleep, 34 young healthy subjects were randomly assigned to a nap or wake condition of about 45min in the early afternoon after learning procedural and declarative memory tasks. Subjects were controlled for alertness and cortisol secretion.	The afternoon naps were dominated by sleep stage 2 but contained some slow wave sleep (SWS) and rapid eye movement (REM) sleep as well. Naps significantly improved procedural, but not declarative, memory. Females showed more improvement than males in the declarative memory tasks irrespective of nap or wake. There was no difference between groups with respect to cortisol secretion or alertness.	A short nap is favorable for consolidation of procedural memory. The possibly confounding effect of gender should always be considered in research on sleep and memory.	
16930754	Hypothesis generation has been regarded as one of the core reasoning processes in creative thinking and scientific discovery. To investigate changes in the amount of information transmission during scientific hypothesis generation, the averaged cross-mutual-information (A-CMI) of EEGs was estimated. Twenty-five 5th grade students were sampled in this study. EEG signals from 16 electrodes on each subject's scalp were recorded using a 32-channel EEG system. In order to generate hypotheses, the students were asked to observe 20 quail eggs that gave rise to questions such as: Why do different sizes and shapes of patterns appear on the surface of the eggs? After the observation, they were asked to generate a scientific hypothesis-a tentative causal explanation for the evoked question. The results of experimentation indicated several distinct brain activities during hypothesis generation interacting between different local brain regions. In addition, it was observed that the amount of information transmission during hypothesis generation increased in a large part of the brain region encompassing the temporal, parietal, and occipital cortexes, which implies the use of declarative and procedural memory systems. Furthermore, this study suggested the possibility that neuropsychological approaches may be potential tools to investigate the neuronal activity of EEGs during hypothesis generation.
16920614	How do brain systems support our subjective experience of recollection and our senses of familiarity and novelty? A new functional imaging study concludes that each of these functions is accomplished by a distinct component of the medial temporal lobe, shedding new light on the functional organization of this memory system.
16891588	On the basis of peripheral (nonbrain) neuroendocrine findings in subjects with posttraumatic stress disorder (PTSD), it has been hypothesized that these individuals also have a greater central (brain) sensitivity to glucocorticoids. In nonpsychiatric subjects, it has been found that working and declarative memory performance is selectively impaired by acute glucocorticoid administration. We hypothesized that subjects with PTSD, as compared to nonpsychiatric controls, would show greater impairments in verbal declarative memory and working memory, but not attention, following exogenous glucocorticoid administration. These data are part of a larger study using functional neuroimaging and peripheral HPA axis measures in these same subjects. Subjects underwent a 0.5-mg dexamethasone suppression test and measurement of basal cortisol, basal plasma lymphocyte glucocorticoid receptor number, and postdexamethasone cortisol on a separate day. Under double-blind randomized crossover conditions, 17-mg hydrocortisone or placebo was administered by intravenous (i.v.) bolus to 15 medication-free PTSD subjects (4 female) and 12 nonpsychiatric control subjects (4 female) matched by age, sex, and education level. Participants then underwent positron emission tomography (PET) scanning and 90 min after the initial drug/placebo administration, cognitive testing was then performed. By repeated measures ANCOVA (covaried for baseline performance on that neuropsychological test), neither attention tasks of digit span forward nor backward showed significant change. However, there were significant drug (F = 17.644, df = 1,25 P < 0.001), group (F = 4.383, df = 1,25 P = 0.048), and drug by group interactions (F = 4.756, df = 1,25 P = 0.040) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The subject group with PTSD experienced a greater decline in verbal declarative memory performance following hydrocortisone administration. For working memory, there were significant group (F = 6.048, df = 1,25 P = 0.022) and drug by group interactions (F = 6.048, df = 1,25 P = 0.022) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The hydrocortisone administration led to impairment in working memory in the group of subjects with PTSD, but not in the control subject group. Exploratory correlations between percent cortisol suppression following dexamethasone and baseline plasma lymphocyte glucocorticoid receptor number with declarative and working memory measures among subject groups separately and in a combined way revealed a negative correlation between lymphocyte glucocorticoid receptor density and working memory (r = -0.54, df = 25, P = 0.008). Brain sensitivity to glucocorticoids appears to be greater in subjects with PTSD. Heightened vulnerability of declarative memory in subjects with PTSD may indicate hippocampal involvement, whereas working memory vulnerability suggests additional brain regions (prefrontal, cingulate, temporal, and parietal cortices) and neurotransmitter systems (dopamine and serotonin) particularly sensitive to glucocorticoids in persons with PTSD.
16891587	Both reduced hippocampal volume and cognitive alterations have been found in posttraumatic stress disorder (PTSD). The purpose of this article was to examine the relationship between hippocampal volume, combat exposure, symptom severity, and memory performance in a sample of combat veterans with and without a history of PTSD. Subjects were 33 male veteran volunteers (16 PTSD+, 17 PTSD-) who underwent an MRI and neuropsychological testing with the California Verbal Learning Test (CVLT), a measure of declarative memory. Relationships between hippocampal volume (i.e., right + left hippocampal volume/whole brain volume) and performance on the CVLT were determined using partial correlational analysis controlled for age and Wechsler Adult Intelligence Scale, Third Edition (WAIS-III) vocabulary scores. Percent hippocampal volume for the entire sample was positively associated with several aspects of memory performance as reflected by the CVLT. In the PTSD+ group, CVLT performance was negatively correlated with lifetime, but not current CAPS symptoms. CVLT performance appears to be strongly correlated with hippocampal volume in a group of trauma survivors with and without PTSD. Insofar as CVLT performance in the PTSD group was negatively associated with worst episode, but not to current PTSD symptoms, memory performance in combat veterans may reflect some aspect of risk related to the magnitude of the psychological response to trauma, rather than current symptoms that may be interfering with cognitive performance. It will be of interest to study cognitive abilities that may relate to the likelihood of specific PTSD symptoms and to track changes in CVLT performance and hippocampal volume over time in persons with and without a history of trauma exposure.
16891562	Impaired declarative memory performance and smaller hippocampal volume have been observed in young and middle-aged adults with chronic posttraumatic stress disorder (PTSD). These alterations may put trauma survivors with PTSD at greater risk for cognitive decline in later life. This article focuses on the emerging literature on neuropsychological impairment in aging trauma survivors, in particular, elderly combat veterans and survivors of the Holocaust. In veterans and in Holocaust survivors, PTSD was associated with substantial impairments in learning, free and cued recall, and recognition memory compared to the respective nonexposed subjects; however, in neither group was PTSD associated with impaired retention or "rapid forgetting." Additionally, PTSD was not associated with smaller right or left hippocampal volume in either cohort. PTSD is associated with considerable cognitive burden with age. Longitudinal studies of older subjects are warranted to examine whether PTSD is associated with accelerated aging or progressive memory loss.
16890518	Interference is one of the most fundamental phenomena in memory research: acquiring new memories causes forgetting of other, related memories. A new study shows that sleep, interposed between learning episodes, can mitigate the extent to which new (post-sleep) learning interferes with recall of previously acquired knowledge.
16888743	It has been proposed that declarative memories can be dependent on both an episodic and a semantic memory system. While the semantic system deals with factual information devoid of reference to its acquisition, the episodic system, characterized by mental time travel, deals with the unique past experience in which an event took place. Episodic memory is characteristically hippocampus-dependent. Place cells are recorded from the hippocampus of rodents and their firing reflects many of the key characteristics of episodic memory. For example, they encode information about "what" happens "where," as well as temporal information. However, when these features are expressed during an animal's behavior, the neuronal activity could merely be categorizing the present situation and could therefore reflect semantic memory rather than episodic memory. We propose that mental time travel is the key feature of episodic memory and that it should take a form, in the awake animal, similar to the replay of behavioral patterns of activity that has been observed in hippocampus during sleep. Using tasks designed to evoke episodic memory, one should be able to see memory reactivation of behaviorally relevant sequences of activity in the awake animal while recording from hippocampus and other cortical structures.
16887790	Sex differences in declarative memory and visuospatial ability are robust in cross-sectional studies. The present longitudinal study examined whether sex differences in cognition were present over a 10-year period, and whether age modified the magnitude of sex differences. Tests assessing episodic and semantic memory, and visuospatial ability were administered to 625 nondemented adults (initially aged 35-80 years), participating in the population-based Betula study at two follow-up occasions. There was stability of sex differences across five age groups and over a 10-year period. Women performed at a higher level than men on episodic recall, face and verbal recognition, and semantic fluency, whereas men performed better than women on a task-assessing, visuospatial ability. Sex differences in cognitive functions are stable over a 10-year period and from 35 to 90 years of age.
16881254	The cortex constituting Broca's area does not exist in isolation. Rather, like other cortical regions, Broca's area is connected to other brain structures, which likely play closely related functional roles. This paper focuses on the basal ganglia, a set of subcortical structures that project through topographically organized "channels" via the thalamus to different frontal regions. It is hypothesized that the basal ganglia project to Broca's area. This circuitry is further posited to encompass at least two channels. One channel can be characterized as subserving procedural memory, while the other underlies the retrieval of knowledge from declarative memory. These hypotheses are supported by both anatomical and functional evidence. Implications and issues for further investigation are discussed.
16881079	The present review considers research on the hippocampus and related areas from humans and experimental animals and makes three main points. First, many of the anatomical details of the hippocampus and adjacent cortical areas in the parahippocampal region are conserved across mammals. Second, the functional role of these areas in declarative memory is also conserved across species. Third, an evolutionary approach will be key to understanding exactly how the local circuitry of the hippocampus and parahippocampal region supports declarative memory. To highlight the utility of this approach, a schematic model is described in which separate streams of spatial and nonspatial information converge on the hippocampus. By this view, a fundamental function of the mammalian hippocampus is to combine incoming information about spatial context from the postrhinal (parahippocampal in primates) cortex and medial entorhinal area with incoming information about nonspatial items from the perirhinal cortex and lateral entorhinal area. The underlying neurobiological computations that arise from local circuitry enable item-in-context memory and are proposed to be fundamental to many examples of declarative memory, including episodic memory in humans and spatial memory in experimental animals.
16876433	Heuristics of evolutionary biology (e.g., survival of the fittest) dictate that phylogenetically older processes are inherently more stable and resilient to disruption than younger processes. On the grounds that non-declarative behaviour emerged long before declarative behaviour, Reber (1992) argues that implicit (non-declarative) learning is supported by neural processes that are evolutionarily older than those supporting explicit learning. Reber suggested that implicit learning thus leads to performance that is more robust than explicit learning. Applying this evolutionary framework to motor performance, we examined whether implicit motor learning, relative to explicit motor learning, conferred motor output that was resilient to physiological fatigue and durable over time. In Part One of the study a fatigued state was induced by a double Wingate Anaerobic test protocol. Fatigue had no affect on performance of participants in the implicit condition; whereas, performance of participants in the explicit condition deteriorated significantly. In Part Two of the study a convenience sample of participants was recalled following a one-year hiatus. In both the implicit and the explicit condition retention of performance was seen and, contrary to the findings in Part One, so was resilience to fatigue. The resilient performance in the explicit condition after one year may have resulted from forgetting (the decay of declarative knowledge) or from consolidation of declarative knowledge as implicit memories. In either case, implicit processes were left to more effectively support motor performance.
16876140	A central cognitive function of sleep is to consolidate newly acquired memories for long-term storage. Here, we investigated whether the overnight consolidation of declarative memory in patients with chronic sleep disturbances is impaired, owing to less slow wave sleep (SWS) and an increased cortisol release.Polysomnographic recordings, serum cortisol concentrations, and overnight memory consolidation in 16 patients with primary insomnia were compared with those of 13 healthy control subjects.	Patients displayed distinctly less overnight consolidation of declarative memory (p < .05), which was significantly correlated with SWS in the control subjects (r = .69) but with rapid eye movement (REM) sleep in the patients (r = .56), who had a diminished amount of SWS (p < .05). Increased cortisol levels in the middle of the night were associated with impaired retrieval of declarative memory after sleep for both control subjects (r = -.52) and patients (r = -.46).	Primary insomnia is associated with a diminished sleep-related consolidation of declarative memory. Efficient overnight consolidation of declarative memory is associated with high amounts of SWS and low serum cortisol levels during the early part of the night. Where SWS is decreased, REM sleep might play a partly compensatory role in the consolidation of declarative memory.	
16868087	Different forms of learning and memory depend on functionally and anatomically separable neural circuits [Squire, L. R. (1992) Psychol. Rev. 99, 195-231]. Declarative memory relies on a medial temporal lobe system, whereas habit learning relies on the striatum [Cohen, N. J. & Eichenbaum, H. (1993) Memory, Amnesia, and the Hippocampal System (MIT Press, Cambridge, MA)]. How these systems are engaged to optimize learning and behavior is not clear. Here, we present results from functional neuroimaging showing that the presence of a demanding secondary task during learning modulates the degree to which subjects solve a problem using either declarative memory or habit learning. Dual-task conditions did not reduce accuracy but reduced the amount of declarative learning about the task. Medial temporal lobe activity was correlated with task performance and declarative knowledge after learning under single-task conditions, whereas performance was correlated with striatal activity after dual-task learning conditions. These results demonstrate a fundamental difference in these memory systems in their sensitivity to concurrent distraction. The results are consistent with the notion that declarative and habit learning compete to mediate task performance, and they suggest that the presence of distraction can bias this competition. These results have implications for learning in multitask situations, suggesting that, even if distraction does not decrease the overall level of learning, it can result in the acquisition of knowledge that can be applied less flexibly in new situations.
16855082	Prevailing theory holds that the medial temporal lobe (MTL) subserves declarative memory exclusively, whereas nondeclarative memory is independent of this brain region. Recent studies in patients with amnesia, however, have shown that performance on declarative memory tasks may not always be dependent on a single MTL memory system, instead highlighting the critical role of anatomically distinct structures in processing different stimulus types. In particular, the hippocampus has been implicated in spatial memory, whereas perirhinal cortex seems critical for object memory. To assess whether stimulus type would also be a key dimension in nondeclarative memory, patients with selective hippocampal lesions were tested on simple categorization and perceptual learning of faces and virtual reality scenes. The patients demonstrated preserved categorization and perceptual learning of faces but abnormal performance when the stimuli to be discriminated were virtual reality scenes. These findings imply that stimulus type may be a more critical predictor of performance on memory tasks (declarative and nondeclarative) than previously thought. They also suggest that reports of good nondeclarative memory after MTL damage may, in some cases, simply reflect the use of stimuli that fail to tap the processes dependent on structures in this region, such as spatial processing in the case of the hippocampus.
16845599	The functional significance of sleep spindles for overnight memory consolidation and general learning aptitude as well as the effect of four 10-minute sessions of spindle frequency (11.6-16 Hz, sigma) neurofeedback-training on subsequent sleep spindle activity and overnight performance change was investigated. Before sleep, subjects were trained on a paired-associate word list task after having received either neurofeedback training (NFT) or pseudofeedback training (PFT). Although NFT had no significant impact on subsequent spindle activity and behavioral outcomes, there was a trend for enhanced sigma band-power during NREM (stage 2 to 4) sleep after NFT as compared to PFT. Furthermore, a significant positive correlation between spindle activity during slow wave sleep (in the first night half) and overall memory performance was revealed. The results support the view that the considerable inter-individual variance in sleep spindle activity can at least be partly explained by differences in the ability to acquire new declarative information. We conclude that the short NFT before sleep was not sufficient to efficiently enhance phasic spindle activity and/or to influence memory processing. NFT was, however, successful in increasing sigma power, presumably because sigma NFT effects become more easily evident in actually trained frequency bands than in associated phasic spindle activity.
16843039	Almost all studies probing neural activity underlying the declarative memory system in humans have investigated either memory encoding or retrieval. Here, however, we suggest integrating encoding and retrieval operations into a single operation executed by the rhinal cortex. The more familiar an item is, the less rhinal processing it requires and the less vigorously it is encoded into memory. Given the anatomical position and the functional properties of the rhinal cortex, this operation fulfills an essential task: it optimally allocates limited encoding resources away from familiar information and towards novel information. We propose a rhinal processing stage that optimizes the declarative memory system by fully integrating encoding and retrieval operations into a single 'gatekeeper' operation.
16839780	The stress hormone cortisol is known to influence declarative memory and associative learning. In animals, stress has often been reported to have opposing effects on memory and learning in males and females. In humans, the effects of cortisol have mainly been studied at the behavioral level. The aim of the present experiment was to characterize the effects of a single cortisol dose (30 mg) on the hemodynamic correlates of fear conditioning. In a double-blind group comparison study subjects (17 females and 17 males) received 30 mg cortisol or placebo orally before participating in a discriminative fear conditioning paradigm. Results revealed that cortisol impaired electrodermal signs of learning (the first interval response) in males, while no conditioned SCRs emerged for the females independent of treatment. fMRI results showed that cortisol reduced activity for the CS+ > CS- comparison in the anterior cingulate, the lateral orbitofrontal cortex and the medial prefrontal cortex in males. Opposite findings (increase in these regions under cortisol) were detected in females. In addition, cortisol reduced the habituation in the CS+ > CS- contrast in the dorsolateral prefrontal cortex independent of sex. Finally, cortisol also modified the response to the electric shock (the UCS) by enhancing the activity of the anterior as well as the posterior cingulate. In sum, these findings demonstrate that in humans cortisol mostly influences prefrontal brain activation during fear conditioning and that these effects appear to be modulated by sex.
16837600	Although studies in animals and patients have demonstrated that brain oscillations play a role in declarative memory encoding and retrieval, little has been done to investigate the temporal dynamics and sources of brain activity in healthy human subjects performing such tasks. In a magnetoencephalography study using pictorial stimuli, we have now identified oscillatory activity in the gamma (60-90 Hz) and theta (4.5-8.5 Hz) band during declarative memory operations in healthy participants. Both theta and gamma activity was stronger for the later remembered compared with the later forgotten items (the "subsequent memory effect"). In the retrieval session, theta and gamma activity was stronger for recognized items compared with correctly rejected new items (the "old/new effect"). The gamma activity was also stronger for recognized compared with forgotten old items (the "recognition effect"). The effects in the theta band were observed over right parietotemporal areas, whereas the sources of the effects in the gamma band were identified in Brodmann area 18/19. We propose that the theta activity is directly engaged in mnemonic operations. The increase in neuronal synchronization in the gamma band in occipital areas may result in a stronger drive to subsequent areas, thus facilitating both memory encoding and retrieval. Alternatively, the gamma synchronization might reflect representations being reinforced by top-down activity from higher-level memory areas. Our results provide additional insight on human declarative memory operations and oscillatory brain activity that complements previous electrophysiological and brain imaging studies.
16835029	Aging adults are vulnerable to the effects of a negative emotional state. The relaxation response (RR) is a mind-body intervention that counteracts the harmful effects of stress. Previous studies with relaxation techniques have shown the non-pharmacological benefit of reducing stress and improving the memory of healthy older adults. Our pilot study evaluated whether a RR training program would decrease anxiety levels, improve attention, declarative memory performance and/or decrease salivary cortisol levels in healthy older adults. Fifteen adults participated and were randomly assigned to a RR training or control groups. Mean age was 71.3 years and mean education level was 17.9 years. Reaction time on a simple attention/psychomotor task was significantly improved (p<0.0025) with RR training, whereas there was no significant improvement on complex tasks of attention, verbal, or visual declarative memory tests. Self-reported state anxiety levels showed a marginally significant reduction (p<0.066). All subjects' salivary cortisol levels were within low-normal range and did not significantly change. Our 5-week program in highly educated, mobile, healthy, aging adults significantly improved performance on a simple attention task.
16824917	Mounting behavioral evidence in humans supports the claim that sleep leads to improvements in recently acquired, nondeclarative memories. Examples include motor-sequence learning; visual-discrimination learning; and perceptual learning of a synthetic language. In contrast, there are limited human data supporting a benefit of sleep for declarative (hippocampus-mediated) memory in humans (for review, see). This is particularly surprising given that animal models (e.g.,) and neuroimaging studies (e.g.,) predict that sleep facilitates hippocampus-based memory consolidation. We hypothesized that we could unmask the benefits of sleep by challenging the declarative memory system with competing information (interference). This is the first study to demonstrate that sleep protects declarative memories from subsequent associative interference, and it has important implications for understanding the neurobiology of memory consolidation.
16818862	Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a brain-derived neurotrophic factor (BDNF) prodomain single nucleotide polymorphism resulting in a valine (Val)-to-methionine (Met) substitution is associated with impaired declarative memory in healthy volunteers and patients with schizophrenia. These studies indicate that the BDNF(Met) variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. To our knowledge, the way in which this functional single nucleotide polymorphism affects other neurocognitive measures has not been examined. Its role in determining cognitive deficits in schizophrenia has also not been systematically studied.To characterize the neurocognitive and brain morphometric phenotypic correlates of the BDNF Val66Met polymorphism and to test the specificity of the BDNF(Met) variant on cognitive dysfunction in schizophrenia.	A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 patients with schizophrenia spectrum disorder at a tertiary care university hospital. Approximately two thirds of the sample also underwent high-resolution magnetic resonance imaging brain scans.	Genotype effects (in Met allele carriers vs Val homozygotes) on 5 cognitive domain z scores and magnetic resonance imaging gray matter brain volume measures (Talairach atlas-based cerebral lobes and optimized voxel-based morphometry) were examined using general linear models.	On verbal memory, there was a significant genotype effect but no genotype x diagnosis effects. In both patients with schizophrenia and healthy volunteers, Met allele carriers had poorer verbal memory performance than their Val-homozygous counterparts. On visuospatial abilities, there were significant genotype and genotype x diagnosis effects. Met allele-associated visuospatial impairment was specific to patients with schizophrenia but not healthy volunteers. There were significant genotype effects on gray matter volumes within brain regions known to subserve these 2 cognitive domains, with Met allele carriers having smaller temporal and occipital lobar gray matter volumes. Optimized voxel-based morphometry further suggests that parietal heteromodal cortical gray matter deficits may underlie visuospatial impairment in patients with schizophrenia carrying the Met allele.	We replicated the association between the BDNF(Met) variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that the BDNF(Met) variant may have a specific role in conferring visuospatial dysfunction in schizophrenia.	
16817877	Sleep fragmentation, a symptom in many clinical disorders, leads to cognitive impairments. To investigate the mechanisms by which sleep fragmentation results in memory impairments, rats were awakened once every 2 min via 30 s of slow movement on an automated treadmill. Within 1 h of this sleep interruption (SI) schedule, rats began to sleep in the 90-s periods without treadmill movement. Total non-rapid eye movement sleep (NREM) sleep time did not change over the 24 h of SI, although there was a significant decline in rapid eye movement sleep (REM) sleep and a corresponding increase in time spent awake. In the SI group, the mean duration of sleep episodes decreased and delta activity during periods of wake increased. Control rats either lived in the treadmill without movement (cage controls, CC), or had 10-min periods of movement followed by 30 min of non-movement allowing deep/continuous sleep (exercise controls, EC). EC did not differ from baseline in the total time spent in each vigilance state. Hippocampal long-term potentiation (LTP), a long-lasting change in synaptic efficacy thought to underlie declarative memory formation, was absent in rats exposed to 24 and 72 h SI. In contrast, LTP was normal in EC rats. However, long-term depression and paired-pulse facilitation were unaltered by 24 h SI. Twenty-four hour SI also impaired acquisition of spatial learning in the hippocampus-dependent water maze test. Twenty-four hour SI elevated plasma corticosterone (CORT) to levels previously shown to enhance LTP (125 ng/mL). The results suggest that sleep fragmentation negatively impacts spatial learning. Loss of N-methyl-D-aspartate (NMDA) receptor-dependent LTP in the hippocampal CA1 region may be one mechanism involved in this deficit.
16814819	Declarative memory impairment is a common long-term sequela of severe closed head injury (CHI). Although veridical memory performance following severe CHI has received attention in the literature, little is known about false memory production in this population. Within the present study, both long-term survivors of severe CHI and matched control participants studied and were tested on six 12-items word lists from the Deese Roediger McDermott (DRM) paradigm. Word lists from the DRM are composed of words that are strongly semantically associated to a non-presented word (i.e., the critical lure). Prior studies have shown that healthy young adults show a high level of false recall and recognition memory for the critical lures, and it was hypothesized individuals with severe CHI would show heightened susceptibility to false memory compared to control participants due to difficulty with monitoring of memory. It was further hypothesized that severe CHI participants would show high confidence in their false memories. Consistent with hypotheses, results indicated that although severe CHI participants remembered fewer actual list items, they made more semantically related intrusion errors (recall) and false-positive responses (recognition) than the control participants. Severe CHI participants also showed greater confidence in their false memories than did control participants. The results are interpreted in the context of theoretical accounts of false memory, and possible structural and functional brain changes that might account for the Severe CHI group's memory performance are discussed.
16805929	Verbal declarative memory is a core deficit in schizophrenia patients, seen to a lesser extent in unaffected biological relatives. Neuroimaging studies suggest volumetric differences and aberrant function in prefrontal and temporal regions in schizophrenia patients compared to controls. These deficits are also reflected in the small number of similar investigations in unaffected biological relatives. However, it is unclear the extent to which dysfunction is genetically mediated or a feature of the established illness.Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation in 68 biological relatives of schizophrenia patients (of whom 27 experienced transient or isolated psychotic symptoms) and 21 controls during verbal classification and recognition.	During word classification, the high-risk group showed a greater response relative to controls in the right inferior frontal gyrus. During correct recognition (relative to correct rejection), the high-risk group showed significantly greater response relative to controls in the right cerebellum. When the high-risk group was split into those with (HR+) and without (HR-) psychotic symptoms, the increased response in the right inferior frontal gyrus was only seen when the HR+ were compared to controls. The greater cerebellar response was seen when both HR groups were compared to controls.	Activation increases in the right inferior frontal gyrus and cerebellum in high-risk subjects compared to controls during a relatively low-load memory task are likely to represent compensation for genetically mediated abnormalities. This is consistent with a leftward shift of the inverted 'U' load-response model of cognitive function in schizophrenia.	
16788812	The ability to detect patterns and organize individual events into complex sequences is a fundamental cognitive skill that is often learned implicitly. The serial response time (SRT) task has been widely used to investigate implicit sequence learning, but it remains unclear whether people learn a perceptual or motor sequence in this task. This study reports three experiments that build on previous research by Goschke and colleagues using an auditory SRT task in which the stimulus-to-response mapping changes on every trial to eliminate spatio-motor sequencing. The current study extends earlier work in three ways. First, healthy young and older adults were tested rather than the neuropsychological patients used in previous research. Second, sequences of different structural complexity were investigated including first- and second-order repeating sequences as well as higher-order probabilistic sequences. Third, the potential role of explicit knowledge was examined using three separate tests of declarative knowledge. Results indicate that young and old adults are able to learn purely perceptual auditory sequences, but that explicit knowledge contributes to learning of repeating sequences by young adults.
16788772	The aim of this study was to examine possible cognitive changes throughout the early course of schizophrenia spectrum disorders.Forty-two patients, aged 15-50 years, admitted to a first episode psychosis program (PAFIP) serving to the community of Cantabria (Spain) and 43 healthy volunteers completed a brief battery of five neurocognitive tests at four time-points over 3 months. The cognitive testing comprise five domains: attention, visuomotor speed, declarative memory, working memory and executive function. Baseline assessment occurred within 72 hour after the initiation of standard pharmacological treatment, and after then parallel forms of the tests were applied at week-2, week-6, and month-3.	Patient scores showed a significant impairment compared to healthy volunteers in the five cognitive domains at baseline and week-2 assessments. After the first 3 months of antipsychotic treatment, the patient group performance reached healthy volunteers level on executive function (Stroop interference) and immediate verbal memory tests. In contrast, performance on working memory, sustained attention, visuomotor speed, and verbal memory delayed recall domains still remained below healthy volunteers, although visuomotor processing speed showed a significant improvement.	Schizophrenia spectrum patients show heterogeneous patterns and degrees of cognitive changes that contribute to stress the importance of when, what, and how neurocognitive functioning in the early phases of the illness is evaluated.	
16785436	The concept of amnestic mild cognitive impairment (MCI) describes older people who show a decline predominantly in memory function, but who do not meet criteria for dementia. Because such individuals are at high risk for developing Alzheimer's disease, they are of great interest for understanding the prodromal stages of the disease process. The mechanism underlying memory dysfunction in people with MCI is not fully understood. The present study uses quantitative, high-resolution structural MRI techniques to investigate, in vivo, the anatomical substrate of memory dysfunction associated with MCI. Changes in brain structures were assessed with two imaging techniques: (i) whole-brain, voxel-based morphometry to determine regions of reduced white matter volume and (ii) sensitive volumetric segmentation of the entorhinal cortex and hippocampus, gray matter regions that are critically important for memory function. In participants with amnestic MCI, compared with age-matched controls, results showed a significant decrease in white matter volume in the region of the parahippocampal gyrus that includes the perforant path. There was also significant atrophy in both the entorhinal cortex and the hippocampus. Regression models demonstrated that both hippocampal volume and parahippocampal white matter volume were significant predictors of declarative memory performance. These results suggest that, in addition to hippocampal atrophy, disruption of parahippocampal white matter fibers contributes to memory decline in elderly individuals with MCI by partially disconnecting the hippocampus from incoming sensory information.
16770797	Behavioral studies with amnesic patients and imaging studies with healthy adults have suggested that medial temporal lobe (MTL) structures known to be essential for long-term declarative memory (LTM) may also be involved in the maintenance of information in working memory (WM). To examine whether MTL structures are involved in WM maintenance for faces, and the nature of that involvement, WM and LTM for faces were examined in normal participants via functional magnetic resonance imaging (fMRI) and in amnesic patients behaviorally. In Experiment 1, participants were scanned while performing a WM task in which they determined if two novel faces, presented 7 s apart, were the same or different. Later, participants' LTM for the faces they saw during the WM task was measured in an unexpected recognition test. During WM maintenance, the hippocampus was activated bilaterally, and there was greater activation during maintenance for faces that were later remembered than faces later forgotten. A conjunction analysis revealed overlap in hippocampal activations across WM maintenance and LTM contrasts, which suggested that the same regions were recruited for WM maintenance and LTM encoding. In Experiment 2, amnesic and control participants were tested on similar WM and LTM tasks. Amnesic patients, as a group, had intact performance with a 1-s maintenance period, but were impaired after a 7-s WM maintenance period and on the LTM task. Thus, parallel neuroimaging and lesion designs suggest that the same hippocampal processes support WM maintenance, for intervals as short as 7 s, and LTM for faces.
16768378	High central nervous system levels of acetylcholine (ACh) are commonly regarded as crucial for learning and memory, and a decline in cholinergic neurotransmission is associated with Alzheimer's dementia. However, recent findings revealed exceptions to this rule: The low ACh tone characterizing slow wave sleep (SWS) has proven necessary for consolidation of hippocampus-dependent declarative memories during this sleep stage. Such observations, together with recent models of a hippocampal-neocortical dialogue underlying systems memory consolidation, suggest that high levels of ACh support memory encoding, whereas low levels facilitate consolidation. We tested this hypothesis in human subjects by blocking cholinergic neurotransmission during wakefulness, starting 30 min after learning. Subjects received the muscarinic antagonist scopolamine (4 microg/kg bodyweight intravenously) and the nicotinic antagonist mecamylamine (5 mg orally). Compared to placebo, combined muscarinic and nicotinic receptor blockade significantly improved consolidation of declarative memories tested 10 hr later, but simultaneously impaired acquisition of similar material. Consolidation of procedural memories, which are not dependent on hippocampal functioning, was unaffected. Neither scopolamine nor mecamylamine alone enhanced declarative memory consolidation. Our findings support the notion that ACh acts as a switch between modes of acquisition and consolidation. We propose that the natural shift in central nervous system cholinergic tone from high levels during wakefulness to minimal levels during SWS optimizes declarative memory consolidation during a period with no need for new memory encoding.
16767759	Recent developments in functional MRI (fMRI) technology with high spatial and temporal resolution have made it possible to noninvasively detect spontaneous low-frequency oscillations (SLOs) and quantify their functional synchrony in the human brain. In the present fMRI study the dynamic characteristics of the functional synchrony between SLOs were quantitatively determined by the phase shift index (PSI). With the use of an fMRI-guided voxel-selection method, the SLOs and their functional synchrony were found to be modulated by different memory tasks. The results demonstrate that SLOs in episodic memory-related circuitry have significantly higher synchrony during the performance of declarative memory-encoding activities compared to nondeclarative memory-encoding activities. It is suggested that the dynamic property of SLOs and the quantitative assessment of their functional synchrony could be utilized as a biomarker to noninvasively characterize localized pathophysiological functions in the human brain.
16741285	Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were examined in mice given post-training intrahippocampal injections of forskolin (FK) aiming at stimulating hippocampal adenylyl cyclases (ACs). The injection was given at different time points over a period of 9 h following acquisition in either an appetitive bar-pressing task or water-maze tasks challenging respectively "response memory" and "place memory." Retention testing (24 h) showed that FK injection altered memory formation only when given within a 3- to 6-h time window after acquisition but yielded opposite memory effects as a function of task demands. Retention of the spatial task was impaired, whereas retention of both the cued-response in the water maze and the rewarded bar-press response were improved. Intrahippocampal injections of FK produced an increase in pCREB immunoreactivity, which was strictly limited to the hippocampus and lasted less than 2 h, suggesting that early effects (0-2 h) of FK-induced cAMP/CREB activation can be distinguished from late effects (3-6 h). These results delineate a consolidation period during which specific cAMP levels in the hippocampus play a crucial role in enhancing memory processes mediated by other brain regions (e.g., dorsal or ventral striatum) while eliminating interference by the formation of hippocampus-dependent memory.
16741280	In recent years, the effect of sleep on memory consolidation has received considerable attention. In humans, these studies concentrated mainly on procedural types of memory, which are considered to be hippocampus-independent. Here, we show that sleep also has a persisting effect on hippocampus-dependent declarative memory. In two experiments, we examined high school students' ability to remember vocabulary. We show that declarative memory is enhanced when sleep follows within a few hours of learning, independent of time of day, and with equal amounts of interference during retention intervals. Sleep deprivation has a detrimental effect on memory, which was significant after a night of recovery sleep. Thus, fatigue accumulating during wake intervals could be ruled out as a confound.
16734950	Patients may present with cognitive impairment in the euthymic phase of affective disorder, but it is unclear whether the impairment is prevalent before onset of the illness. The aim of the present study was to examine the hypothesis that genetic liability to affective disorder is associated with cognitive impairment.In a cross-sectional high-risk case-control study, healthy monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (the control group/Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. Cognitive performance of 203 High-Risk and Low-Risk twins was compared.	Healthy twins discordant for unipolar disorder showed lower performance on almost all measures of cognitive function: selective and sustained attention, executive function, language processing and working and declarative memory, and also after adjustment for demographic variables, subclinical symptoms and minor psychopathology. Healthy twins discordant for bipolar disorder showed lower performance on tests measuring episodic and working memory, also after adjustment for the above-mentioned covariables. The discrete cognitive impairment found seemed to be related to genetic liability, as the MZ High-Risk twins showed significant impairment on selective and sustained attention, executive function, language processing and working and declarative memory, whereas the DZ High-Risk twins presented with significantly lower scores only on language processing and episodic memory.	The hypothesis that discrete cognitive impairment is present before the onset of the affective disorder and is genetically transmitted was supported. Thus, cognitive function may be a candidate endophenotype for affective disorders.	
16734498	This article reviews the literature on the long-term pharmacological treatment of post-traumatic stress disorder (PTSD). A PUBMED search was conducted; only studies on the effects of long-term (>14-weeks) pharmacological treatment for PTSD in adults or children were considered. Our search identified three randomised, double-blind, placebo-controlled studies (one each for sertraline, fluoxetine and risperidone), four open-label studies (one each for sertraline, paroxetine, nefazodone and valproate), one retrospective case series (clozapine) and one pooled analysis (sertraline). All studies involved adult populations, with the exception of the study of clozapine. The studies demonstrate that long-term treatment of PTSD with SSRIs effectively maintains the previous treatment response and improvement in quality of life, converts more patients to responder status and accounts for one-third of overall treatment gains. Greater PTSD severity predicts a longer time to response to these drugs. Discontinuation of SSRI treatment after 12 weeks results in a greater risk of relapse and symptom exacerbation compared with extended treatment. In addition to improved PTSD symptoms, extended treatment with paroxetine improves verbal declarative memory and increases hippocampal volume. Long-term treatment of PTSD with atypical antipsychotics (risperidone and clozapine), non-SSRI antidepressants (nefazodone) and antiepileptic drugs (AEDs; valproate) also appears to result in significant improvements in PTSD symptoms. In conclusion, long-term treatment of PTSD with SSRIs improves the psychiatric and clinical outcome of patients with the disorder and prevents relapse and symptom exacerbation. The effect of other agents (atypical antipsychotics, AEDs and other psychotropic medications) requires further controlled study.
16731215	To compare errorless learning with trial-and-error (T&E) learning of declarative facts in children with memory disorders secondary to traumatic brain injury (TBI).Retrospective within-subjects concurrent treatment design.	Participants' school or home.	Thirty-four children, ages 6 to 18 years, with mild, moderate, or severe postacute TBI who met criteria for memory impairment.	Conditions consisted of an errorless learning method and a T&E method. Within a session, half the items were taught with the errorless learning method and half with the T&E method. Each child received two 1-hour sessions a week for 7 weeks.	Relative effectiveness of errorless learning and T&E methods for (1) initial learning and (2) retention over time for learned items.	There was an advantage for T&E on initial learning. In children with mild, but not moderate or severe TBI, 2-day retention was better with the errorless learning technique; 7-day retention was better with errorless learning in young children with mild TBI. Seventy-seven-day retention revealed an advantage for errorless learning in younger children with severe TBI.	Findings did not support errorless learning as a generalized intervention for learning difficulties after TBI or identify specific age- or injury-severity groups that benefited from this technique.	
16714084	Recent evidence suggests that the sleep-dependent consolidation of declarative memories relies on the non-rapid eye movement (NREM) rather than the rapid eye movement (REM) phase of sleep. Moreover, a few studies both at the cellular and the behavioural levels have suggested the involvement of sleep spindles, the most synchronous oscillatory waveforms during NREM sleep stage 2, in this process. Our previous study showed that overnight verbal memory retention correlates with the total number of sleep spindles in left frontocentral areas, while spindling in other regions did not correlate with mnemonic retention. In the present study, we show that retention of visuospatial memories over a 24-h period correlates with the total number of sleep spindles detected over parietal regions during the intervening night-time sleep. This result provides further evidence for the association between sleep spindle activity and declarative memory consolidation, and suggests that visuospatial and verbal memory retention differ in the topographic distribution of the NREM spindle activity with which they are associated.
16714037	Posttraumatic stress disorder (PTSD) is thought to be characterized by dysfunctional memory processes, i.e., the automatic re-experiencing of the traumatic event and the inability to consciously recall facts about the traumatic event, as well as altered emotional processing of trauma-relevant cues. The present study examined the cerebral mechanisms underlying the cued recall of trauma-specific memories and the emotional processing of the presented cues in 16 PTSD patients, 15 trauma-exposed subjects without PTSD and 16 healthy controls. Subjects received questions about their specific trauma as well as other disastrous and neutral events while the electroencephalogram and heart rate were measured. The PTSD patients showed no impairment in trauma-specific declarative memory compared to non-PTSD subjects but had some deficits in general declarative memory as assessed by the Wechsler Memory Scale-Revised. Compared to healthy control subjects, PTSD patients displayed increased P300 and late positive complex amplitudes to trauma-specific questions, indicating enhanced emotional processing of these cues. In line with their behavioral performance, both trauma-exposed groups showed decreased terminal contingent negative variation amplitudes to trauma-specific questions over frontal electrodes reflecting altered memory retrieval. Within-group comparisons revealed that only the PTSD group but not the other groups showed a differentiation between trauma-specific and neutral questions with respect to the LPC, tCNV and P300. Concordantly with previous studies, PTSD patients showed elevated resting heart rate compared to the healthy controls. These findings are discussed in the context of current models of the role of declarative memory in the development and maintenance of PTSD.
16687511	There is increasing evidence to suggest that the hippocampus and perirhinal cortex may mediate processes beyond long-term declarative memory. We assessed patients with Alzheimer's disease (AD) or semantic dementia (SD) on a visual oddity judgment task that did not place an explicit demand on long-term memory and is known to be sensitive to hippocampal and perirhinal cortex lesions. Importantly, within the medial temporal lobe, AD is associated with predominant hippocampal atrophy, whereas SD patients have greater perirhinal cortex damage. The AD group was selectively impaired in oddity judgment for scenes, whereas the SD patients demonstrated a deficit in face oddity judgment only. This compelling double dissociation supports the idea that the hippocampus and perirhinal cortex may be critical for the processing of scenes and objects, respectively, in the domain of perception or very short-term working memory.
16687496	The importance of the hippocampus in declarative memory is limited to recently acquired memory, and remotely acquired memory is believed to be stored somewhere in the neocortex. However, it remains unknown how the memory network is reorganized from a hippocampus-dependent form into a neocortex-dependent one. We reported previously that the medial prefrontal cortex (mPFC) is important for this neocortex-dependent remote memory in rat trace eyeblink conditioning. Here, we investigate the involvement of NMDA receptors in the mPFC in this reorganization and determine the time window of their contribution using chronic infusion of an antagonist into the mPFC, specifically during the postlearning consolidation period. The rats with blockade of the mPFC NMDA receptors during the first 1 or 2 weeks after learning showed a marked impairment in memory retention measured 6 weeks after learning, but relearned normally with subsequent conditioning. In contrast, the same treatment had no effect if it was performed during the third to fourth weeks or during the first day just after learning. The specificity of NMDA receptor blockade was confirmed by the reduced long-term potentiation in the hippocampal-prefrontal pathway in these rats. These results suggest that successful establishment of remotely acquired memory requires activation of NMDA receptors in the mPFC during at least the initial week of the postlearning period. Such NMDA receptor-dependent processes may mediate the maturation of neocortical networks that underlies permanent memory storage and serve as a way to reorganize memory circuitry to the neocortex-dependent form.
16677713	A number of studies have reported evidence of cognitive deficits in euthymic bipolar patients. Qualitative reviews of the literature have indicated impairments in executive functions and declarative memory are most consistently reported. However, not all primary studies conducted to date have had sufficient power to detect statistically significant differences and there have been few attempts to quantify the magnitude of impairments. This review aims to combine data from available studies to identify the profile of neuropsychological deficits in euthymic bipolar patients and quantify their magnitude.Systematic literature review and meta-analysis.	Large effect sizes (d>or=0.8) were noted for aspects of executive function (category fluency, mental manipulation) and verbal learning. Medium effect sizes (0.5<or=d<0.8) were found for aspects of immediate and delayed verbal memory, abstraction and set-shifting, sustained attention, response inhibition, and psychomotor speed. Small effect sizes (0.2<or=d<0.5) were reported for verbal fluency by letter, immediate memory, and sustained attention.	Sufficient data were not available to investigate all domains. For example analyses did not include measures of visuospatial function.	Euthymic bipolar patients demonstrate relatively marked impairment in aspects of executive function and verbal memory. It is not yet clear whether these are two discrete areas of impairment or are related to one another. Future investigations should clarify the functional significance of deficits and indicate whether patients will benefit from ameliorative interventions.	
16675403	We examined anticipatory mechanisms of reward-motivated memory formation using event-related FMRI. In a monetary incentive encoding task, cues signaled high- or low-value reward for memorizing an upcoming scene. When tested 24 hr postscan, subjects were significantly more likely to remember scenes that followed cues for high-value rather than low-value reward. A monetary incentive delay task independently localized regions responsive to reward anticipation. In the encoding task, high-reward cues preceding remembered but not forgotten scenes activated the ventral tegmental area, nucleus accumbens, and hippocampus. Across subjects, greater activation in these regions predicted superior memory performance. Within subject, increased correlation between the hippocampus and ventral tegmental area was associated with enhanced long-term memory for the subsequent scene. These findings demonstrate that brain activation preceding stimulus encoding can predict declarative memory formation. The findings are consistent with the hypothesis that reward motivation promotes memory formation via dopamine release in the hippocampus prior to learning.
16647579	Sleep may positively influence declarative memory through the processing, which transforms items of declarative knowledge into contents of mental sleep experience (MSE). A prediction from this general hypothesis is that the consolidation level should be higher for the output of items repeatedly processed and transformed into identical or very similar (so-called interrelated) contents of distinct MSEs of the same night rather than for the output of items presumably processed once (that is, all other, non-interrelated contents). Two experiments examined whether and how far the frequency and long-term retention of interrelated contents depend on the repeated processing of given items rather than on the experimental procedure applied for detection of interrelated contents. This procedure entails both multiple awakenings and a verbal report of MSE after awakening. Multiple awakenings could facilitate the re-access and elaboration of some contents into the subsequent (i.e. contiguous) MSE rather than non-contiguous MSEs; verbal reports could enhance the delayed recall of interrelated contents in as much as repeatedly encoded. The first experiment showed that interrelated contents were more frequent and better retained than both non-interrelated and pseudo-interrelated (i.e. by-chance similar or identical) contents, and even more in pairs of contiguous than non-contiguous MSEs collected from the first four periods of REM sleep on each experimental night. The second experiment showed that the frequency and retention rate of interrelated contents, while higher than those of non-interrelated and pseudo-interrelated contents, were not significantly different in pairs of MSEs which were verbally or mentally recalled after awakening provoked during the first four periods of REM sleep in each experimental night. Taken together, these findings indicate that the advantage provided by repeated processing during REM sleep for the consolidation of the output of items of declarative knowledge is conspicuous and largely independent from the experimental procedure, as this only slightly enhances the frequency and retention rate of interrelated contents.
16647282	The specialized role that sleep-specific brain physiology plays in memory processing is being rapidly clarified with a greater understanding of the dynamic, complex, and exquisitely orchestrated brain state that emerges during sleep. Behaviorally, the facilitative role of non-REM (NREM) sleep (primarily slow wave sleep) for declarative but not procedural memory performance in humans has been demonstrated in a number of nocturnal sleep studies. However, subjects in these studies were tested after periods of sleep that contained REM sleep in addition to NREM sleep, and comparison wake groups were subjected to mild sleep deprivation. To add some clarity to the findings of these nocturnal studies, we assessed performance on declarative and procedural memory tasks following a daytime training-retest interval containing either a short nap that included NREM without REM sleep, or wakefulness. Consistent with previous findings we show that, after a comparatively brief sleep episode, subjects that take a nap improve more on a declarative memory task than subjects that stay awake, but that improvement on a procedural memory task is the same regardless of whether subjects take a nap or remain awake. Slow wave sleep was the only sleep parameter to correlate positively with declarative memory improvement. These findings are discussed with reference to the general benefits of napping and within the broader context of a growing literature suggesting a role for NREM-specific physiology for the processing of declarative memory.
16631256	Unipolar and bipolar depression are known to exert detrimental effects on learning and memory processes. However, few comparisons have been undertaken between bipolar and unipolar patients with comparable illness histories, and predictors of impairment are not well understood. Adult outpatients with unipolar major depressive illness (UP, n = 30) and bipolar disorder (BP, n = 30), group-matched for illness duration and severity of depressive symptomatology (16% clinically remitted, 42% partially remitted, 42% depressed), and 30 demographically matched controls completed measures of general cognitive functioning and declarative memory. Despite comparable general intellectual abilities, BP and UP patients exhibited significant memory deficits relative to healthy controls. A similar deficit profile was observed in both patient groups, involving poorer verbal recall and recognition. Impairments were not secondary to strategic processing deficits or rapid forgetting. Although depression severity was not associated with neurocognitive performance, number of hospitalizations and family history of mood disorder significantly affected memory function in BP, but not UP, patients. Results suggest qualitatively similar patterns of memory impairment in BP and UP patients, consistent with a primary encoding deficit. These impairments do not appear to be secondary to clinical state, but rather suggest a similar underlying pathophysiology involving medial temporal dysfunction.
16621327	In the search for the mechanisms that mediate the effects of sleep on the consolidation of memories, growth hormone (GH) recently became of interest, because in humans it is released mainly during slow-wave sleep (SWS), a period of enhanced declarative memory consolidation. In addition, recent studies showed that GH is involved in proper memory function in GH deficient and elderly humans and this effect has been linked to regulatory influences of GH on hippocampal NMDA receptors. Here, we blocked GH secretion by intravenous infusion of somatostatin in healthy young subjects during the first 3 h of sleep, which contain mainly SWS. Declarative and procedural memory consolidation was tested across this period, using a word pair association task and a mirror tracing task, respectively. Although GH was effectively suppressed, memory performance as well as sleep were entirely unaffected by this suppression. Whereas GH may in the long run generally support brain systems required for maintaining proper memory function, our data exclude a necessary contribution of the nocturnal surge in pituitary GH secretion to the acute processing and formation of specific memories during sleep.
16573587	Relative to the characteristically profound deficits of explicit memory, components of implicit memory remain largely intact in patients with alcohol-induced Korsakoff syndrome (KS). Perceptual priming occurs in KS and transfer of learning has been consistently observed on mirror reading, a perceptual reversal task. Although priming also occurs with fragmented pictures, a perceptual closure task, it is unclear whether transfer of learning can occur. This study examined visuoperceptual learning in 4 men with alcoholic KS, 9 recently detoxified alcoholic men (ALC), 21 healthy age-matched normal control men (NC), and 6 young normal control men (YNC). Subjects were tested with the Gollin Incomplete Pictures Test at initial and 1-hour and 1-day retest sessions. Both alcoholic groups (KS, ALC) were impaired in visuoperceptual ability. All subject groups showed visuoperceptual learning. The KS group showed additional learning after continued exposure to the stimuli, despite their nonmnemonic visuospatial deficits and profound explicit memory impairment for the test stimuli. Transfer of learning to similar but new stimuli was not evident in either the KS or young healthy control subjects; learning occurred only for the specific items presented. The persistence of learning beyond the life of the percept, which was independent of declarative features (such as item recall), suggests that perceptual learning and memory reflects an intact cognitive memory process in KS. This process is likely mediated by posterior cortical networks relatively unaffected in KS and that are independent of the hippocampal-diencephalic declarative memory system.
16564752	Aerial respiratory in Lymnaea is driven by a three-neuron CPG whose sufficiency and necessity has been directly demonstrated. While this CPG is 'hard-wired' it displays a tremendous amount of plasticity. That is, it is possible by employing specific training procedures to alter how it functions in a specific hypoxic environment. Thus, it is possible to study directly the causal mechanisms of long-term memory formation, forgetting, and modulation of the memory at a single cell level. Thus, it is possible to use a relatively simple three-neuron CPG to study not only important questions concerning regulation of important homeostatic mechanisms but to also use it to study how learning and non-declarative memory are mediated at a cellular level.
16564189	At a time when several studies have highlighted the relationship between sleep, learning and memory processes, an in-depth analysis of the effects of sleep deprivation on student learning ability and academic performance would appear to be essential. Most studies have been naturalistic correlative investigations, where sleep schedules were correlated with school and academic achievement. Nonetheless, some authors were able to actively manipulate sleep in order to observe neurocognitive and behavioral consequences, such as learning, memory capacity and school performance. The findings strongly suggest that: (a) students of different education levels (from school to university) are chronically sleep deprived or suffer from poor sleep quality and consequent daytime sleepiness; (b) sleep quality and quantity are closely related to student learning capacity and academic performance; (c) sleep loss is frequently associated with poor declarative and procedural learning in students; (d) studies in which sleep was actively restricted or optimized showed, respectively, a worsening and an improvement in neurocognitive and academic performance. These results may been related to the specific involvement of the prefrontal cortex (PFC) in vulnerability to sleep loss. Most methodological limitations are discussed and some future research goals are suggested.
16545463	Cognitive functions not only depend on the localization of neural activity, but also on the precise temporal pattern of activity in neural assemblies. Synchronization of action potential discharges provides a link between large-scale EEG recordings and cellular plasticity mechanisms. Here, we focus on the role of neuronal synchronization in different frequency domains for the subsequent stages of memory formation. Recent EEG studies suggest that synchronized neural activity in the gamma frequency range (around 30-100 Hz) plays a functional role for the formation of declarative long-term memories in humans. On the cellular level, gamma synchronization between hippocampal and parahippocampal regions may induce LTP in the CA3 region of the hippocampus. In order to encode spatial locations or sequences of multiple items and to guarantee a defined temporal order of memory processing, synchronization in the gamma frequency range has to be accompanied by a stimulus-locked phase reset of ongoing theta oscillations. Simultaneous gamma- and theta-dependent plasticity leads to complex learning rules required for realistic declarative memory formation. Subsequently, consolidation of declarative memories may occur via replay of newly acquired patterns in so-called sharp wave-ripple complexes, predominantly during slow-wave sleep. These irregular bursts induce longer lasting forms of synaptic plasticity in output regions of the hippocampus and in the neocortex. In summary, synchronization of neural assemblies in different frequency ranges induces specific forms of cellular plasticity during subsequent stages of memory formation.
16543129	The ability to distinguish novel from familiar stimuli allows nervous systems to rapidly encode significant events following even a single exposure to a stimulus. This detection of novelty is necessary for many types of learning. Neurons in the medial temporal lobe (MTL) are critically involved in the acquisition of long-term declarative memories. During a learning task, we recorded from individual MTL neurons in vivo using microwire electrodes implanted in human epilepsy surgery patients. We report here the discovery of two classes of neurons in the hippocampus and amygdala that exhibit single-trial learning: novelty and familiarity detectors, which show a selective increase in firing for new and old stimuli, respectively. The neurons retain memory for the stimulus for 24 hr. Thus, neurons in the MTL contain information sufficient for reliable novelty-familiarity discrimination and also show rapid plasticity as a result of single-trial learning.
16542180	The notion that sufferers of bipolar disorder achieve complete syndromal and functional recovery between illness episodes has been brought into question by evidence that a large proportion of patients fail to regain premorbid levels of functioning after the resolution of major affective symptoms. A growing body of evidence suggests that bipolar patients exhibit neuropsychological impairment that persists even during the euthymic state, which may be a contributory factor to poor psychosocial outcome. However, the aetiology of such impairment and its relation to progression of illness are not well understood. This review aims to consider evidence from studies investigating both the relationship between cognitive impairment and clinical outcome and studies of neurocognitive function in unaffected first-degree relatives (FDRs) of bipolar sufferers to address issues of the temporal evolution of cognitive impairment in bipolar disorder.Systematic literature review.	The weight of evidence suggests that greater neuropsychological dysfunction in bipolar disorder is associated with a worse prior course of illness, particularly the number of manic episodes, hospitalizations and length of illness. The most consistent finding was a negative relationship between the number of manic episodes and verbal declarative memory performance. Impairment in unaffected FDRs was reported in verbal declarative memory and some facets of executive function.	Cognitive impairment may be a trait vulnerability factor for bipolar disorder that is present before illness onset and worsens as the illness progresses. Further investigation into the causal relationship between cognitive impairment and illness course is essential.	
16539720	This quasi-experimental study was designed to assess two important learning types - procedural and declarative--in children and adolescents affected by posterior fossa tumours (astrocytoma vs. medulloblastoma), given that memory has an important impact on the child's academic achievement and personal development.We had three groups: two clinical (eighteen subjects) and one control (twelve subjects). The learning types in these groups were assessed by two experimental tasks evaluating procedural-implicit and declarative memory. A Serial Reaction-Time Task was used to measure procedural sequence learning, and the Spanish version 1 of the California Verbal Learning Test-Children's Version- CVLT- 2 to measure declarative-explicit learning. The learning capacity was assessed considering only the blocks that represent learning, and were compared with MANOVA in clinical and normal subjects. The Raven, simple reaction-time, finger-tapping test, and grooved pegboard tests were used to assess the overall functioning of subjects. The results were compared with those from a control group of the same age, and with Spanish norm-referenced tools where available.	The results indicate the absence of procedural-implicit learning in both clinical groups, whereas declarative-explicit learning is maintained in both groups.	The clinical groups showed a conservation of declarative learning and a clear impairment of procedural learning. The results support the role of the cerebellum in the early phase of procedural learning.	
16525800	Using a declarative memory paradigm, the anatomical correlates of spatial location encoding and retrieval in the healthy human brain as reflected by BOLD fMRI were investigated. During encoding, subjects were instructed to view and keep in mind different locations of an object on a platform seen from different viewpoints in virtual 3D. In retrieval trials, subjects had to recognize previously learned object locations. Comparing activation patterns associated with encoding and recognition on a voxel-by-voxel basis, we found regions in the precuneus bilaterally activated by both processes. To our knowledge, this is the first study that directly compared human brain activation patterns associated with allocentric encoding and retrieval of spatial locations in virtual 3D. Our results provide further information concerning the role of the precuneus in declarative memory processes, pointing to precuneus involvement in encoding and retrieval of spatial locations.
16510225	We report five cases with caudate infarction due to Heubner's recurring artery occlusion, in which we conducted detailed memory examinations in terms of explicit memory and implicit memory. We performed the auditory verbal learning test as explicit memory tasks, and motor and cognitive procedural memory tasks, developed by Komori, as implicit memory tasks. Comparing normal control subjects with patients with left caudate infarction due to Heubner's recurring artery occlusion demonstrated lower scores on both declarative and motor procedural memory tasks. These results suggest that the left caudate nucleus may be related with both declarative memory and procedural memory.
16483453	Psychological and pharmacological studies in humans suggest that emotional arousal enhances long-term memory. In this paper we used, in an Italian sample, an adaptation of a paradigm previously utilized in American samples to study the relationship between emotion and long-term memory. Seventy-two healthy adults from different educational backgrounds were randomly assigned either to a neutral group or to an emotional arousal group and then told a short story, presented audio-visually. In both groups, the slides shown and the slide sequence were the same, and the images were accompanied by a narrative. The two versions of the story differed primarily in their emotional content. Shortly after viewing the slide presentation, the participants were asked to rate the emotionality of the narrative, and ten days later were submitted to a retention test. The emotionally-arousing version of the story was rated as more emotional than the neutral one. Compared with the members of the neutral group, the subjects in the arousal group recalled a significantly higher number of elements from the story. There was no overall difference between the two groups in performance on the recognition memory test. These results confirm that the emotional content of stimuli enhances long-term declarative memory of those stimuli, and indicate the possible usefulness of applying the paradigm utilized in this study to different clinical samples from various cultural backgrounds.
16469525	The traditional theory of the medial temporal lobe (MTL) memory system asserts that the primate MTL (hippocampus, perirhinal, entorhinal and parahippocampal cortices) is exclusively involved in consolidating declarative memories. However, several recent reports have directly challenged this dogma by arguing that MTL structures also contribute to perception. Controversy remains as many of the behavioural tasks used have confounded memory with perception. We review the evidence here and highlight new studies in humans and macaques that indicate a perceptual role for MTL in the absence of such confounds. We argue that the challenge to MTL memory system theory is substantiated and that the implications are considerable, namely that most psychologists and neuroscientists have held a fundamentally flawed view of how memory is implemented in the brain.
16462609	Declarative memories are thought to be initially stored in the hippocampus, and then transferred to the neocortex. This is a key feature of the standard model of consolidation and is supported by studies reporting a requirement for activity within the neocortex for recall of remote, but not recent, hippocampal-dependent memories. New evidence from our and other laboratories, however, suggests that, for trace fear conditioning, memories are stored in the rodent medial prefrontal cortex and in the hippocampus from the time of training. Consistent with this, we show that activity in the medial prefrontal cortex is necessary for retrieval of recent and remote memories, suggesting that information stored in this neocortical structure from the time of training is necessary for memory recall.
16458545	Corticosteroids are essential for life and an integral part of the stress response. However, in excess, corticosteroids can be associated with a variety of effects on the brain including hippocampal atrophy and even neuronal death, mood changes, and declarative memory impairment. The magnitude of mood change in patients receiving prednisone is reportedly associated with previous lifetime corticosteroid exposure, consistent with a sensitization or kindling process whereby greater effects are observed with repeated exposure. To our knowledge, the effect of multiple corticosteroid exposures on mood and memory has not been previously examined prospectively in animals or humans. In this study, 30 human volunteers, with no history of systemic prescription corticosteroid therapy, were given (in random order using a crossover design) two 3-day exposures of prednisone (60 mg/day) and one of identical placebo, with 11-day washouts between each medication exposure. Before and after each 3-day prednisone/placebo exposure, declarative memory was assessed using different versions of the Rey Auditory Verbal Learning Test (RAVLT) to minimize practice or learning effects, while mood was assessed with the 21-item Hamilton Rating Scale for Depression, Young Mania Rating Scale and Internal State Scale. No significant mood changes were found. However, a significant decrease in aspects of RAVLT performance was observed after the first prednisone exposure consistent with a decline in declarative memory performance. The decline in RAVLT performance was significantly smaller after the second prednisone exposure as compared to the initial prednisone exposure. Thus, a second prednisone exposure was associated with an attenuated prednisone-effect on declarative memory. These data suggest tolerance or habituation, rather than sensitization, to prednisone effects on declarative memory during a second exposure. Implications and possible explanations for the findings are discussed.
16449407	To investigate the association of reaction time and brief measures of memory and spatial ability with all-cause mortality.Participants were from the UK Health and Lifestyle Survey (HALS), a national sample survey of adults in England, Scotland, and Wales. In 1984/1985, data on lifestyle factors, socioeconomic status, and health were collected for 9,003 people. Cognitive data were collected for 7,414 individuals. All-cause mortality was investigated over 19 years of follow-up in relation to simple and choice reaction time, performance on a short-term verbal declarative memory test, and on a test of visual-spatial reasoning.	Slower and more variable simple and choice reaction times were significantly related to increased risk of all-cause mortality over 19 years of follow-up. The increased risk of all-cause mortality was partly attenuated after adjustments for socioeconomic status, health behaviors, and health status. A novel finding was the existence of an effect of reaction time on all-cause mortality in young adults. Poorer verbal memory ability was also significantly related to an increased risk of dying in young adults independently of reaction time score.	Slower and more variable reaction time was related to higher mortality risk in younger as well as older participants. Among younger adults, higher memory ability was also associated with lower risk of dying. The cognition-mortality relationship may be explained in part by the brain's efficiency of information processing and memory performance.	
16445392	Women are better than men at verbal memory tasks, such as remembering word lists. These tasks depend on declarative memory. The declarative/procedural model of language, which posits that the lexicon of stored words is part of declarative memory, while grammatical composition of complex forms depends on procedural memory, predicts a female superiority in aspects of lexical memory. Other neurocognitive models of language have not made this prediction. Here we examine the prediction in past-tense over-regularizations (e.g. holded) produced by children. We expected that girls would remember irregular past-tense forms (held) better than boys, and thus would over-regularize less. To our surprise, girls over-regularized far more than boys. We investigated potential explanations for this sex difference. Analyses showed that in girls but not boys, over-regularization rates correlated with measures of the number of similar-sounding regulars (folded, molded). This sex difference in phonological neighborhood effects is taken to suggest that girls tend to produce over-regularizations in associative lexical memory, generalizing over stored neighboring regulars, while boys are more likely to depend upon rule-governed affixation (hold+-ed). The finding is consistent with the hypothesis that, likely due to their superior lexical abilities, females tend to retrieve from memory complex forms (walked) that men generally compose with the grammatical system (walk+-ed). The results suggest that sex may be an important factor in the acquisition and computation of language.
16443292	Several studies suggest that emotional arousal can promote memory storage. In this study, we evaluated the effects of emotional content on declarative memory, utilizing an adaptation of two versions of the same story, with different arousing properties (neutral or emotional), which have been already employed in experiments involving the enhancing effects of emotions on memory retention. We used event related potentials (ERP) to evaluate whether there is a sex-related hemispheric lateralization of electrical potentials elicited by the emotional content of a story. We compared left and right hemisphere P300 waves, recorded in P3 and P4 electrode sites, in response to emotional or neutral stimuli in men and women. In the left hemisphere, emotional stimuli elicited a stronger P300 in women, compared to men, as indexed by both amplitude and latency measures; moreover, the emotional content of the story elicited a stronger P300 in the right hemisphere in men than in women. The better memory for the arousal material may be related to the differential P300 at encoding. These data indicate that both sex and cerebral hemisphere constitute important, interacting influences on neural correlates of emotion, and of emotionally influenced memory.
16439848	Growth hormone (GH) and insulin-like growth factor I (IGF-I) are expressed in specific regions of the central nervous system during early human development. They may consequently influence aspects of cognition, or emotional and behavioural adjustment from childhood to adulthood, in conditions associated with abnormalities of the somatotropic axis. GH receptors are relatively common within hippocampal and perihippocampal regions that are primarily involved in declarative memory for facts and events. They are also located in structures (e.g. the putamen) that are involved in the processing of social perceptions. IGF-I receptors have been discovered in the amygdala and prefrontal cortex, which contribute to the neural circuits known as the 'social brain'. The evaluation of emotional, social and behavioural adjustment among children who have deficiencies in GH or IGF-I functional integrity requires the objective assessment of their social-cognitive competence. We describe a computerized test battery, the Schedules for the Assessment of Social Intelligence (SASI), which has been shown to possess excellent psychometric properties in terms of reliability and validity. The SASI, which can be used by both children and adults, may provide new evidence for deficits and treatment effects of GH/IGF-I on emotional, behavioural and cognitive functions.
16421310	The hippocampus is necessary for declarative memory in humans and episodic memory in rodents. Considerable current research is focused on the role of plasticity within specific subfields of the hippocampus. Here, using a viral vector to temporally control a focal deletion of the NR1 gene, we show that learning novel paired associations between specific cues and their context is dependent on CA3 NMDA receptors. Deletion of CA3 NR1 genes in <30% of the dorsal hippocampus was sufficient to disrupt new learning, whereas the same treatment does not prevent expression of previously acquired paired associates and does not affect the ability to discriminate contexts or paired associate learning when either the cues or the context is familiar. The findings suggest that CA3 NMDA receptors specifically support the encoding of new experiences to involve incidental and contingent associations.
16413066	Pavlovian delay conditioning, in which a conditioned stimulus (CS) and unconditioned stimulus (US) co-terminate, is thought to reflect non-declarative memory. In contrast, trace conditioning, in which the CS and US are temporally separate, is thought to reflect declarative memory. Hippocampal lesions impair acquisition and expression of trace conditioning measured by the conditioned freezing and eyeblink responses, while having little effect on the acquisition of delay conditioning. Recent evidence suggests that lesions of the ventral hippocampus (VH) impair conditioned fear under conditions in which dorsal hippocampal (DH) lesions have little effect. In the present study, we examined the time-course of fear expression after delay and trace conditioning using the fear-potentiated startle (FPS) reflex, and the effects of pre- and post-training lesions to the VH and DH on trace-conditioned FPS. We found that both delay- and trace-conditioned rats displayed significant FPS near the end of the CS relative to the unpaired control group. In contrast, trace-conditioned rats displayed significant FPS throughout the duration of the trace interval, whereas FPS decayed rapidly to baseline after CS offset in delay-conditioned rats. In experiment 2, both DH and VH lesions were found to significantly reduce the overall magnitude of FPS compared to the control group, however, no differences were found between the DH and VH groups. These findings support a role for both the DH and VH in trace fear conditioning, and suggest that the greater effect of VH lesions on conditioned fear might be specific to certain measures of fear.
16411985	Basal levels of glucocorticoids, such as cortisol, are generally unaltered in bipolar disorder. However, neuroendocrine tests of glucocorticoid receptor (GR) function such as the dexamethasone suppression test (DST) are frequently abnormal. Neuropsychological impairment is well documented in healthy volunteers after administration of glucocorticoids and in patients with bipolar affective disorder. This suggests a potential link between neuropsychological and hypothalamic-pituitary-adrenal axis function. We examined the hypothesis that neuropsychological impairment in bipolar disorder is associated with abnormal GR function.Seventeen euthymic bipolar patients and 16 controls completed tests of verbal declarative and working memory (WM) tests and the DST. The correlation between neuroendocrine and neuropsychological function was examined.	Bipolar patients made significantly more errors of omission and commission on the WM paradigm and demonstrated impaired verbal recognition memory. Patients' post-dexamethasone cortisol correlated with WM commission errors (r(s) = 0.64, p = 0.0006). No such relationship was evident in controls.	Deficits in declarative memory and WM are evident in patients with bipolar disorder. The deficit in retrieval accuracy from WM appears to be correlated with abnormal GR function.	
16407110	Retrieval of recently acquired declarative memories depends on the hippocampus, but with time, retrieval is increasingly sustainable by neocortical representations alone. This process has been conceptualized as system-level consolidation. Using functional magnetic resonance imaging, we assessed over the course of three months how consolidation affects the neural correlates of memory retrieval. The duration of slow-wave sleep during a nap/rest period after the initial study session and before the first scan session on day 1 correlated positively with recognition memory performance for items studied before the nap and negatively with hippocampal activity associated with correct confident recognition. Over the course of the entire study, hippocampal activity for correct confident recognition continued to decrease, whereas activity in a ventral medial prefrontal region increased. These findings, together with data obtained in rodents, may prompt a revision of classical consolidation theory, incorporating a transfer of putative linking nodes from hippocampal to prelimbic prefrontal areas.
16406249	The hippocampus has been shown to be abnormal in schizophrenia. The fornix is one of the main fiber tracts connecting the hippocampus with other brain regions. Few studies have evaluated the fornix in schizophrenia, however. A focus on fornix abnormalities and their association with hippocampal abnormalities might figure importantly in our understanding of the pathophysiology of schizophrenia.Line-scan diffusion tensor imaging (DTI) was used to evaluate diffusion in the fornix in 24 male patients with chronic schizophrenia and 31 male control subjects. Maps of fractional anisotropy (FA) and mean diffusivity (D(m)), which are indices sensitive to white-matter integrity, were generated to quantify diffusion within the fornix. We used high spatial resolution magnetic resonance imaging (MRI) to measure hippocampal volume.	FA and cross-sectional area of the fornix were significantly reduced in patients compared with control subjects. D(m) was significantly increased, whereas hippocampal volume was bilaterally reduced in patients. Reduced hippocampal volume was correlated with increased mean D(m) and reduced cross-sectional area of the fornix for patients. Patients also showed a significant correlation between reduced scores on neuropsychologic measures of declarative-episodic memory and reduced hippocampal volumes.	These findings demonstrate a disruption in fornix integrity in patients with schizophrenia.	
16403181	Few magnetic resonance imaging (MRI) studies of bipolar disorder (BPD) have investigated the entire cerebral cortex. Cortical gray matter (GM) volume deficits have been reported in some studies of adults with BPD; this study assessed the presence of such deficits in children with BPD.Thirty-two youths with DSM-IV BPD (mean age 11.2 +/- 2.8 years) and 15 healthy controls (HC) (11.2 +/- 3.0 years) had structured and clinical interviews, neurological examinations, neurocognitive testing, and MRI scanning on a 1.5 T GE Scanner. Image parcellation divided the neocortex into 48 gyral-based units per hemisphere, and these units were combined into frontal (FL), temporal (TL), parietal (PL), and occipital (OL) lobe volumes. Volumetric differences were examined using univariate linear regression models with alpha = 0.05.	Relative to controls, the BPD youth had significantly smaller bilateral PL, and left TL. Analysis of PL and TL gyri showed significantly smaller volume in bilateral postcentral gyrus, and in left superior temporal and fusiform gyri, while the parahippocampal gyri were bilaterally increased in the BPD group. Although the FL overall did not differ between groups, an exploratory analysis showed that the right middle frontal gyrus was also significantly smaller in the BPD group.	Children with BPD showed deficits in PL and TL cortical GM. Further analyses of the PL and TL found differences in areas involved in attentional control, facial recognition, and verbal and declarative memory. These cortical deficits may reflect early age of illness onset.	
16403180	Impaired verbal declarative memory has been proposed as a trait marker for adult bipolar disorder. However, similar impairments in juvenile-onset bipolar disorder have not been yet documented. Here, we assessed declarative memory in a large sample of clinically well-characterized children with bipolar disorder.Forty-one children and adolescents with bipolar disorder [21 bipolar I disorder (BP-I), 10 bipolar II disorder (BP-II), and 10 bipolar disorder, not otherwise specified (BP-NOS)] and 17 demographically matched healthy participants completed a standardized learning and memory test.	BP-I children recalled and recognized significantly fewer words than healthy subjects, whereas children with BP-II and BP-NOS did not differ from controls. However, individuals with BP-NOS made more perseverative errors and intrusions than the other groups. Severity of mood symptomatology was not associated with memory performance in any bipolar subtype.	Findings suggest that declarative memory impairments in juvenile BP-I are similar to those seen in the adult form of the illness. These impairments do not appear to be secondary to clinical state; rather, they may reflect trait-related impairments. Distinct performance patterns in BP-I, BP-II, and BP-NOS suggest that the broadly defined phenotype is significantly heterogeneous, and may not be informative for pathogenetic investigations of bipolar disorder.	
16386160	The clinical management of functional mobility problems of individuals with primary musculoskeletal impairments is complicated by the concurrent presence of neurologic diagnoses. There are few case descriptions present in the literature of clinical decision making in the context of combined musculoskeletal and neurologic impairments. The purpose of this case report is to describe the application and use of a systems model of motor control for defining the appropriate rehabilitation program for an individual with both orthopedic and neurologic impairments leading to complaints of frequent losses of balance and falls during community mobility.RG was a 67-year-old male referred to physical therapy because of balance problems. Review of his previous medical history revealed that he had suffered an anoxic brain injury 5 years earlier but had recovered full independence in activities of daily living (ADLs) with shortterm memory deficits being the primary residual effect of the brain injury. His balance problems developed only after having undergone a unilateral total knee arthroplasty 4 months prior to his initial physical therapy examination. Through examination and evaluation, RG's problems were determined to be consistent with postsurgery induced deconditioning coupled with anoxic brain injury related motor and cognitive deficits.	Physical therapy intervention focused on increasing RG's strength, decreasing the range of motion limitations in his lower extremities, balance exercises specific to his dynamic balance deficits, as well as increased amounts of practice to maximize procedural learning. Upon completion of his initial episode of care, RG's musculoskeletal impairments had improved; his scores on balance tests had increased, and his frequency of falls had decreased. Following his discharge, RG continued with a physical therapist designed secondary prevention program.	This case report describes the successful rehabilitation of an individual with concurrent orthopedic and neurologic diagnoses. Important components of this rehabilitation course include: (1) the application of a systems model of motor control to guide clinical interventions, (2) the consideration of the effects of memory deficits on rehabilitation outcomes, and (3) the utilization of a secondary prevention program to prevent reoccurrence of balance problems.	
16331358	There is a basic distinction between declarative memories, which can be stated verbally, and non-declarative memory, such as how to ride a bicycle, which cannot be expressed in words. With age it is the performance of declarative memory, particularly episodic memory that requires recall of events placed in time, that declines. As memory is not a unitary phenomenon, it should be ideally monitored using a range of tests that reflect theoretical conceptions of the topic. If circumstances demand the use of a single test then a measure of episodic memory is suggested. When it proves only possible to use a rating scale it should be ensured that memory is distinguished from other aspects of cognition and that different types of memory are not confused. The tests used, and the form in which they are used, need to be chosen to be of appropriate difficulty for the sample studied. A major conclusion is that the selection of the measure of memory used in the study of a dietary intervention should never be routine. It is inevitable that the form of the test used will need to be chosen carefully for the population being studied.
16325347	The aim of the present study was to investigate the spatio-temporal characteristics of the neural correlates of declarative memory formation as assessed by the subsequent memory effect, i.e. the difference in encoding activity between subsequently remembered and subsequently forgotten items. Different operations could account for these effects. In particular, it has been proposed that successful memory formation depends on the organization of the information at the time of encoding, an operation accomplished by the working memory system. Consequently, functional magnetic resonance imaging studies have already shown that the very same regions that are involved in certain working memory processes are also involved in declarative memory formation. Here, we used magnetoencephalography to investigate whether the subsequent memory effects in these regions are present throughout picture stimulus presentation, postulating ongoing working memory operations as an effective factor. The results showed that subsequent memory effects began to appear after about 300 ms post stimulus onset over bilateral temporal areas and left parietal regions and were sustained throughout the recording epoch (1000 ms). Roughly parallel to these effects, we identified a left frontal subsequent memory effect, which, however, was less sustained than the other effects. In addition, we revealed a late subsequent memory effect over the right occipital region, which has not been described previously in the event-related potential literature. These sustained subsequent memory effects are suggestive of working memory processes that may enable deep semantic and perceptual processing. Additionally, contextually constrained visual perception after top-down modulation may account for a more efficient encoding of the complex scene.
16319311	The present study investigated fear-potentiated startle and autonomic learning in brain-lesioned patients in a classical fear-conditioning paradigm. Startle blink and skin conductance responses of 30 patients who underwent unilateral temporal lobectomy because of drug-resistant epilepsy were compared with those of 32 healthy controls. As expected, temporal lobectomy patients showed a general impairment in fear conditioning relative to controls. This impairment did not differ with respect to the affected hemisphere. Moreover, while fear-conditioned startle potentiation in healthy controls was independent of contingency awareness, skin conductance discrimination was only observed for those participants who correctly recognized the stimulus contingencies. Patients who acquired a declarative memory of the contingencies also showed intact skin conductance discrimination but failed to exhibit fear-potentiated startle. The present findings support a two-levels-of-learning account of human fear conditioning and also demonstrate that the amygdala is crucially involved in fear learning.
16300967	Semantic dementia (SD) and Alzheimer's disease (AD) are both disorders in which early pathology affects the temporal lobe yet they produce distinct syndromes of declarative memory impairment-loss of established semantic knowledge with relatively preserved episodic memory in the former and the converse in the latter. Groups with mild SD and mild AD who showed a double dissociation in these two aspects of declarative memory were studied-the SD group's episodic memory and the AD group's semantic knowledge each being comparable to controls. Positron emission tomography and volumetric magnetic resonance imaging were used to map deficits in regional cerebral metabolic rate and mesial temporal lobe (MTL) atrophy, respectively. Episodic memory impairment in AD was associated with dysfunction of an integrated network (mesial temporal lobe, mamillary bodies, dorso-mesial thalamus and posterior cingulate). Semantic memory impairment in SD was associated with bilateral rostral temporal lobe hypometabolism. The SD group had comparable MTL atrophy and hypometabolism to that found in AD but the remainder of their limbic-diencephalic network was preserved suggesting that the latter explains their ability to acquire new episodic memories. The results challenge the view that amnesia in early AD can be explained by the degree of MTL damage alone while showing that semantic impairment can occur with damage restricted to the rostral temporal lobes.
16300905	The case of HM, a man with intractable epilepsy who became amnesic following bilateral medial temporal lobe surgery nearly half a century ago has instigated ongoing research and theoretical speculation on the nature of memory and the role of the hippocampus. Neuropsychological testing showed that although HM had extensive anterograde memory loss he could still acquire motor and cognitive skills implicitly, but could not remember the context of this learning. This has lead to declarative and procedural descriptions of the memory process. Cholinergic and monoaminergic neurotransmitter systems have also been implicated in the memory process and anticholinergic drugs traditionally have been associated with impairment of declarative memory. The cholinergic hypothesis of Alzheimer's disease is a classic example of an application of these neuropharmacological findings. In schizophrenia, preattentive deficits have been amply demonstrated by unconscious priming studies. Memory processes are also impaired in these patients. Dopamine, glutamate and even cholinergic dysfunction has been implicated in the clinical picture of schizophrenia. The present paper will attempt to bring together both the anatomical and pharmacological data from these disparate fields of research under a cohesive theory of cognition and memory. A hypothesis is presented for an inverse relationship between monoaminergic and cholinergic systems in the modulation of implicit (unconscious) and explicit (conscious) cognitive processes. It is postulated that muscarinic cholinergic receptors and monoaminergic systems facilitate unconscious and conscious processes, respectively, and they disfacilitate conscious and unconscious processes, respectively (the purported inverse relationship). In fact, the muscarinic and monoaminergic modulations of a neural network are proposed to be finely balanced such that, if, the activity of one receptor system is modified then this by necessity has effects on the other system. It takes into account receptor subtypes and their effects mediated through excitatory and inhibitory G-protein complexes. For example, m1/D2 and D1/m4 paired receptor subtypes, colocalized on separate neurons would have opposing functional effects. A theory is then presented that the critical underlying pathophysiology of schizophrenia involves a hypofunctional muscarinic cholinergic system, which induces abnormal facilitation of monoaminergic subsystems such as dopamine (e.g., a decrease in m1R function would potentiate D2R function). This extends the idea of an inverted U function for optimal monoaminergic concentrations. Not only would this impair unconscious preattentive processes, but according to the hypothesis, explicit cognition as well including memory deficits and would underlie the mechanism of psychosis. Contrary to current thinking a different view is also presented for the role of the hippocampus in the memory process. It is postulated that long-term explicit memory traces in the neocortex are laid down by phasic coactivation of forebrain projecting monoaminergic systems above some basal firing rate, such as the rostral serotonergic raphe, which projects diffusely to the cortex and according to a modified Hebbian principle. This is the proposed principal function of the hippocampal theta rhythm. The phasic activation of the cholinergic basal forebrain is mediated by projections from a separate cortical structure, possibly the lateral prefrontal cortex. Phasic muscarinic receptor activation is proposed to strengthen implicit memory traces (at a synaptic level) in the neocortex. Thus, the latter are spared by medial temporal surgery explaining the dissociation of explicit from implicit memory.
16290273	An issue of great recent interest is whether motor memory consolidates in a manner analogous to declarative memory--that is, with the formation of a memory that progresses over time from a fragile state, which is susceptible to interference by a lesion or a conflicting motor task, to a stabilized state, which is resistant to such interference. Here, we first review studies that examine the anatomical basis for motor consolidation. Evidence implicates cerebellar circuitry in two types of associative motor learning--eyelid conditioning and vestibulo-ocular reflex adaptation--and implicates primary motor cortex in skilled finger movements. We also review evidence for and against a consolidation process for adaptation of arm movements. We propose that contradictions have arisen because consolidation can be masked by inhibition of memory retrieval.
16275027	Computational models of the hippocampal region link psychological theories of associative learning with their underlying physiological and anatomical substrates. Our approach to theory development began with a broad description of the computations that depend on the hippocampal region in classical conditioning (Gluck and Myers, 1993 and Gluck and Myers, 2001). In this initial model, the hippocampal region was treated as an Information-processing system that transformed stimulus representations, compressing (making more similar) representations of inputs that co-occur or are otherwise redundant, while differentiating (or making less similar) representations of inputs that predict different future events. This model led to novel predictions for the behavioral consequences of hippocampal-region lesions in rodents and of brain damage in humans who have amnesia or are in the earliest stages of Alzheimer's disease. Many of these predictions have, since been confirmed by our lab and others. Functional brain imaging studies have provided further supporting evidence. In more recent computational modeling, we have shown how some aspects of this proposed information-processing function could emerge from known anatomical and physiological characteristics of the hippocampal region, including the entorhinal cortex and the septo-hippocampal cholinergic system. The modeling to date lays the groundwork for future directions that increase the depth of detail of the biological modeling, as well as the breadth of behavioral phenomena addressed. In particular, we are working now to reconcile these kinds of incremental associative learning models with other models of the hippocampal region that account for the rapid formation of declarative memories.
16274857	To examine the association of salivary cortisol with cognitive changes in a 3 year longitudinal study. Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition.Salivary cortisol samples were collected at home by 79 cognitively intact older persons (mean age 78+/-7 years) at 08:00, 15:00 and 23:00h, and collections were repeated annually for 3 years. Cognitive function was also assessed annually.	The mean cortisol level of samples taken at three times of day and the cortisol concentration at 23:00h were significantly associated with poorer performance on tasks of declarative memory and executive function. Of 46 subjects who completed the entire 3 year study, higher initial cortisol concentration at 23:00h predicted a decline in performance of delayed paragraph recall.	These results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.	
16271459	The medial temporal lobe (MTL) includes several structures--the hippocampus, and the adjacent perirhinal, entorhinal and parahippocampal cortices--that have been associated with memory for at least the past 50 years. These components of the putative 'MTL memory system' are thought to operate together in the service of declarative memory--memory for facts and events--having little or no role in other functions such as perception. Object perception, however, is thought to be independent of the MTL, and instead is usually considered to be the domain of the ventral visual stream (VVS) or 'what' pathway. This 'textbook' view fits squarely into the prevailing paradigm of anatomical modularisation of psychological function in the brain. Recent studies, however, question this view, indicating that first, the MTL is functionally heterogeneous, and second, structures in the MTL might have a role in perception. Furthermore, the specific contributions of the individual structures within the MTL are being elucidated. These new findings indicate that it might no longer be useful to assume a strict functional dissociation between the MTL and the VVS, and that psychological functions might not be modularised in the way usually assumed. We propose an alternative approach to understanding the functions of these brain regions in terms of what computations they perform, and what representations they contain.
16269237	A model of hippocampal function, centered on region CA3, reproduces many of the cognitive and behavioral functions ascribed to the hippocampus. Where there is precise stimulus control and detailed quantitative data, this model reproduces the quantitative behavioral results. Underlying the model is a recoding conjecture of hippocampal computational function. The expanded conjecture includes a special role for randomization and, as recoding progresses with experience, the occurrence of sequence learning and sequence compression. These functions support the putative higher-order hippocampal function, i.e. production of representations readable by a linear decoder and suitable for both neocortical storage and forecasting. Simulations confirm the critical importance of randomly driven recoding and the neurocognitive relevance of sequence learning and compression. Two forms of sequence compression exist, on-line and off-line compression: both are conjectured to support neocortical encoding of context and declarative memory as described by .
16267231	Investigations of memory in rats and nonhuman primates have demonstrated functional specialization within the medial temporal lobe (MTL), a set of heavily interconnected structures including the hippocampal formation and underlying entorhinal, perirhinal, and parahippocampal cortices. Most studies in humans, however, especially in patients with brain damage, suggest that the human MTL is a unitary memory system supporting all types of declarative memory, our conscious memory for facts and events. To resolve this discrepancy, amnesic patients with either selective hippocampal damage or more extensive MTL damage were tested on variations of an object discrimination task adapted from the nonhuman primate literature. Although both groups were equally impaired on standard recall-based memory tasks, they exhibited different profiles of performance on the object discrimination test, arguing against a unitary view of MTL function. Cases with selective hippocampal damage performed normally, whereas individuals with broader MTL lesions were impaired. Furthermore, deficits in this latter group were related not to the number of discriminations to be learned and remembered, but to the degree of "feature ambiguity," a property of visual discriminations that can emerge when features are part of both rewarded and unrewarded stimuli. These findings resolve contradictions between published studies in humans and animals and introduce a new way of characterizing the impairments that arise after damage to the MTL.
16267221	A characteristic usually attributed to declarative memory is that what is learned is accessible to awareness. Recently, the relationship between awareness and declarative (hippocampus-dependent) memory has been questioned on the basis of findings from transitive inference tasks. In transitive inference, participants are first trained on overlapping pairs of items (e.g., A+B-, B+C-, C+D-, and D+E-, where + and - indicate correct and incorrect choices). Later, participants who choose B over D when presented with the novel pair BD are said to demonstrate transitive inference. The ability to exhibit transitive inference is thought to depend on the fact that participants have represented the stimulus elements hierarchically (i.e., A>B>C>D>E). We found that performance on five-item and six-item transitive inference tasks was closely related to awareness of the hierarchical relationship among the elements of the training pairs. Participants who were aware of the hierarchy performed near 100% correct on all tests of transitivity, but participants who were unaware of the hierarchy performed poorly (e.g., on transitive pair BD in the five-item problem; on transitive pairs BD, BE, and CE in the six-item problem). When the five-item task was administered to memory-impaired patients with damage thought to be limited to the hippocampal region, the patients were impaired at learning the training pairs. All patients were unaware of the hierarchy and, like unaware controls, performed poorly on the BD pair. The findings indicate that awareness is critical for robust performance on tests of transitive inference and support the view that awareness of what is learned is a fundamental characteristic of declarative memory.
16263261	The study of population dynamics in hippocampal place cells has emerged as one of the most powerful tools for understanding the encoding, storage and retrieval of declarative memory. Recent work has laid out the contours of an attractor-based hippocampal population code for memory in recurrent circuits of the hippocampus. The code is based on inputs from a topographically organized, path-integration-dependent spatial map that lies upstream in the medial entorhinal cortex. The recurrent networks of the hippocampal formation enable these spatial inputs to be synthesized with nonspatial event-related information.
16251993	Numerous studies have investigated the effects of alcohol on motor processes during rising and declining blood alcohol concentrations (BAC), however, relatively little research has examined the alcohol-induced impairment of cognitive performance on the two limbs of the BAC curve. This experiment administered a neuropsychological test battery to assess the degree to which rising and declining BACs during an acute dose of alcohol impair nine cognitive processes within an individual. In all, 20 healthy male social drinkers (university students) were assigned to one of two groups (n = 10) who received a beverage containing either 0.0 g/kg (placebo) or 0.65 g/kg alcohol and performed the test battery when BAC was increasing and was decreasing. Comparisons of alcohol and placebo groups revealed impairment (slower response and/or increased errors) in seven of the cognitive processes: long-term verbal memory; information processing; declarative memory; inhibitory control; short-term visual memory; long-term visual memory, and visual-spatial working memory. However, some processes were impaired only during rising BACs whereas the impairment of others during declining BACs was evident only by an increase in errors. These results show cognitive tasks performed by an individual are not similarly affected by rising and declining BACs, and call attention to the importance of assessing both speed and accuracy on both limbs of the BAC curve. The particular cognitive processes differentially affected by rising vs declining BACs raised the possibility that acute alcohol intoxication may impair one cerebral hemisphere to a greater degree than the other, and this could be explored by neuroimaging techniques.
16251217	Compared with waking state attention, volition and semantic processing play a minor role during sleep. Thus, investigating declarative memory formation during sleep may allow us to isolate mnemonic core processes. The most feasible approach to memory formation during sleep is the analysis of dream memories. Lesion and imaging studies have demonstrated that encoding of declarative memories, i.e. consciously accessible events and facts, depends on operations within the rhinal cortex and the hippocampus, two substructures of the medial temporal lobe. Successful memory formation is accompanied by a transient rhinal-hippocampal interaction. Consequently, the ability to memorize dreams may be related to mediotemporal connectivity. Therefore, we recorded EEG during sleep from rhinal and hippocampal depth electrodes implanted in 12 epilepsy patients (eight women, mean age 41.1 +/- 6.4 years). They were awakened during rapid eye movement sleep (REM) and asked to recall their dream. Via coherence analyses we show that rhinal-hippocampal connectivity values are approximately twice as large for patients with good dream recall versus those patients with poor recall. This suggests that rhinal-hippocampal connectivity is a key factor in determining declarative memory formation.
16229931	We measured the effects of a stressful experience on memory for emotionally arousing and neutral material learned after exposure to a stressor which induces a significant increase in corticosteroid stress hormones. Because memory performance can be influenced by circadian changes in corticosteroid levels, subjects were tested either in the morning or in the afternoon. Nineteen healthy men (9 in the morning group and 10 in the afternoon group) were submitted to a psychological stress task before viewing a story composed of emotionally negative and neutral segments, while another 20 healthy males (10 in the morning group and 10 in the afternoon group) viewed the story without being exposed to the psychological stressor. Salivary cortisol levels were measured before and after the stressor. Memory performance was assessed by a one week post learning delayed recall. Results show that stress-induced increases in salivary cortisol levels impaired delayed free recall of emotionally arousing material in the morning group, but not in the afternoon group. There was no effect of stress on memory for neutral material. Altogether, these findings suggest that stressing participants in the morning, at a time of high circulating levels of corticosteroids, over stimulated the corticosteroid receptors in the brain, impairing declarative memory for emotionally arousing material unrelated to the stressor. These findings suggest that the experimental context, i.e., time of day at which the experiment occurs, the nature of the to-be-remembered material (remembering the stressful event itself or material unrelated to the stressor) and the valence of the to-be-remembered material (emotionally arousing vs. neutral), modulates the effects of stress on human declarative memory.
16224581	We studied the effect of a new nootropic dipeptide Noopept and reference nootropic preparation piracetam injected subcutaneously on days 8-20 of life on learning of alternative feeding response in a 6-arm-maze in male and female rats. Early postnatal administration of Noopept disturbed the dynamics of learning by parameters of declarative and procedural memory. Piracetam impaired learning by parameters of procedural, but not declarative memory (only in males). Both preparations decreased the ratio of successfully learned males (but not females). The observed effects were not associated with changes in locomotor activity.
16217697	To investigate the psychometric properties of the German version of the CERAD-NP, neuropsychological deficits were compared between 49 patients with mild cognitive impairment (MCI), 80 patients with Alzheimer's disease (AD), 36 with major depression (MD), and 26 elderly controls. All participants were outpatients of the memory clinic of the Section of Geriatric Psychiatry, Heidelberg University. Diagnoses were established based on clinical examination, laboratory testing, neuroimaging, and routine neuropsychological testing according to the criteria of aging-associated cognitive decline (AACD) for MCI, NINCDS-ADRDA for AD, and DSM-IV for MD, respectively. All CERAD-NP subtests discriminated between controls and AD patients with the latter showing significantly (p< or = 0.05) lower test scores. The subtests verbal fluency and constructive apraxia differed significantly between mildly and moderately AD, while the subtests assessing declarative (epsisodic) memory performance showed only minor, non-significant differences between the respective groups. The LKB patients took an intermediate position between controls and AD patients with significantly lower scores in verbal fluency and declarative memory performance than the controls. When compared with the AD patients, MCI patients were significantly impaired in all subtests except constructive apraxia. Relative to the controls, the patients with MD showed a decreased episodic memory performance but no evidence suggesting an impairment in other neuropsychological domains. Our results indicate that the CERAD-NP is a psychometric instrument which allows a sensitive discrimination between mild and moderate AD, MCI, MD and healthy controls. However, sensitivity of discrimination between different stages of dementia varies with respect to the different subtest. While the subtest for episodic memory showed floor effects already for mild dementia, subtests for verbal fluency and constructive apraxia were able to discriminate even between more advanced stages of the disease.
16199138	Memory of contextual information is essential to one's quality of living. This study investigated if the different components of prose memory, across three recall conditions: first learning trial immediate recall, fifth learning trial immediate recall, and 30-min delayed recall, are differentially impaired in people with schizophrenia, relative to healthy controls. A total of 39 patients with schizophrenia and 39 matched healthy controls were recruited. Their prose memory, in terms of recall accuracy, temporal sequence, recognition accuracy and false positives, commission of distortions, and rates of learning, forgetting, and retention were tested and compared. After controlling for the level of intelligence and depression, the patients with schizophrenia were found to commit more distortions. Furthermore, they performed poorer on recall accuracy and temporal sequence accuracy only during the first initial immediate recall. On the other hand, the rates of forgetting/retention and recognition accuracy were comparable between the two groups. These findings suggest that people with schizophrenia could be benefited by repeated exposure to the materials to be remembered. These results may have important implications for rehabilitation of verbal declarative memory deficits in schizophrenia.
16199055	There is mounting evidence that declarative memory processes are impaired in patients with bipolar disorder. However, predictors of the observed impairment are not well understood. This study seeks to: (i) better characterize the nature of declarative memory impairment in bipolar disorder, and (ii) determine the relationship between clinical variables and memory function in bipolar disorder.49 adult patients with bipolar disorder in varying mood states and 38 demographically matched healthy participants completed a comprehensive neurocognitive battery assessing general cognitive functioning, processing speed, and declarative memory. The California verbal learning test was used to characterize learning and memory functions.	Although patients with bipolar disorder utilized a similar semantic clustering strategy to healthy controls, they recalled and recognized significantly fewer words than controls, suggesting impaired encoding of verbal information. In contrast, lack of rapid forgetting suggests relative absence of a storage deficit in bipolar patients. While severity of mood symptomatology and illness duration were not associated with task performance, gender and family history significantly affected memory function.	Results suggest that declarative memory impairments in bipolar patients: (1) are consistent with deficits in learning, but do not appear to be related to different organizational strategies during learning, and (2) do not appear to be secondary to clinical state, but rather may be associated with the underlying pathophysiology of the illness.	
16194971	The medial temporal lobe (MTL) has been considered traditionally to subserve declarative memory processes only. Recent studies in nonhuman primates suggest, however, that the MTL may also be critical to higher order perceptual processes, with the hippocampus and perirhinal cortex being involved in scene and object perception, respectively. The current article reviews the human neuropsychological literature to determine whether there is any evidence to suggest that these same views may apply to the human MTL. Although the majority of existing studies report intact perception following MTL damage in human amnesics, there have been recent studies that suggest that when scene and object perception are assessed systematically, significant impairments in perception become apparent. These findings have important implications for current mnemonic theories of human MTL function and our understanding of human amnesia as a result of MTL lesions.
16194969	The perirhinal cortex was once thought to be "silent cortex", virtually ignored by researchers interested in the neurobiology of learning and memory. Following studies of brain damage associated with cases of amnesia, perirhinal cortex is now widely regarded as part of a "medial temporal lobe (MTL) memory system". This system is thought to be more or less functionally homogeneous, having a special role in declarative memory, and making little or no contribution to other functions such as perception. In the present article, we summarize an alternative view. First, we propose that components of the putative MTL system such as the hippocampus and perirhinal cortex have distinct and dissociable functions. Second, we provide evidence that the perirhinal cortex has a role in visual discrimination. In addition, we propose a specific role for perirhinal cortex in visual discrimination: the contribution of complex conjunctive representations to the solution of visual discrimination problems with a high degree of "feature ambiguity". These proposals constitute a new view of perirhinal cortex function, one that does not assume strict modularity of function in the occipito-temporal visual stream, but replaces this idea with the notion of a hierarchical representational continuum.
16190892	Entorhinal cortex (EC) relays information from the hippocampus to the cerebral cortex. The origin of this entorhino-cortical pathway was studied semiquantitatively and topographically with the use of 23 retrograde tracer injections in cortical areas of the frontal, temporal, and parietal lobes of the monkey. To assess possible alternative, parallel pathways, the parahippocampal region, comprised of temporal pole (TP), perirhinal (PRC), and posterior parahippocampal cortices (PPH), was included in the study. The majority of the cortical areas receive convergent projections from EC and the parahippocampal region. Strong EC layer V output is directed to temporal pole, medial frontal and orbitofrontal cortices, and the rostral part of the polysensory area of the superior temporal sulcus (sts). Moderate EC output is directed to the caudal superior temporal gyrus, area TE, and parietal cortex, and little to none to the lateral frontal cortex. With the exception of the projection to the medial frontal cortex, output from TP, PRC, and PPH surpassed that from EC, although with regional differences. TP layers II-III, V-VI project strongly to all areas injected except parietal cortex and caudal superior temporal gyrus, while PRC layers III/V-VI send strong projections to rostral parts of area TE and sts. PPH layers III/V-VI project heavily to parietal cortex and caudal superior temporal gyrus. These results suggest that the medial temporal output is primarily organized hierarchically, but at the same time, it has multiple exits of information. These parallel, alternative routes may influence local circuitry in the cerebral cortex and participate in the consolidation of declarative memory.
16175845	The ability of amnesic patients to learn and retain non-declarative information has been consistently demonstrated in the literature. This knowledge provided by basic cognitive neuroscience studies has been widely neglected in neuropsychological rehabilitation of memory impaired patients. This study reports the case of a 43 year old man with severe amnesia following an anterior communicating artery (ACoA) aneurysm rupture. The patient integrated a comprehensive (holistic) day treatment programme for rehabilitation of brain injury. The programme explored the advantages of using preserved non-declarative memory capacities, in the context of commonly used rehabilitation approaches (i.e. compensation for lost function and domain-specific learning). The patient's ability to learn and retain new cognitive and perceptual-motor skills was found to be critical for the patient's improved independence and successful return to work.
16156047	This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October, 2004. Chronic alcoholism follows a fluctuating course, which provides a naturalistic experiment in vulnerability, resilience, and recovery of human neural systems in response to presence, absence, and history of the neurotoxic effects of alcoholism. Alcohol dependence is a progressive chronic disease that is associated with changes in neuroanatomy, neurophysiology, neural gene expression, psychology, and behavior. Specifically, alcohol dependence is characterized by a neuropsychological profile of mild to moderate impairment in executive functions, visuospatial abilities, and postural stability, together with relative sparing of declarative memory, language skills, and primary motor and perceptual abilities. Recovery from alcoholism is associated with a partial reversal of CNS deficits that occur in alcoholism. The reversal of deficits during recovery from alcoholism indicates that brain structure is capable of repair and restructuring in response to insult in adulthood. Indirect support of this repair model derives from studies of selective neuropsychological processes, structural and functional neuroimaging studies, and preclinical studies on degeneration and regeneration during the development of alcohol dependence and recovery form dependence. Genetics and brain regional specificity contribute to unique changes in neuropsychology and neuroanatomy in alcoholism and recovery. This symposium includes state-of-the-art presentations on changes that occur during active alcoholism as well as those that may occur during recovery-abstinence from alcohol dependence. Included are human neuroimaging and neuropsychological assessments, changes in human brain gene expression, allelic combinations of genes associated with alcohol dependence and preclinical studies investigating mechanisms of alcohol induced neurotoxicity, and neuroprogenetor cell expansion during recovery from alcohol dependence.
16140164	This study examined contributions of the hippocampus, amygdala and perirhinal cortex to memory. Rats performed a cover task, and changes to stimulus identity or relationships were used to test incidental memory. Rats with hippocampal damage showed deficient responses to relationship changes, but demonstrated knowledge of the position and identity of the target object. They over-focused on the most predictive stimuli, and failed to acquire associations including surrounding cues. Rats with amygdala damage responded to changes involving distal stimuli, and showed deficient responses to novel objects and object relationships. These rats may be highly reliant on relational representations, resulting in a reduced salience for individual novel stimuli. Rats with perirhinal damaged responded to novel stimulus relationships and distal cues, but showed deficient responses to novel objects, suggesting that changes in identity had reduced salience. Implications for declarative and conjunctive hippocampal theories are discussed.
16138432	We report on two brain-damaged patients who show contrasting patterns of deficits in memory and language functioning. One patient (AW) suffers from a lexical retrieval deficit and failed to produce many irregularly inflected words such as spun, forgotten, and mice, but demonstrated intact production of regularly inflected words such as walked and rats. She also had preserved declarative memory for facts and events. The other patient (VP) presented with a severe declarative memory deficit but showed no signs of impairment in producing either regular or irregular inflections. These patterns of deficits reveal that the retrieval of irregular inflections proceeds relatively autonomously with respect to declarative memory. We interpret these deficits with reference to three current theories of lexical structure: (a) Pinker's "words and rules" account, which assumes distinct mechanisms for processing regular and irregular inflections and proposes that lexical and semantic processing are subserved by distinct but interacting cognitive systems; (b) Ullman's "declarative/procedural" model, which assumes that mechanisms for the retrieval of irregular inflections are part of declarative memory; (c) Joanisse and Seidenberg's connectionist model, in which semantic information is critical for the retrieval of irregular inflections.
16129403	Declarative memory permits an organism to recognize stimuli that have been previously encountered, discriminating them from those that are novel. One basis for recognition is item memory strength, which may support the perception of stimulus familiarity. Though the medial temporal lobes are known to be critical for declarative memory, at present the neural mechanisms supporting perceived differences in memory strength remain poorly specified. Here, functional MRI (fMRI) and anatomically constrained magnetoencephalography (MEG) indexed correlates of graded memory strength in the human brain, focusing on medial temporal cortex. fMRI revealed a decrease in medial temporal cortical activation that tracked parametric levels of perceived memory strength. Anatomically constrained MEG current estimates revealed that strength-dependent signal reductions onset within 150-300 ms. Memory strength appears to be rapidly signaled by medial temporal cortex through repetition suppression (activation reductions), providing a basis for the subjective perception of stimulus familiarity or novelty.
16087901	Research criteria for subcortical vascular dementia are based on radiologic evidence of vascular pathology and greater impairment on tests of executive control than memory. The relationship(s) between neuroradiological evidence of subcortical vascular disease and neuropsychological impairments has not been specified.To define these research criteria, the authors rated the severity of MRI white matter abnormalities (WMAs) and neuropsychological data from patients with dementia.	Sixty-nine outpatients who met the criteria for dementia were studied with neuropsychological tests that assessed executive (mental) control, declarative memory, visuoconstruction (clock drawing), and language (semantic category fluency). MRI-WMAs were rated using a leukoaraiosis (LA) scale (range 0 to 40).	First, regression analyses demonstrated that neuropsychological measures accounted for 60.7% of the variance in WMA severity (47.3% of this variance attributable to executive/visuoconstructive test performance, 13.4% attributable to memory/language test performance). Second, patients were grouped according to the severity of WMAs (i.e., low, moderate, and severe white matter groups). Only patients with mild WMA (mean LA = 3.61 +/- 2.63, approximately 2.4 to 15.6% of the subcortical white matter) presented with greater impairment on memory/language tests vs executive control/visuoconstructive tests, a neuropsychological profile typically associated with Alzheimer disease. Patients with moderate WMA (mean LA = 12.76 +/- 2.49, approximately 25.6 to 38.1% of the subcortical white matter) presented with equal impairment on executive/visuoconstructional vs memory/language tests. Patients with severe WMA (mean LA = 21.76 +/- 2.97, approximately 46.9 to 62.4% of the subcortical white matter) displayed a profile of greater executive/visuoconstructional impairment relative to memory/language disabilities.	A profile of equal impairment on tests of executive control and memory along with radiologic evidence involving about one-fourth of the cerebral white matter as measured by the Leukoaraiosis Scale may be sufficient for a diagnosis of subcortical vascular dementia.	
16087262	This experiment explores a suggestion by [Maxwell, J.P., Masters, R.S.W., Kerr, E., Weedon, E. (2001). The implicit benefit of learning without errors. Quarterly Journal of Experimental Psychology A 54, 1049-1068] that an initial bout of implicit motor learning confers beneficial performance characteristics, such as robustness under secondary task loading, despite subsequent explicit learning. Participants acquired a complex motor skill (golf putting) over 400 trials. The environment was constrained early in learning to minimize performance error. It was predicted that in the absence of explicit instruction, reducing error would prevent hypothesis testing strategies and the concomitant accrual of declarative (explicit) knowledge, thereby reducing dependence on working memory resources. The effect of an additional cognitive task on putting performance was used to assess reliance on working memory. Putting performance of participants in the Implicit-Explicit condition was unaffected by the additional cognitive load, whereas the performance of Explicit participants deteriorated. The relationship between error correction and episodic verbal reports suggested that the explicit group were involved in more hypothesis testing behaviours than the Implicit-Explicit group early in learning. It was concluded that a constrained, uninstructed, environment early in learning, results in procedurally based motor output unencumbered by disadvantages associated with working memory control.
16054861	Although the parietal lobe is not traditionally thought to support declarative memory, recent event-related fMRI studies of episodic retrieval have consistently revealed a range of memory-related influences on activation in lateral posterior parietal cortex (PPC) and precuneus extending into posterior cingulate and retrosplenial cortex. This article surveys the fMRI literature on PPC activation during remembering, a literature that complements earlier electroencephalography data. We consider these recent memory-related fMRI responses within the context of classical ideas about parietal function that emphasize space-based attention and motor intention. We conclude by proposing three hypotheses concerning how parietal cortex might contribute to memory.
16049487	Habit memory is thought to involve slowly acquired associations between stimuli and responses and to depend on the basal ganglia. Habit memory has been well studied in experimental animals but is poorly understood in humans because of their strong tendency to acquire information as conscious (declarative) knowledge. Here we show that humans have a robust capacity for gradual trial-and-error learning that operates outside awareness for what is learned and independently of the medial temporal lobe. We tested two patients with large medial temporal lobe lesions and no capacity for declarative memory. Both patients gradually acquired a standard eight-pair object discrimination task over many weeks but at the start of each session could not describe the task, the instructions or the objects. The acquired knowledge was rigidly organized, and performance collapsed when the task format was altered.
16036465	In a former study of a patient with cerebellar agenesis (HK) mild motor deficits, problems in delay eyeblink conditioning and mild to moderate deficits in IQ, planning behavior, visuospatial abilities, visual memory, and attention were found. The present study reports additional findings in the same patient. In the motor domain, impairments in fine motor manipulations, trace eyeblink conditioning and motor imagination in a functional magnetic resonance (fMRI) study were found. Based on fMRI findings; however, cortical areas involved in a tapping task did not significantly differ from a healthy control group. In the cognitive domain, deficits in speech comprehension as well as verbal learning and declarative memory were present. No significant affective symptoms were observed. Although problems in executive, visuospatial and language tasks are in agreement with the so-called cerebellar cognitive affective syndrome-other possibilities remain. Non-motor impairments in HK might also be a consequence of lacking motor abilities in development and motor deficits may interfere with the performance of parts of the cognitive tasks. In addition, lack of promotion and learning opportunities in childhood may contribute and mental retardation based on extracerebellar dysfunction cannot be excluded.
16029094	This study has 2 objectives: (a) to explore typical paths of cognitive development associated with aging, terminal decline, and dementia and (b) to promote and illustrate an individual-oriented approach to the study of cognitive aging based on longitudinal panel data from a population-based sample (N = 500; age range-sub(T1)= 60-80, where T refers to time) tested at 3 occasions 5 years apart. Results document interindividual differences in multivariate patterns of change. Although cognitive changes generally covary, the present study indicates that subgroups of individuals develop along different paths characterized by selective changes in subsets of cognitive functions. Typical progression of dementia followed a developmental cascade from low declarative memory, via low functioning across all observed cognitive measures, to dementia diagnosis, and finally, death.
16010661	There has been considerable debate as to whether the hippocampus and perirhinal cortex may subserve both memory and perception. We administered a series of oddity tasks, in which subjects selected the odd stimulus from a visual array, to amnesic patients with either selective hippocampal damage (HC group) or more extensive medial temporal damage, including the perirhinal cortex (MTL group). All patients performed normally when the stimuli could be discriminated using simple visual features, even if faces or complex virtual reality scenes were presented. Both patient groups were, however, severely impaired at scene discrimination when a significant demand was placed on processing spatial information across viewpoint independent representations, while only the MTL group showed a significant deficit in oddity judgments of faces and objects when object viewpoint independent perception was emphasized. These observations provide compelling evidence that the human hippocampus and perirhinal cortex are critical to processes beyond long-term declarative memory and may subserve spatial and object perception, respectively.
16008597	The literature indicates that high daily doses of gluco-corticosteroids have a degenerating effect upon the hippocampus and thus result in reduced declarative memory capacities. In order to prevent rejection, renal transplant recipients are treated with moderate daily doses of gluco-corticosteroids and, if necessary, with high pulse-doses during a few days. The question, therefore, arises as to whether or not such standard treatments result in memory impairments. For this reason, declarative memory capacities were measured, by means of a Dutch version of Rey's 15 Words Test, in a group of 52 renal transplant recipients. Results clearly indicated severe reductions in declarative memory capacities in these patients.
16006102	Despite evidence for diverse neuropsychological impairment in schizophrenia, verbal declarative memory has emerged as a core deficit in the disorder. Similar but less marked impairments have been demonstrated in unaffected biological relatives of patients with schizophrenia, but the nature and extent of the memory impairment in relatives compared to controls is unclear. We have conducted a systematic review and meta-analysis of the literature investigating declarative memory in unaffected biological relatives of schizophrenics and controls, with the aim of quantifying memory deficits in relatives. The standardised mean difference between groups was calculated for nine measures of declarative memory and two measures of intellectual ability, based on 21 studies of several hundred relatives of schizophrenics and controls. Unaffected relatives showed poorer performance relative to controls on all tests of memory examined. Small to moderate effect sizes, with overlapping 95% confidence intervals, were greatest on immediate (trial 1) list recall (0.65), followed by immediate (0.53) and delayed story recall (0.52). Verbal and general IQ showed smaller standardised mean differences as the latter tests, while the smallest standardised mean difference was shown on delayed visual recall (0.32). Results suggest greater deficits on tests of increasing memory load or which place demands on effective encoding processes but more studies with these tasks are needed. Investigation of sub-groups within these cohorts (e.g. age groups within or beyond the maximum age of risk) is recommended in order to identify deficits specific to the disease process.
16005438	Previous research indicates that hippocampus-dependent declarative memory benefits from early nocturnal sleep, when slow-wave sleep (SWS) prevails and cortisol release is minimal, whereas amygdala-dependent emotional memory is enhanced through late sleep, when rapid eye movement (REM) sleep predominates. The role of the strong cortisol rise accompanying late sleep for emotional memory consolidation has not yet been investigated.Effects of the cortisol synthesis inhibitor metyrapone on sleep-associated consolidation of memory for neutral and emotional texts were investigated in a randomized, double-blind, placebo-controlled study in 14 healthy men. Learning took place immediately before treatment, which was followed by 8 hours of sleep. Retrieval was tested at 11 am the next morning.	Metyrapone suppressed cortisol during sleep and blocked particularly the late-night rise in cortisol. It reduced SWS and concomitantly impaired the consolidation of neutral texts. Emotional texts were spared from this impairing influence, however. Metyrapone even amplified emotional enhancement in text recall indicating amygdala-dependent memory.	Cortisol blockade during sleep impairs hippocampus-dependent declarative memory formation but enhances amygdala-dependent emotional memory formation. The natural cortisol rise during late sleep may thus protect from overshooting emotional memory formation, a mechanism possibly pertinent to the development of posttraumatic stress disorder.	

15980148	The functional magnetic resonance imagery responses of declarative memory tasks in the medial temporal lobe (MTL) are examined by using large deformation diffeomorphic metric mapping (LDDMM) to remove anatomical variations across subjects. LDDMM is used to map the structures of the MTL in multiple subjects into extrinsic atlas coordinates; these same diffeomorphic mappings are used to transfer the corresponding functional data activation to the same extrinsic coordinates. The statistical power in the averaged LDDMM mapped signals is significantly increased over conventional Talairach-Tournoux averaging. Activation patterns are highly localized within the MTL. Whereas the present demonstration has been aimed at enhancing alignment within the MTL, this technique is general and can be applied throughout the brain.
15979789	A polymorphism (Val 158 Met) in the gene for catechol-O-methyl transferase (COMT) was previously associated with differences in cognitive ability and personality. Here we examine associations between this polymorphism and cognitive ability, cognitive aging, personality and mood in 460 relatively healthy people born in 1921. All had cognitive ability measured at age 11 in the Scottish Mental Survey of 1932, and again at age 79. COMT genotype was not associated with childhood IQ. At age 79, COMT genotype was significantly related to differences in verbal declarative memory (scores on the Logical Memory test; p=0.028) and to scores on the personality trait of intellect/imagination (p=0.023), adjusted for sex and childhood IQ. In both cases the Val/Met heterozygotes had higher scores than both homozygous groups. There were trends toward the heterozygotes having higher scores on the personality traits of agreeableness and conscientiousness. The effect of COMT genotype on Logical Memory scores was independent of the effect of APOE genotype, and similar in effect size. Therefore, COMT genotype may contribute to differences in normal cognitive aging and to differences in some of the major personality traits in old age.
15975730	Cognitive decline in old age is not universal or inevitable. Associations have been observed with neuroendocrine function, but the relevance of other physiological processes is unclear. We predicted that impairment of memory in an ageing population would be related to the dysregulation of neuroendocrine and cardiovascular responses. One hundred and thirty-nine participants (65-80 years) were recruited from general practice in London. Two standardised verbal paired-associates recall tasks were administered in order to determine declarative memory performance, and a fluid intelligence task (matrix reasoning) was also performed. Salivary cortisol samples were collected every 10 min, while blood pressure and heart rate were measured before, during and after each task. Illness history and medication use were obtained from medical records. Multiple linear regression analysis, adjusted for age, gender, education, chronic illness, and medication use, revealed that cortisol responses were inversely related to memory performance. Additionally, superior memory was associated with more effective post-task recovery of heart rate (in both men and women) and diastolic blood pressure recovery in men. Cardiovascular recovery effects were independent of covariates, and of levels of heart rate and blood pressure measured during tasks themselves. These associations were also independent of subjective ratings of stress and perceived performance. Neither neuroendocrine nor cardiovascular responses were related to performance of the reasoning task. We conclude that memory in the elderly is associated both with hypothalamic-pituitary-adrenocortical function and cardiovascular regulation. Disturbances of neuroendocrine and hemodynamic function may be related to greater vulnerability to cognitive decline.
15974835	To achieve a better understanding of learning and declarative memory under mild transient stress, we investigated the effect of brief hypobaric hypoxia on spatial orientation in rats. Young male Wistar rats aged 30 days were exposed for 60 min to hypobaric hypoxia, simulating an altitude of 7,000 m (23,000 ft) either shortly prior to attempting or after mastering an allothetic navigation task in the Morris water maze with a submerged platform. The post-hypoxic group performed significantly better in the navigation task than the control animals (the mean difference in escape latencies was 11 seconds; P=0.0033, two-way ANOVA with repeated measures, group x session). The experimental group also achieved a remarkably higher search efficiency (calculated as a percentage of successful trials per session), especially during the first four days following hypoxic stress (P=0.0018). During the subsequent training, the post-hypoxic group performed better than the control animals, whilst the efficiency levels of both groups progressively converged. Spatial memory retention and recall of well-trained rats were not affected by the transient hypobaric hypoxia. These results indicate that brief hypobaric hypoxia enhances rats' spatial orientation. Our findings are consistent with several studies, which also suggested that mild transient stress improves learning.

15963684	Epidemiological data demonstrate an association between systemic low-grade inflammation defined as 2- to 3-fold increases in circulating inflammatory mediators and age-related decline in cognitive function. However, it is not known whether small elevations of circulating cytokine levels cause direct effects on human neuropsychological functions. We investigated changes in emotional, cognitive, and inflammatory parameters in an experimental in vivo model of low-grade inflammation. In a double-blind crossover study, 12 healthy young males completed neuropsychological tests before as well as 1.5, 6, and 24 h after an intravenous injection of Escherichia coli endotoxin (0.2 ng/kg) or saline in two experimental sessions. Endotoxin administration had no effect on body temperature, cortisol levels, blood pressure or heart rate, but circulating levels of tumor necrosis factor (TNF) and interleukin (IL)-6 increased 2- and 7-fold, respectively, reaching peak values at 3 h, whereas soluble TNF-receptors and IL-1 receptor antagonist peaked at 4.5 h. The neutrophil count increased and the lymphocyte count declined. In this model, low-dose endotoxemia did not affect cognitive performance significantly but declarative memory performance was inversely correlated with cytokine increases. In conclusion, our findings demonstrate a negative association between circulating IL-6 and memory functions during very low-dose endotoxemia independently of physical stress symptoms, and the hypothalamo-pituitary-adrenal axis.
15955958	Thirty patients with multiple sclerosis were randomized to 500 or 2,000 mg of methylprednisolone (MP) over 5 days. They were prospectively studied neuropsychologically before and at days 6 and 60 after onset of the therapy, using a double-blind study design. Patients showed selective deterioration of declarative memory retrieval at day 6, which was fully reversible at day 60. Although the sample size was small, these effects were independent of the administered MP dose.
15944861	The purpose of the present experiments was to investigate the generation of conscious awareness (i.e., of verbal report) in an incidental learning situation. While the single-system account assumes that all markers of learning, verbal or nonverbal, index the same underlying knowledge representation, multiple-systems accounts grant verbal report a special status as a marker of learning because they assume that the nonverbal and verbal effects of learning rely on different memory representations. We tested these two accounts in two experiments in which we held the amount of learning in the nonverbal memory system constant while manipulating independent variables aimed at affecting learning in the declarative system. The results of both experiments revealed significant differences in verbal report between experimental conditions, but no significant differences in response times. Overall, these results provide clear evidence in favor of the multiple-systems account.
15913009	Many behavioral models of the comprehension of suffixed words assume a dual-route mechanism in which these words are accessed sometimes from the mental lexicon as whole units and sometimes in terms of their component morphemes (such as happi+ness). In related neuropsychological work, Ullman et al. (1997) proposed a dual-route model for past tense processing, in which the lexicon (used for access to irregularly inflected forms) corresponds to declarative memory and a medial temporal/ parietal circuit, and the rule system (used for computation of regularly inflected forms) corresponds to procedural memory and a frontal (including Broca's area)/basal ganglia circuit. We used functional MRI and a memory encoding task to test this model for derivationally suffixed words, comparing those words that show evidence of decompositional processing in behavioral studies (-ness, -less, and -able words) with derived words that do not show decomposition effects (-ity and -ation words). By examining Broca's area and the basal ganglia as regions of interest, we found that "decomposable" derived and inflected words showed increases in activity relative to nondecomposable suffixed words. Results support a dual-route model of lexical access of complex words that is consistent with the Ullman et al. proposal.
15910510	Sleep function remains elusive despite our rapidly increasing comprehension of the processes generating and maintaining the different sleep stages. Several lines of evidence support the hypothesis that sleep is involved in the off-line reprocessing of recently-acquired memories. In this review, we summarize the main results obtained in the field of sleep and memory consolidation in both animals and humans, and try to connect sleep stages with the different memory systems. To this end, we have collated data obtained using several methodological approaches, including electrophysiological recordings of neuronal ensembles, post-training modifications of sleep architecture, sleep deprivation and functional neuroimaging studies. Broadly speaking, all the various studies emphasize the fact that the four long-term memory systems (procedural memory, perceptual representation system, semantic and episodic memory, according to Tulving's SPI model; Tulving, 1995) benefit either from non-rapid eye movement (NREM) (not just SWS) or rapid eye movement (REM) sleep, or from both sleep stages. Tulving's classification of memory systems appears more pertinent than the declarative/non-declarative dichotomy when it comes to understanding the role of sleep in memory. Indeed, this model allows us to resolve several contradictions, notably the fact that episodic and semantic memory (the two memory systems encompassed in declarative memory) appear to rely on different sleep stages. Likewise, this model provides an explanation for why the acquisition of various types of skills (perceptual-motor, sensory-perceptual and cognitive skills) and priming effects, subserved by different brain structures but all designated by the generic term of implicit or non-declarative memory, may not benefit from the same sleep stages.
15897257	The crucial role of the medial temporal lobe (MTL) in episodic memory is well established. Although there is little doubt that its anatomical subregions-the hippocampus, peri-, entorhinal and parahippocampal cortex (PHC)-contribute differentially to mnemonic processes, their specific functions in episodic memory are under debate. Data from animal, human lesion, and neuroimaging studies suggest somewhat contradictory perspectives on this functional specialization: a general participation in declarative memory, an exclusive involvement in associative mnemonic processes, and a specific contribution to spatial memory are reported for the hippocampus, adjacent cortices, and the PHC. A functional lateralization in humans dependent on the verbalizability of the material is also discussed herein. To further elucidate the differential contributions of the various MTL subregions to encoding, we employed an object-location association memory paradigm. The memory for each of the studied associations was tested twice: by the object, and by the location serving as retrieval cue. The memory accuracy in response to both cue types was also assessed parametrically. Brain activity during encoding which leads to different degrees of subsequent memory accuracy under the two retrieval conditions was compared. We found the bilateral posterior PHC to participate in encoding of both the object associated with a location and the location associated with an object. In contrast, activity in an area in the left anterior PHC and the right anterior MTL was only correlated with the memory for the location associated with an object.
15892980	Glucocorticoids are known to modulate memory functions, with elevated cortisol levels being associated with impaired declarative memory. This specific effect has been shown in several studies using pharmacological doses of cortisol. The present study was designed to assess the effects of stress-induced cortisol elevations on (1) the type of memory processing (encoding, consolidation and retrieval), and (2) on the emotional valence of the material under study. Sixteen healthy females were presented neutral and emotional material (words and paragraphs) before and after a stress challenge. Declarative memory was tested immediately after presentation and 24 h later (delayed recall). Delayed, but not immediate recall of the information presented after the stress challenge was significantly reduced compared with delayed recall of information presented before the stress challenge. In line with this, strong negative correlations were found for delayed recall of words and spatial memory presented after the challenge with post-stress cortisol levels, whereas no significant correlations were found between cortisol levels and delayed recall at day 1. These results suggest that stress-induced cortisol specifically affects long-term consolidation of declarative memories. These findings may have implications for understanding the effects of traumatic stress on memory functioning in patients with stress-related psychiatric disorders.
15892905	The Verbal Learning Test (VLT; Rey, 1958) evaluates the declarative memory. Despite its extensive use, it has been difficult to establish normative data because test administration has not been uniform. The purpose of the present study was to gather normative data for the VLT for a large number (N = 1855) of healthy participants aged 24-81 years, using a procedure in which the words to be learned were presented either verbally or visually. The results showed that VLT performance decreased in an age-dependent manner from an early age. The learning capacity of younger versus older adults differed quantitatively rather than qualitatively. Females and higher educated participants outperformed males and lower educated participants over the entire age range tested. Presentation mode affected VLT performance differently: auditory presentation resulted in a better recall on Trial 1 (a short-term or working memory measure), whereas visual presentation yielded a better performance on Trial 3, Trial 4, and Delta (a learning measure).
15892901	Arithmetic skills and their cognitive correlates were studied in 24 children with myelomeningocele and shunted hydrocephalus (MM), 27 children with severe traumatic brain injuries (TBI), and 26 children with orthopedic injuries (OI). Their average age was 11.56 years (SD = 2.36). They completed the WRAT-3 Arithmetic subtest and a subtraction task consisting of 20 problems of varying difficulty, as well as measures of working memory, declarative memory, processing speed, planning skills, and visuospatial abilities. The MM group performed more poorly on the WRAT-3 Arithmetic subtest and the subtraction task than the other two groups, which did not differ from each other on either measure. The groups did not differ in the number of math fact errors or visual-spatial errors on the subtraction task, but the MM group made more procedural errors than the OI group. The five cognitive abilities explained substantial variance in performance on both arithmetic tests; processing speed, working memory, declarative memory, and planning accounted for unique variance. Exploratory analyses showed that the cognitive correlates of arithmetic skills varied across groups and ages. Congenital and acquired brain disorders are associated with distinct patterns of arithmetic skills, which are related to specific cognitive abilities.
15879582	Changes in the hypothalamo-pituitary-adrenal (HPA) axis and its rhythm with aging have interesting implications for sleep. Herein, the authors review sleep and HPA changes associated with normal aging and point out the similarities in how they change over time. The authors also discuss the effects of sleep on declarative memory consolidation, in particular. This focused review suggests that some of the declarative memory dysfunction with normal aging, and possibly procedural memory dysfunction, may be partially reversible by instituting methods to augment slow-wave sleep (SWS). Also, agents that decrease nocturnal corticotropin-releasing hormone and the cortisol nadir and enhance SWS may offer potential ways to manipulate the HPA axis/rhythm and improve sleep and memory. In this regard, the authors propose that drugs that act directly on the HPA axis (e.g., mineralocorticoid agonists) may be potentially quite useful for improving both sleep and declarative memory consolidation during sleep.
15877932	Functional abnormalities in muscarinic and nicotinic receptors are associated with a number of disorders including Alzheimer's disease and schizophrenia. While the contribution of muscarinic receptors in modulating cognition is well established in humans, the effects of nicotinic receptors and the interactions and possible synergistic effects between muscarinic and nicotinic receptors have not been well characterized in humans. The current study examined the effects of selective and simultaneous muscarinic and nicotinic receptor antagonism on a range of cognitive processes. The study was a double-blind, placebo-controlled, repeated measures design in which 12 healthy, young volunteers completed cognitive testing under four acute treatment conditions: placebo (P); mecamylamine (15 mg) (M); scopolamine (0.4 mg i.m.) (S); mecamylamine (15 mg)/scopolamine (0.4 mg i.m.) (MS). Muscarinic receptor antagonism with scopolamine resulted in deficits in working memory, declarative memory, sustained visual attention and psychomotor speed. Nicotinic antagonism with mecamylamine had no effect on any of the cognitive processes examined. Simultaneous antagonism of both muscarinic and nicotinic receptors with mecamylamine and scopolamine impaired all cognitive processes impaired by scopolamine and produced greater deficits than either muscarinic or nicotinic blockade alone, particularly on working memory, visual attention and psychomotor speed. These findings suggest that muscarinic and nicotinic receptors may interact functionally to have synergistic effects particularly on working memory and attention and suggests that therapeutic strategies targeting both receptor systems may be useful in improving selective cognitive processes in a number of disorders.
15871604	Specific Language Impairment (SLI) has been explained by two broad classes of hypotheses, which posit either a deficit specific to grammar, or a non-linguistic processing impairment. Here we advance an alternative perspective. According to the Procedural Deficit Hypothesis (PDH), SLI can be largely explained by the abnormal development of brain structures that constitute the procedural memory system. This system, which is composed of a network of inter-connected structures rooted in frontal/basal-ganglia circuits, subserves the learning and execution of motor and cognitive skills. Crucially, recent evidence also implicates this system in important aspects of grammar. The PDH posits that a significant proportion of individuals with SLI suffer from abnormalities of this brain network, leading to impairments of the linguistic and non-linguistic functions that depend on it. In contrast, functions such as lexical and declarative memory, which depend on other brain structures, are expected to remain largely spared. Evidence from an in-depth retrospective examination of the literature is presented. It is argued that the data support the predictions of the PDH, and particularly implicate Broca's area within frontal cortex, and the caudate nucleus within the basal ganglia. Finally, broader implications are discussed, and predictions for future research are presented. It is argued that the PDH forms the basis of a novel and potentially productive perspective on SLI.
15859221	The authors claim that projective identification in the process of analysis should be considered in a circumscribed manner and seen as a very specific type of communication between the patient and the analyst, characterised through a modality that is simultaneously active, unconscious and discrete. In other words, the patient actively, though unconsciously and discretely--that is, in specific moments of the analysis--brings about particular changes in the analysts state. From the analyst's side, the effect of this type of communication is a sudden change in his general state--a sense of passivity and coercion and a change in the state of consciousness. This altered consciousness can range from an almost automatic repetition of a relational script to a moderate or serious contraction of the field of attention to full-fledged changes in the analyst's sense of self. The authors propose the theory that this type of communication is, in fact, the expression of traumatic contents of experiences emerging from the non-declarative memory. These contents belong to a pre-symbolic and pre-representative area of the mind. They are made of inert fragments of psychic material that are felt rather than thought, which can thus be viewed as a kind of writing to be completed. These pieces of psychic material are the expression of traumatic experiences that in turn exercise a traumatic effect on the analyst, inducing an altered state of consciousness in him as well. Such material should be understood as belonging to an unrepressed unconscious. Restitution of these fragments to the patient in representable forms must take place gradually and without trying to accelerate the timing, in order to avoid the possibility that the restitution itself constitute an acting on the part of the analyst, which would thus be a traumatic response to the traumatic action of the analytic material.
15839797	The present study investigated the effect of a single oral dose of hydrocortisone (cortisol) on retrieval of verbal and nonverbal declarative memory. Fifty-nine healthy participants were randomly assigned to either receive 25 mg cortisol or a placebo 45 min before retrieval in a standardized memory test procedure. There was no global effect of cortisol on either verbal or nonverbal memory. However, a specific negative effect on free recall of associative verbal material appeared. In addition, high responders (salivary cortisol concentration>68.25 nmol/L) exhibited impaired verbal memory compared with low responders (<68.25 nmol/L). The results suggest specific nonlinear effects of cortisol on declarative memory retrieval, which appear to be more pronounced for verbal material.
15832873	To examine prospective and declarative memory problems following moderate and severe traumatic brain injury (TBI) and the relationship between prospective memory (PM) and declarative memory and PM and other cognitive functions.The performance of persons who suffered a TBI (n = 25) was compared with that of a demographically matched control group (n = 25).	Measures of time- and event-based PM, visual and verbal declarative memory, attention and executive functioning were administered to both groups.	The group with a TBI performed more poorly on event- and time-based PM, verbal declarative memory, certain aspects of attention and executive functioning. The correlations between the measures of PM, declarative memory and the other cognitive tests were all non-significant.	Problems with declarative memory, attention, and executive functioning do not adequately account for poorer PM performance following a TBI, suggesting that PM should also be assessed following TBI.	
15830236	It is widely accepted that sleep facilitates memory consolidation. Hypnotics (e.g., benzodiazepines), which reportedly increase sleep efficiency but also modify sleep architecture, could affect memory improvement that occurs during sleep.The present study examined the effects of single doses of two short half-life hypnotics, zolpidem and triazolam, on sleep-induced improvement of memory.	Twenty-two healthy volunteers participated in this randomized, double-blind, crossover study. All subjects received a single oral dose of zolpidem (10 mg), triazolam (0.25 mg) or placebo at 9 P.M.: and slept for 7.5+/-0.2 h. The effect of sleep on memory was investigated by comparing the performance of this group of volunteers with a group of 21 subjects in wakefulness condition. Declarative memory was evaluated by using a free-recall test of ten standard word and seven nonword lists. Subjects memorized the word and nonword lists 1 h before dosing and they were asked to recall the memorized lists 10 h after dosing. Digit symbol substitution test (DSST) and forward and backward digit tests were also given 1 h before and 10 h after dosing.	Subjects who slept remembered more nonwords than those in wakefulness condition, but they did not recall significantly more standard words. Neither zolpidem nor triazolam affected the enhanced nonword recall observed after sleep. Finally, none of the hypnotics affected the improvement in the DSST performance of subjects who slept.	The hypnotics tested did not interfere with the nocturnal sleep-induced improvement of memory.	
15828417	Ivan Solomonovich Beritashvili (Beritov) is one of the great Russian physiologists who have created the Russian route of the modern science of behavior. He has proposed and experimentally substantiated a concept of psychoneural activity according to which the behavior controlled by images is the main and higher form of the behavior of vertebrates. Behaviors on the basis of conditioned reflexes and images are qualitatively different activities underlain by different neural substrates. Recently, the Beritashvili's principle ideas have been confirmed by multiple experimental studies of the animal and human cognitive behavior. At present, the concept of the procedural memory formed by training and acquisition and episodic memory formed on the basis of images is commonly accepted. The episodic memory stores the environmental events and phenomena perceived by an animal or a human. Each time when the image is reproduced during perception of environment or its part, an animal performs the same behavioral act as during the actual perception. Beritashvili's viewpoint that the procedural and declarative memories are controlled by different brain structures has been confirmed by experiments.
15820643	A prominent account of conceptual knowledge proposes that information is distributed over visual, tactile, auditory, motor and verbal-declarative attribute domains to the degree to which these features were activated when the knowledge was acquired [D.A. Allport, Distributed memory, modular subsystems and dysphagia, In: S.K. Newman, R. Epstein (Eds.), Current perspectives in dysphagia, Churchill Livingstone, Edinburgh, 1985, pp. 32-60]. A corollary is that when drawing upon this knowledge (e.g., to answer questions), particular aspects of this distributed information is re-activated as a function of the requirements of the task at hand [L.J. Buxbaum, E.M. Saffran, Knowledge of object manipulation and object function: dissociations in apraxic and non-apraxic subjects. Brain and Language, 82 (2002) 179-199; L.J. Buxbaum, T. Veramonti, M.F. Schwartz, Function and manipulation tool knowledge in apraxia: knowing 'what for' but not 'how', Neurocase, 6 (2000) 83-97; W. Simmons, L. Barsalou, The similarity-in-topography principle: Reconciling theories of conceptual deficits, Cognitive Neuropsychology, 20 (2003) 451-486]. This account predicts that answering questions about object manipulation should activate brain regions previously identified as components of the distributed sensory-motor system involved in object use, whereas answering questions about object function (that is, the purpose that it serves) should activate regions identified as components of the systems supporting verbal-declarative features. These predictions were tested in a functional magnetic resonance imaging (fMRI) study in which 15 participants viewed picture or word pairs denoting manipulable objects and determined whether the objects are manipulated similarly (M condition) or serve the same function (F condition). Significantly greater and more extensive activations in the left inferior parietal lobe bordering the intraparietal sulcus were seen in the M condition with pictures and, to a lesser degree, words. These findings are consistent with the known role of this region in skilled object use [K.M. Heilman, L.J. Gonzalez Rothi, Apraxia, In: K.M. Heilman, E. Valenstein (Eds.), Clinical Neuropsychology, Oxford University Press, New York, 1993, pp. 141-150] as well as previous fMRI results [M. Kellenbach, M. Brett, K. Patterson, Actions speak louder than functions: the importance of manipulability and action in tool representation, Journal of Cognitive Neuroscience, 15 (2003) 30-46] and behavioral findings in brain-lesion patients [L.J. Buxbaum, E.M. Saffran, Knowledge of object manipulation and object function: dissociations in apraxic and non-apraxic subjects, Brain and Language, 82 (2002) 179-199]. No brain regions were significantly more activated in the F than M condition. These data suggest that brain regions specialized for sensory-motor function are a critical component of distributed representations of manipulable objects.
15814006	Neuroimaging and neuropsychological data suggest that episodic and semantic memory may be mediated by distinct neural systems. However, an alternative perspective is that episodic and semantic memory represent different modes of processing within a single declarative memory system. To examine whether the multiple or the unitary system view better represents the data we conducted a network analysis using multivariate partial least squares (PLS ) activation analysis followed by covariance structural equation modeling (SEM) of positron emission tomography data obtained while healthy adults performed episodic and semantic verbal retrieval tasks. It is argued that if performance of episodic and semantic retrieval tasks are mediated by different memory systems, then there should differences in both regional activations and interregional correlations related to each type of retrieval task, respectively. The PLS results identified brain regions that were differentially active during episodic retrieval versus semantic retrieval. Regions that showed maximal differences in regional activity between episodic retrieval tasks were used to construct separate functional models for episodic and semantic retrieval. Omnibus tests of these functional models failed to find a significant difference across tasks for both functional models. The pattern of path coefficients for the episodic retrieval model were not different across tasks, nor were the path coefficients for the semantic retrieval model. The SEM results suggest that the same memory network/system was engaged across tasks, given the similarities in path coefficients. Therefore, activation differences between episodic and semantic retrieval may ref lect variation along a continuum of processing during task performance within the context of a single memory system.
15813497	Sex invariance of a six-factor, higher order model of declarative memory (two second-order factors: episodic and semantic memory; and four first-order factors: recall, recognition, fluency, and knowledge) was established for 1,796 participants (35-85 years). Metric invariance of first- and second-order factor loadings across sex was demonstrated. At the second-order level, a female advantage was observed for both episodic and semantic memory. At the first-order level, sex differences in episodic memory were apparent for both recall and recognition, whereas the differences in semantic memory were driven by a female superiority in fluency. Additional tests of sex differences in three age groups (35-50, 55-65, and 70-85 years of age) indicated that the female superiority in declarative memory diminished with advancing age. The factor-specific sex differences are discussed in relation to sex differences in hippocampal function.
15802203	Despite strong evidence supporting a role for sleep in the consolidation of newly acquired declarative memories, the contribution of specific sleep stages remains controversial. Based on electrophysiological studies in animals, synchronous sleep oscillations have been long proposed as possible origins of sleep-related memory improvement. Nevertheless, no studies to date have directly investigated the impact of sleep oscillations on overnight memory retention in humans. In the present study we provide evidence that overnight verbal memory retention is highly correlated with the number of sleep spindles detected by an automatic algorithm over left frontocentral areas. At the same time, overnight retention of newly learned faces was found to be independent of spindle activity but correlated with non-rapid-eye-movement sleep time. The data strongly support theories suggesting a link between sleep spindle activity and verbal memory consolidation.
15801514	This paper examines some of the mechanisms through which interpretation aimed primarily at increasing conscious awareness can nonetheless produce unconscious changes, the latter being deemed the basic aim of psychoanalysis. The concept of valency or motivational weight of the interpretation is proposed to assess which forces of the various motivational systems the interpretation mobilizes (hetero/self-preservation, sensual/sexual, attachment, narcissistic, psychobiological regulation etc.), on which of the above-mentioned systems interpretation relies, and which would oppose therapeutic intervention and why. Certain conditions are also analyzed that could explain the so-called 'change through the analytic relationship', pointing out that, despite the major differences between this form of change and change through interpretation, both of them would share certain mechanisms. This conclusion leads to the need to qualify the idea that interpretation would be exclusively aimed at declarative memory, with no effects upon procedural memory. The paper examines the potential consequences for therapeutic techniques derived from recent findings in neuroscience on so-called labile state memory, and proposes the coupling of experiences as one of the analytical instruments used for therapeutic change. A clinical vignette is included to illustrate some of the theoretical and technical aspects considered.
15795006	Within the field of cognitive neuroscience, it has become widely accepted to distinguish between declarative and nondeclarative memory, with different neurobiological substrates subserving these memory structures. This distinction has been inferred from the study of amnesic patients, including those suffering from Korsakoff's syndrome. It is commonly agreed that Korsakoff patients demonstrate intact memory for motor and perceptual skills (nondeclarative) whereas memory of various forms of factual knowledge (declarative) is severely impaired. In the present study, Korsakoff patients and a group of age-matched controls learned a new bimanual motor skill whereby performance was assessed in the presence and absence of augmented visual information feedback. Findings demonstrated that Korsakoff patients were able to learn and retain this skill when directive augmented information feedback was provided while no learning occurred at all in the absence of this information. These observations shed new light on the conditions required for preserved memory in amnesic patients and challenge the classic view that nondeclarative memory is invariably preserved. Instead, the quality of memory across both motor and cognitive dimensions appears to depend on the availability of task-specific information to guide performance, presumably allowing amnesic patients to bypass affected brain areas. This prompts for a reevaluation of current notions about procedural memory capacity in Korsakoff patients.
15788259	Snyder and Mitchell (1999) have argued that the extraordinary skills of savants, including mathematics and drawing, are within us all but cannot normally be accessed without some form of brain damage. It has also been argued that such skills can be made accessible to normal people by switching off part of their brain artificially using magnetic pulses (Carter, 1999). Using repetitive transcranial magnetic stimulation (rTMS) to interrupt the function of the frontotemporal lobe, a region of the brain implicated in the development of savant skills (Miller et al., 1996,1998), we tested this hypothesis. Here we show that savant-type skills improved in 5 out of 17 participants during the period of stimulation. The enhanced skills included declarative memory, drawing, mathematics, and calendar calculating. In addition to overall improvement being observed, striking improvements in individual performance on various tasks were also seen.
15784435	Functional magnetic resonance imaging (fMRI) was used to map hippocampal activation during a declarative memory task in a sample of 14 adolescents with antecedents of prematurity (AP). The sample with AP was matched by age, sex and handedness with 14 full-term controls with no history of neurological or psychiatric illness. The target task consisted in learning 16 novel face-name pairs, and the control task involved the examination of two repeated face-name pairs. Stereological methods were also used to quantify hippocampal volumes. In both groups, we observed increased activation in the learning condition compared to the control task in the right fusiform gyrus and the left inferior occipital gyrus, but only premature subjects activated the hippocampus. Group comparison of the activation versus control conditions showed that prematures had greater activity in the right hippocampus than controls during the encoding of the word-face association. Volumetric analyses showed a significant left hippocampal volume loss in adolescents with AP. In addition, we found a significant positive correlation in the premature group between right hippocampal activation and face-name recognition. Functional MRI data also correlated with structural MRI data: right hippocampal activation correlated positively with right hippocampal volume. Our findings are consistent with previous studies of brain plasticity after focal lesions. Left hippocampal tissue loss may be related to an increase in contralateral brain activity, probably reflecting a compensatory mechanism. Our data also suggest that this plasticity is not enough to achieve normal performance.
15782361	This review describes the concepts, temporal dynamics and main features of learning and memory systems from a comprehensive molecular, neuroanatomical, neurophysiological, cognitive and behavioural approach.Starting with molecular mechanisms of synaptic plasticity we describe the memory stages, implicit and explicit memory systems, working memory, remembering and forgetting. Each process is illustrated with examples of recent experimental and clinical research.	Learning and memory are closely related brain processes which give rise to adaptive changes in behaviour. Implicit memory is a kind of unconscious and rigid memory for habits, which is based on brain regions processing perceptions and motor and emotional information, like the neocortex, the neostriatum, the cerebellum or the amygdala. Explicit or declarative memory is a conscious and flexible memory, hippocampus-dependent. Working memory is actually a system of executive cognition, based on interactions between the prefrontal cortex and other brain regions. The retrieval of complex memories consist of an active process of reconstruction of the past which incorporates new experiences of the subject who is remembering. The reactivation of memories can initiate genuine processes of reconsolidation and extinction. Forgetting could depend on alterations in the neural networks storing the information or, otherwise, on active processes which hinder consolidation or block the expression of the memories.	
15769210	Five-year changes in episodic and semantic memory were examined in a sample of 829 participants (35-80 years). A cohort-matched sample (N=967) was assessed to control for practice effects. For episodic memory, cross-sectional analyses indicated gradual age-related decrements, whereas the longitudinal data revealed no decrements before age 60, even when practice effects were adjusted for. Longitudinally, semantic memory showed minor increments until age 55, with smaller decrements in old age as compared with episodic memory. Cohort differences in educational attainment appear to account for the discrepancies between cross-sectional and longitudinal data. Collectively, the results show that age trajectories for episodic and semantic memory differ and underscore the need to control for cohort and retest effects in cross-sectional and longitudinal studies, respectively.
15763174	Sleep may partly exert a positive influence on memory through the processing underlying the transformation of items of declarative knowledge into contents of mental sleep experience (MSE). This hypothesis implies that the level of consolidation (and thus, long-term retention) should be enhanced for those items which are repeatedly processed and transformed into identical or very similar (so-called interrelated) contents of distinct MSEs developed over the same night. To test this prediction, we examined accessibility at delayed recall (i.e., the next morning) of the interrelated contents of MSEs reported (immediate recall) by 14 subjects who were awakened during the first four periods of rapid eye-movement (REM) sleep in two experimental nights. Interrelated contents were much more frequent, and at delayed recall much better retained, than other, non-interrelated contents in report pairs of MSEs. Moreover, they were also more frequent and better retained than by-chance similar or identical contents, as estimated in report pairs of MSEs of different subjects. These findings provide partial but coherent evidence in favour of the hypothesis that a generation effect occurs during sleep, with a further consolidation of the input and the output of MSE processing (respectively, the items of declarative knowledge and the contents of MSEs resulting from their elaboration during sleep).
15737670	In humans and animals, corticosteroid excess is associated with impairment in declarative memory and changes in hippocampal structure. In animals, phenytoin pretreatment blocks the effects of stress on memory and hippocampal histology, although no studies have examined the use of phenytoin to prevent corticosteroid-associated memory changes in humans. Mood changes are also common with corticosteroids, but few treatment data are available. This report examines whether phenytoin can prevent mood or declarative memory changes secondary to bursts of prescription corticosteroids.Thirty-nine patients with allergies or pulmonary or rheumatologic illnesses and given systemic corticosteroid therapy were randomized to receive either phenytoin (300 mg/day) or placebo concurrently with the corticosteroids. Mood was assessed with the Hamilton Rating Scale for Depression, Young Mania Rating Scale, and Activation (ACT) subscale of the Internal State Scale; declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and after approximately 7 days of corticosteroid plus phenytoin or placebo therapy.	The two groups were similar in age, gender, education, and corticosteroid dose. The phenytoin-treated group showed significantly smaller increases on the ACT, a mania self-report scale, than the placebo-treated group. Groups did not differ significantly on RAVLT change scores.	This is the first placebo-controlled study to examine whether a medication can prevent mood and memory changes secondary to corticosteroids. Phenytoin blocked the hypomanic effects of prescription corticosteroids; however, phenytoin did not block the declarative memory effects of corticosteroids.	
15729134	Few studies have tested the correlation between traditional declarative memory scores and functional brain imaging measures of memory. We examined the predictable capabilities of magnetoencephalography-derived measures, scanned during a high-load encoding-memory task, in the immediate (LM-1) and delayed (LM-2) recall from the Wechsler memory scale. The number of activity sources on the left frontal pole (between 300 and 600 ms) predicted scores in LM-1 and LM-2. Collapsing the activity in the left frontal pole and the orbitofrontal cortex increased the goodness of the solution for the LM-2 scores. The fact that rostral-frontal measures achieved significant values highlights the importance of executive processes, such as the implementation of memory strategies and top-down control mechanisms, in the performance of high-load memory tasks.
15716474	Arithmetic reasoning is arguably one of the most important cognitive skills a child must master. Here we examine neurodevelopmental changes in mental arithmetic. Subjects (ages 8-19 years) viewed arithmetic equations and were asked to judge whether the results were correct or incorrect. During two-operand addition or subtraction trials, for which accuracy was comparable across age, older subjects showed greater activation in the left parietal cortex, along the supramarginal gyrus and adjoining anterior intra-parietal sulcus as well as the left lateral occipital temporal cortex. These age-related changes were not associated with alterations in gray matter density, and provide novel evidence for increased functional maturation with age. By contrast, younger subjects showed greater activation in the prefrontal cortex, including the dorsolateral and ventrolateral prefrontal cortex and the anterior cingulate cortex, suggesting that they require comparatively more working memory and attentional resources to achieve similar levels of mental arithmetic performance. Younger subjects also showed greater activation of the hippocampus and dorsal basal ganglia, reflecting the greater demands placed on both declarative and procedural memory systems. Our findings provide evidence for a process of increased functional specialization of the left inferior parietal cortex in mental arithmetic, a process that is accompanied by decreased dependence on memory and attentional resources with development.
15707912	Psychologists have shown that recall of sentences describing previously performed actions is enhanced compared to recall of heard-only action-phrases (enactment effect). One interpretation of this effect argues that subjects benefit from a multi-modal encoding where movement plays a major role. In line with this motor account, it is conceivable that the beneficial effect of enactment might rely, at least in part, on procedural learning, thus tapping more directly implicit memory functions. Neuropsychological observations support this hypothesis, as shown by the fact that the enactment effect is quite insensitive to perturbations affecting declarative memories. i.e. Alzheimer disease. Memory for subject performed tasks in patients with Korsakoff syndrome. The present study attempts to evaluate whether pure motor activity is sufficient to guarantee the described memory facilitation or alternatively, whether first-person experience in carrying out the action (i.e. true enactment) would be required. To this purpose, in a first experiment on healthy subjects, we tested whether sentence meaning and content of the executed action should match in order to produce facilitation in recall of enacted action-phrases. In a second experiment, we explored whether the enactment effect is present in patients suffering from psychiatric disorders supposed to spare procedural memory but to alter action awareness (e.g. schizophrenia). We show that better recall for action phrases is found only when the motor component is a true enactment of verbal material. Moreover, this effect is nearly lost in schizophrenia. This latter result, on the one hand, queries the automatic/implicit nature of the enactment effect and supports the role of the experience of having performed the action in the first-person. On the other hand, it questions the nature of the memory impairments detected in schizophrenia.
15698895	A new apparatus, the olfactory tubing maze for mice, was developed recently to study learning and memory processes in mice in regard to their ethological abilities. As in humans, BALB/c mice with selective bilateral lesions of the hippocampal formation showed selective impairment of subcategories of long-term memory when tested with the olfactory tubing maze. After three learning sessions, control mice reached a high percentage of correct responses. They consistently made the olfactory-reward associations, but antero-dorsal and postero-ventral hippocampal-lesioned mice did not. However, all lesioned mice learned the paradigm and the timing of the task as fast and as well as control mice. These data suggest that the olfactory tubing maze can be used to study subcategories of memory, such as declarative and non-declarative memory, which are similar in some respects to those observed in humans. Consequently, possible memory effects of classical approaches (i.e., pharmacological or lesion studies) or genetic modifications in transgenic or gene-targeting mice can be effectively analyzed using this new apparatus.
15685392	Evidence for a response-control-related kind of declarative memory during deep propofol anesthesia has recently been reported. Connectivity within the mediotemporal lobe (MTL), and in particular rhinal-hippocampal synchronization within the gamma band, has been shown to be crucial for declarative memory formation. Thus, we analyzed EEG recordings obtained from the scalp, as well as directly from within the hippocampus and from the anterior parahippocampal gyrus, which is covered by rhinal cortex, in patients with unilateral temporal lobe epilepsy during propofol anesthesia, which preceded electrode explantation. For the gamma band a power decrease starting with induction of anesthesia was observed at scalp position Cz, but a power increase was detected at MTL locations. In contrast to prior results for sleep recordings, rhinal-hippocampal coherence did not decrease within the gamma band at deeper levels of anesthesia. These findings may represent an indirect electrophysiological correlate of partially intact declarative memory formation during deep propofol sedation. Furthermore, we investigated how well the plasma propofol level, as well as different stages of anesthesia including the burst suppression phase, could be monitored by different spectral as well as by nonlinear EEG measures. We observed that conventional spectral power measures, most prominently those recorded from mediotemporal locations, are most closely correlated with the plasma propofol level, whereas different stages of anesthesia can be distinguished best by nonconventional spectral as well as nonlinear measures.
15683137	Functional significance of stage 2 sleep spindle activity for declarative memory consolidation.Randomized, within-subject, multicenter.	Weekly sleep laboratory visits, actigraphy, and sleep diary (4 weeks).	Twenty-four healthy subjects (12 men) aged between 20 and 30 years.	Declarative memory task or nonlearning control task before sleep.	This study measured spindle activity during stage 2 sleep following a (declarative) word-pair association task as compared to a control task. Participants performed a cued recall in the evening after learning (160 word pairs) as well as in the subsequent morning after 8 hours of undisturbed sleep with full polysomnography. Overnight change in the number of recalled words, but not absolute memory performance, correlated significantly with increased spindle activity during the experimental night (r24 = .63, P < .01). Time spent in each sleep stage could not account for this relationship.	A growing body of evidence supports the active role of sleep for information reprocessing. Whereas past research focused mainly on the distinct rapid eye movement and slow-wave sleep, these results indicate that increased sleep stage 2 spindle activity is related to an increase in recall performance and, thus, may reflect memory consolidation.	

15677410	Nocturnal cortisol release in humans is synergistically regulated by circadian rhythm and sleep. Cortisol concentrations typically reach a nadir during the slow wave sleep-rich periods of early nocturnal sleep, whereas during the late night, when rapid eye movement (REM) sleep predominates, cortisol levels are enhanced. Here we review a series of our own studies examining whether and how this regulation of cortisol release affects the consolidation of memories during sleep. The studies show that increasing cortisol during early slow wave sleep-rich periods of nocturnal sleep impairs hippocampus-dependent declarative memory formation. Preventing the natural increase in cortisol during REM sleep-rich sleep in the late night appears to enhance amygdala-dependent emotional memory. The findings are consistent with the view that cortisol via activation of limbic glucocorticoid receptors generally diminishes memory consolidation.
15677402	Brain imaging studies have mapped out the neural circuitry of posttraumatic stress disorder (PTSD), implicating brain areas sensitive to stress such as the hippocampus. Animal studies show that antidepressants promote hippocampal neurogenesis and block the effects of stress on the hippocampus. We found that treatment of PTSD patients for a year with the serotonin reuptake inhibitor (SSRI) paroxetine resulted in a 5% increase in hippocampal volume and a 35% improvement in verbal declarative memory function. Patients subjectively reported an improvement in cognition and work performance. These studies are consistent with the idea that antidepressants have a beneficial effect on hippocampal function in PTSD patients.
15664114	The high abundance of the cannabinoid receptor type 1 (CB1) in the brain and the discovery of its endogenous ligands possessing neuromodulatory activities suggest an important potential of the endocannabinoid system to influence the functions of other receptor systems in the brain, including the corticotropin releasing hormone (CRH) system. Several studies evidenced a cross-talk between these two receptor systems. In trying to detail functional interactions between CB1 and the CRH receptor type 1 (CRHR1), we performed double-label-in situ hybridisation on mouse forebrain sections to localise the transcripts encoding the two receptors at a cellular level. Colocalisation of both receptor mRNAs was only detected in low CB1-expressing cells, which are mainly principal projecting neurons, whereas high CB1-expressing cells, which are considered to be mostly GABAergic did not contain mRNA encoding CRHR1. CB1 is differentially coexpressed with CRHR1 in olfactory regions, in several cortical and limbic structures, and in some hypothalamic and thalamic nuclei. These observations suggest a complex mechanism underlying the mutual interrelation and modulation of the two receptor systems. In particular, high levels of coexpressing cells in cortical and limbic areas may relate to cognitive functions, such as working memory, emotional and declarative learning. Colocalisation of CB1 and CRHR1 in hypothalamic regions strongly suggests functional interactions regarding the neuroendocrine homeostasis, including feeding behaviour.
15660850	The second year of life is marked by changes in the robustness of recall memory. Both retrieval and storage processes have been implicated as the major source of age-related improvements in recall. Children 13 to 20 months of age were matched for levels of learning of laboratory events (thereby eliminating encoding as a source of developmental difference) and tested for recall after delays as long as 6 months. In Experiment 1, 16-month-olds evidenced less loss of information and more relearning than 13-month-olds. In Experiment 2, 20-month-olds evidenced less loss of information and more relearning than 16-month-olds. Patterns of performance across test trials and in relearning implicate a decline in susceptibility to storage failure as the primary source of the observed developmental trend.
15659423	The Declarative/Procedural Model of Pinker, Ullman and colleagues claims that the basal ganglia are part of a fronto-striatal procedural memory system which applies grammatical rules to combine morphemes (the smallest meaningful units in language) into complex words (e.g. talk-ed, talk-ing). We tested this claim by investigating whether striatal damage or loss of its dopaminergic innervation is reliably associated with selective regular past tense deficits in patients with subcortical cerebrovascular damage, Parkinson's disease or Huntington's disease. We focused on past tense morphology since this allows us to contrast the regular past tense (jump-jumped), which is rule-based, with the irregular past tense (sleep-slept), which is not. We used elicitation and priming tasks to test patients' ability to comprehend and produce inflected forms. We found no evidence of a consistent association between striatal dysfunction and selective impairment of regular past tense morphology, suggesting that the basal ganglia are not essential for processing the regular past tense as a sequence of morphemes, either in comprehension or production, in contrast to the claims of the Declarative/Procedural Model. All patient groups showed normal activation of semantic and morphological representations in comprehension, despite difficulties suppressing semantically appropriate alternatives when trying to inflect novel verbs. This is consistent with previous reports that striatal dysfunction spares automatic activation of linguistic information, but disrupts later language processes that require inhibition of competing alternatives.
15652874	It has been suggested that hypercortisolemia may cause or exacerbate both neurocognitive impairment and symptoms in schizophrenia. We hypothesized that antiglucocorticoid treatments, particularly glucocorticoid receptor (GR) antagonists, would improve neurocognitive functioning and clinical symptoms in this disorder.Twenty patients with schizophrenia were treated with 600 mg/day of the GR-antagonist mifepristone (RU-486) or placebo for 1 week in a double-blind, crossover design. Neurocognitive function was evaluated at baseline and 2 weeks after each treatment. Neuroendocrine profiling was performed at these times and also immediately after each treatment. Symptoms were evaluated weekly.	Mifepristone administration resulted in a temporary two- to threefold increase in plasma cortisol levels (p < .0001). No significant effects were observed on any measure of neurocognitive function, including the primary outcome measures of spatial working memory and declarative memory. Minor changes in symptoms occurred in both arms of the study and were indicative of a general improvement over time, irrespective of treatment.	In contrast to our earlier report of positive effects in bipolar disorder, these data suggest that the GR-antagonist mifepristone has no effect on neurocognitive function or symptoms in this group of patients with schizophrenia. Future studies in schizophrenia should examine patients with demonstrable hypothalmic-pituitary-adrenal axis dysfunction.	
15645067	Memory is broadly divided into declarative and nondeclarative forms of memory. The hippocampus is required for the formation of declarative memories, while a number of other brain regions including the striatum, amygdala and nucleus accumbens are involved in the formation of nondeclarative memories. The formation of all memories require morphological changes of synapses: new ones must be formed or old ones strengthened. These changes are thought to reflect the underlying cellular basis for persistent memories. Considerable advances have occurred over the last decade in our understanding of the molecular bases of how these memories are formed. A key regulator of synaptic plasticity is a signaling pathway that includes the mitogen activated protein (MAP) kinase. As this pathway is required for normal memory and learning, it is not surprising that mutations in members of this pathway lead to disruptions in learning. Neurofibromatosis, Coffin-Lowry syndrome and Rubinstein-Taybi syndrome are three examples of developmental disorders that have mutations in key components of the MAP kinase signaling pathway.
15629753	Patients with Dissociative Identity Disorder (DID) frequently report episodes of interidentity amnesia, that is amnesia for events experienced by other identities. The goal of the present experiment was to test the implicit transfer of trauma-related information between identities in DID. We hypothesized that whereas declarative information may transfer from one identity to another, the emotional connotation of the memory may be dissociated, especially in the case of negative, trauma-related emotional valence. An evaluative conditioning procedure was combined with an affective priming procedure, both performed by different identities. In the evaluative conditioning procedure, previously neutral stimuli come to refer to a negative or positive connotation. The affective priming procedure was used to test the transfer of this acquired valence to an identity reporting interidentity amnesia. Results indicated activation of stimulus valence in the affective priming task, that is transfer of emotional material between identities.
15626819	Recent investigations in several species have suggested a role for brain-derived neurotrophic factor (BDNF) in memory, which may be mediated by the influence of BDNF on neuronal plasticity in the hippocampus. BDNF polymorphisms have also been associated with mood disorders. Catechol-O-methyltransferase (COMT) metabolizes dopamine and has been implicated in prefrontal function, another area of the brain relevant for memory. In a sample of 63 young adults with a history of childhood-onset mood disorder, we typed three BDNF polymorphisms, including the BDNF Val66Met single nucleotide polymorphism (SNP), and the COMT Val108/158Met SNP. Multivariate analysis of variance was used to test the association between BDNF and COMT markers and measures of declarative memory. Variants at the three BDNF markers and one COMT marker were not associated with declarative memory function p-values ranged from 0.25 to 0.98. Higher IQ (F = 6.18, df = 4, 58, p = 0.0003) and female gender (F = 4.41, df = 4, 58, p = 0.0035) were associated with more optimal performance on the memory tasks. This study did not provide evidence supporting an association between BDNF and COMT genes and declarative memory phenotypes.
15622510	Recent developments in neuroscience have increased our knowledge of the physiology of sleep and dreaming, and thus the number of studies about the influence of sleep on learning and memory have increased rapidly. In this review the objective is to assess the relationship between sleep and memory considering the evidence regarding the neurobiology of sleep and dreaming.This is a retrospective literature review and the relevant studies from the last 10 years are included. For this purpose the PubMed search engine and the key words "sleep, neurobiology, synaptic plasticity, memory" were used.	Sleep-wake and NREM-REM cycles are accompanied by neuromodulatory influences on forebrain structures that affect behavior, consciousness and cognition. Animal and human studies in which learning paradigms are used to assess the influence of sleep deprivation on memory show the influence of sleep on memory consolidation. Different sleep stages have different effects on memory processes. Some investigators claim that NREM improves declarative memory while REM improves procedural and implicit memory. Other investigators suggest that NREM and REM affect memory in a complementary and sequential way. Molecular and electrophysiological evidence suggests that the influence of sleep on memory is through synaptic plasticity.	Studies about the physiology of sleep and dreaming will help us to understand consciousness and memory better. The reverse is also true: understanding the contribution of sleep stages to memory will help us to determine the advantages of sleep and dreaming in an evolutionary perspective.	
15608014	We investigated residual brain damage in subjects who suffered severe traumatic brain injury (TBI) in childhood, and its relationship with declarative memory impairment. Magnetic resonance imaging (MRI) volumetric data and memory performance were compared between 16 adolescents with antecedents of severe TBI and 16 matched normal controls. Volumes of grey matter, white matter, cerebrospinal fluid (CSF), hippocampus, and caudate nuclei were measured. Verbal memory was assessed by the Rey's Auditory Verbal Learning test and visual memory by the Rey's Complex Figure. TBI patients performed significantly worse than controls in both verbal and visual memory. Patients presented decreased white matter volume and increased CSF. The hippocampus was reduced, but not the caudate nuclei. Memory performance correlated with CSF. Plasticity is incomplete for structural and functional deficits in children with TBI. Hippocampal atrophy, white matter loss, and memory impairment remain until adolescence. Memory sequelae are related more to diffuse brain injury, as reflected by MRI findings of increased CSF, than to hippocampal injury.
15607689	Verbal declarative memory is one of the most reliably impaired cognitive functions in schizophrenia. Important issues are whether the problem is reversible, and which brain regions underlie improvement. We showed previously that glucose administration improved declarative memory in patients with schizophrenia, and sought in this pilot study to identify whether glucose affects the location or degree of activation of brain regions involved in a verbal encoding task. Seven clinically stable and medicated patients with schizophrenia or schizoaffective disorder, who showed deficits on a clinical test of memory, participated in the study. Subjects served as their own controls in a double-blind, crossover protocol that consisted of two sessions about a week apart. In each session, subjects ingested a beverage flavored with lemonade that contained 50 g of glucose on one occasion, and saccharin on the other. Blood glucose was measured before and 15, 50, and 75 min after ingestion. After ingesting the beverage, they performed a verbal encoding task while undergoing brain functional magnetic resonance imaging. The results showed significantly greater activation of the left parahippocampus during novel sentence encoding in the glucose condition, compared to the saccharin condition, despite no change in memory performance. A trend towards greater activation of the left dorsolateral prefrontal cortex (p<.07) was also evident in the glucose condition. These pilot findings emphasize the sensitivity of both the medial temporal and prefrontal regions to effects of glucose administration during encoding, and are consistent with the hypothesis that these regions also participate in declarative memory improvements following glucose administration.
15602981	The central pattern generator (CPG) that drives aerial respiratory behaviour in Lymnaea consists of 3 neurons. One of these, RPeD1--the cell that initiates activity in the circuit, plays an absolutely necessary role as a site for memory formation, memory reconsolidation, and extinction. Using an operant conditioning training procedure that results in a long-term non-declarative memory (LTM), we decrease the occurrence of aerial respiratory behaviour. Since snails can still breathe cutaneously learning this procedure is not harmful. Concomitant with behavioural memory are changes in the spiking activity of RPeD1. Going beyond neural correlates of memory we directly show that RPeD1 is a necessary site for LTM formation. Expanding on this finding we show that this neuron is also a necessary site for memory reconsolidation and 'Pavlovian' extinction. As far as we can determine, this is the first time a single neuron has been shown to be a necessary site for these different aspects memory. RPeD1 is thus a key neuron mediating different hierarchical aspects of memory. We are now in a position to determine the necessary neuronal, molecular and proteomic events in this neuron that are causal to memory formation, reconsolidation and extinction.
15598125	The present study aimed to assess the effects of aging and awareness on conditional discrimination learning within an eyeblink conditioning procedure by using a consecutive age-groups design (20-35 years, 36-50 years, 51-65 years, 66-80 years). Increasing age was associated with a decline in overall eyeblink conditioned response (CR) frequency and a deficit in conditional discrimination learning in the 2 older groups. Awareness of stimulus contingencies affected discrimination performance but not overall CR rates in younger subjects. Older subjects did not achieve eyeblink conditional discrimination learning, regardless of awareness. Discrimination performance correlated with measures of declarative memory. The pattern of results is discussed with respect to the involvement of hippocampal-cerebellar interactions and awareness in the mediation of age-related conditioning changes.
15585567	To determine the role played by the beta-adrenergic and corticosteroid systems in the modulatory effects of stress on declarative memory function, 42 young men were administered a placebo, propranolol (beta-adrenergic blocker), or metyrapone (corticosteroid synthesis inhibitor) before being submitted to a psychological stress protocol. Immediately after stress, subjects viewed a neutral story, unrelated to the stressor. Short- (5 min post learning) and long-term (1 wk post learning) recall of the story was assessed. Placebo and propranolol groups showed significant stress-related increases in corticosteroid levels, whereas metyrapone prevented corticosteroid reactivity to the stressor. Stress triggered significant elevations in cardiac activity (heart rate, systolic and diastolic blood pressure levels) in all three groups, with the metyrapone group showing the strongest elevation in heart rate levels in response to stress. Compared with placebo, propranolol had no effect on short- and long-term recall of the story learned after stress, whereas metyrapone impaired short-term recall of the story, with no further effects on long-term declarative memory. These results suggest that, contrary to the beta-adrenergic system, the corticosteroid system is implicated in declarative memory function after stress in humans.
15583117	The etiology of Tourette syndrome (TS) involves disturbances in the structure and function of the basal ganglia. The basal ganglia mediate habit learning.To study habit learning in persons with TS.	Patients with TS were compared with normal controls in performance on a probabilistic classification, or habit-learning task (weather prediction).	University research institute.	One hundred twenty-three children and adults, 56 with a diagnosis of TS and 67 healthy control subjects.	Habit learning was assessed by the extent of improvement in accuracy of predictions and reaction times over trial blocks during performance of the weather prediction task. Declarative learning was assessed by performance on 3 tasks that required intact declarative memory functioning.	Children with TS were impaired at habit learning relative to normal controls (P = .01). This finding was replicated in the independent sample of adults with TS (P = .01). The rate of learning correlated inversely with the severity of tic symptoms across both samples (r = -0.34; P = .01). Thus, impaired learning accompanied more severe symptoms. Measures of declarative memory functioning, in contrast, were normal in the TS groups.	Striatal learning systems are uniquely dysfunctional in both children and adults with TS. The correlation of habit learning with symptom severity suggests that the number and severity of tics are a function of the degree to which the system for habit learning is dysfunctional. Thus, both the deficits in habit learning and the tic symptoms of TS are likely to be consequences of the previously reported anatomical and functional disturbances of the striatum in children and adults who have TS. The existence of a well-developed animal model for this learning system, which permits study of the neural and molecular bases of habit learning, has important implications for the neurobiological study of TS and for the development of new or improved therapeutics for this condition.	
15576885	Of late, an increasing number of studies have shown a strong relationship between sleep and memory. Here we summarize a series of our own studies in humans supporting a beneficial influence of slow-wave sleep (SWS) on declarative memory formation, and try to identify some mechanisms that might underlie this influence. Specifically, these experiments show that declarative memory benefits mainly from sleep periods dominated by SWS, whereas there is no consistent benefit of this memory from periods rich in rapid eye movement (REM) sleep. A main mechanism of declarative memory formation is believed to be the reactivation of newly acquired memory representations in hippocampal networks that stimulates a transfer and integration of these representations into neocortical neuronal networks. Consistent with this model, spindle activity and slow oscillation-related EEG coherence increase during early sleep after intense declarative learning in humans, signs that together point toward a neocortical reprocessing of the learned material. In addition, sleep seems to provide an optimal milieu for declarative memory reprocessing and consolidation by reducing cholinergic activation and the cortisol feedback to the hippocampus during SWS.
15576883	Do our memories remain static during sleep, or do they change? We argue here that memory change is not only a natural result of sleep cognition, but further, that such change constitutes a fundamental characteristic of declarative memories. In general, declarative memories change due to retrieval events at various times after initial learning and due to the formation and elaboration of associations with other memories, including memories formed after the initial learning episode. We propose that declarative memories change both during waking and during sleep, and that such change contributes to enhancing binding of the distinct representational components of some memories, and thus to a gradual process of cross-cortical consolidation. As a result of this special form of consolidation, declarative memories can become more cohesive and also more thoroughly integrated with other stored information. Further benefits of this memory reprocessing can include developing complex networks of interrelated memories, aligning memories with long-term strategies and goals, and generating insights based on novel combinations of memory fragments. A variety of research findings are consistent with the hypothesis that cross-cortical consolidation can progress during sleep, although further support is needed, and we suggest some potentially fruitful research directions. Determining how processing during sleep can facilitate memory storage will be an exciting focus of research in the coming years.
15576060	Elevated endogenous levels of corticosteroids cause neural dysfunction and loss, especially within the hippocampus, as well as cognitive impairment in hippocampus-mediated tasks. Because Cushing's syndrome patients suffer from hypercortisolism, they represent a unique opportunity to study the impact of elevated glucocorticoids on cognitive functions. The aim of this study was to examine the performance of Cushing's syndrome patients on trace eyeblink conditioning, a cross-species, hippocampal-mediated test of learning and memory.Eleven Cushing's syndrome patients and 11 healthy control subjects participated in an eyeblink trace conditioning test (1000-msec trace) and a task of declarative memory for words. Salivary cortisol was collected in both the patients and the control subjects, and urinary free cortisol was collected in the patients only.	The patients exhibited fewer conditional responses and remembered fewer words, compared with the control subjects. Cortisol levels correlated with immediate and delayed declarative memory only. Conditional response correlated with delayed recall after controlling for the magnitude of unconditional response.	The integrity of the hippocampus seems to be compromised in Cushing's syndrome patients. Trace eyeblink conditioning might be useful both as a clinical tool to examine changes in hippocampus function in Cushing's disease patients and as a translational tool of research on the impact of chronic exposure of glucocorticoids.	
15572179	Alterations in the hypothalamic-pituitary-adrenal (HPA) axis and hippocampal-based memory have been associated with posttraumatic stress disorder (PTSD), and the administration of exogenous glucocorticoids has been shown to result in a transient verbal declarative memory impairment in healthy human subjects. The purpose of this study was to assess the effects of the glucocorticoid dexamethasone on verbal declarative memory function in patients with PTSD. Forty-two men and women with (n=14) and without (n=28) PTSD received placebo or dexamethasone (1 and 2 mg on two successive days) in a double-blind, randomized fashion. Declarative memory was assessed with paragraph recall at baseline (day 1) and day 3. There was a significant interaction between diagnosis and drug (dexamethasone vs. placebo) on paragraph recall related to a relative detrimental effect of dexamethasone on memory function in healthy subjects, but not those with PTSD. These findings are consistent with an altered sensitivity of declarative memory function in PTSD to regulation by glucocorticoids, possibly explainable by alterations in glucocorticoid receptors in the hippocampus or other brain regions mediating declarative memory.
15567563	The hypothesis that polymorphisms in the gene for nicastrin (NCSTN) are associated with differences in cognitive level and ageing was tested in 462 relatively healthy surviving participants of the Scottish Mental Survey 1932. None had a history of dementia. They were tested on the Moray House Test of verbal reasoning at age 11 in 1932 and at age 79 between 1999 and 2001. At age 79 they also took tests of non-verbal reasoning, short- and long-term verbal declarative memory, Verbal Fluency, and a short screening test for dementia. Subjects who possessed at least one copy of the NCSTN B haplotype (Hap B) had higher scores on the Moray House Test (a test principally of verbal reasoning) at age 11 (p=0.036) and age 79 (p=0.027). The effect of Hap B on cognition at age 79 was non-significant after adjusting for the effect at age 11. Therefore, the effect of Hap B in this sample is on the life-long stable trait of cognitive ability, and not on age-related cognitive change. The possibility that this result might be a selection effect was not supported by the samples being in Hardy-Weinberg equilibrium with respect to the distribution of NCSTN genotypes.
15560766	Presleep stimuli to be retained for further recall is often incorporated into dream contents. To establish whether processing for insertion into dream contents may improve consolidation, we compared the retention rate at delayed recall of contents resulting from incorporation of presleep sentence-stimuli with those of other contents of the same dream experiences. We hypothesized that association with a cognitive task of recall facilitates access to recently acquired items of declarative knowledge such as presleep stimuli, and triggers the deep elaboration of their semantic features, which involves rehearsal. Twelve subjects were given a task of delayed recall for three nonsense sentences delivered once a time before each of the sleep (re-)onsets over an experimental night. After each awakening in rapid eye movement sleep, subjects were asked to report dream experience and recall the sentence to be retained. In the morning, after spontaneous awakening, subjects were unexpectedly requested to again report their dream experiences and to recall the stimuli. Two pairs of judges independently identified possible incorporations of the stimuli, and parsed dream reports into propositional content units. The proportion of night reports with at least one incorporation of the stimulus delivered (i.e. valid incorporations) was higher than that of reports with contents similar to a stimulus(-i) not yet delivered (forward pseudo-incorporations) or delivered prior to an earlier sleep period (backward pseudo-incorporations). The proportion of content units common to night and morning reports (considered to be better consolidated) was significantly higher for incorporated contents than for other contents, including pseudo-incorporated contents. Instead, the retention at morning recall of words of sentence-stimuli corresponding to incorporated contents was not significantly higher than that of other words. The better retention of incorporated contents provides a partial confirmation (that is, limited to the output of the processing) that a generation effect, which benefits retention of actively processed information, is operative during sleep as well as in waking.
15558543	The hippocampus is widely considered to be a critical component of a medial temporal lobe memory system, necessary for normal performance on tests of declarative memory. Object recognition memory is thought to be a classic test of declarative memory function. However, previous tests of the effects of hippocampal lesions on object recognition memory have not always supported this view. One possible reason for this inconsistency is that previously reported effects of hippocampal lesions on object recognition memory tasks may have stemmed not from a deficit in object recognition memory per se, but as a result of spatial and contextual confounds in the task. Thus, in the present study, we used a spontaneous object recognition test in a modified apparatus designed to minimize spatial and contextual factors. A group of rats with complete excitotoxic lesions of the hippocampus and a group of control rats were tested on this modified spontaneous object recognition task with retention delays of up to 48 h. These rats were also tested on a spatial nonmatching-to-place task. Spatial memory performance was abolished following hippocampal lesions, whereas performance on the recognition memory task was intact at all delays tested.
15555677	Contextual fear conditioning is an important behavioral paradigm for studying the neurobiology of learning and memory and the mnemonic function of the hippocampus. We suggest that research in this domain can profit by a better theoretical understanding of the processes that contribute to this phenomenon. To facilitate this understanding, we describe a theory which assumes that physical elements of a conditioning context represented in the brain as either (a) a set of independent features or (b) features bound into a conjunctive representation by the hippocampus which supports pattern completion. Conditioning produced by shocking a rat in a particular context, in principle, can be produced by strengthening connections between the feature representations and/or the conjunctive representation and basolateral region of the amygdala. We illustrate how this theory clarifies some of the complexities associated with the existing literature and how it can be used to guide future empirical work. We also argue that the mechanisms (conjunctive representations and pattern completion) that mediate the contribution the hippocampus makes to contextual fear conditioning are the same ones that enable the hippocampus to support declarative memory in humans.
15555674	The assessment of cognitive functions in rodents represents a critical experimental variable in many research fields, ranging from the basic cognitive neurosciences to psychopharmacology and neurotoxicology. The increasing use of animal behavioral tests as 'assays' for the assessment of effects on learning and memory has resulted in a considerable heterogeneity of data, particularly in the field of behavioral and psycho pharmacology. The limited predictive validity of changes in behavioral performance observed in standard animal tests of learning and memory indicates that a renewed effort to scrutinize the validity of these tests is warranted. In humans, levels of processing (effortful vs. automatic) and categories of information (procedural vs. episodic/declarative) are important variables of cognitive operations. The design of tasks that assess the recall of 'episodic' or 'declarative' information appears to represent a particular challenge for research using laboratory rodents. For example, the hypothesis that changes in inspection time for a previously encountered place or object are based on the recall of declarative/episodic information requires substantiation. In order to generalize findings on the effects of neuronal or pharmacological manipulations on learning and memory, obtained from one species and one task, to other species and other tasks, the mediating role of important sets of variables which influence learning and memory (e.g. attentional, affective) needs to be determined. Similar to the view that a neuronal manipulation (e.g. a lesion) represents a theory of the condition modeled (e.g. a degenerative disorder), an animal behavioral task represents a theory of the behavioral/cognitive process of interest. Therefore, the test of hypotheses regarding the validity of procedures used to assess cognitive functions in animals is an inherent part of the research process.
15547452	Visuospatial and visuoperceptual deficits have consistently been observed in detoxified alcoholics; however, the severity of impairment varies with test and task type. Identifying the component processes and factors that underlie a particular deficit may reveal why some visuospatial and visuoperceptual tasks are more compromised than others and may lead to the specification of neural systems that are particularly vulnerable in alcoholism.We examined visuoperception and perceptual learning with a picture fragment identification task in 51 recently detoxified nonamnesic alcoholic men (aged 29-66 years) compared with 63 normal control men (aged 21-70 years). Executive function and explicit declarative memory were also assessed.	Despite deficits in the primary components of visuoperception and explicit memory for visuospatial stimuli, the alcoholics showed normal perceptual learning. Although the alcoholics and controls performed at comparable levels on the perceptual learning task, multiple regression analyses indicated that the factors accounting for perceptual learning variance differed between and within groups. Visuoperceptual abilities consistently predicted perceptual learning in the control subjects but not the alcoholic subjects. Explicit memory contributed to perceptual learning performance in both the alcoholic and control groups. Frontal executive ability consistently predicted perceptual learning in the alcoholic subjects, but it had predictive ability only in the control subjects as time elapsed. Age was significantly correlated with perceptual learning performance in both groups. Lifetime alcohol consumption, but not alcoholism duration, was an independent predictor of 1-hr perceptual learning.	These correlational analyses suggest that controls invoke basic visuospatial processes to perform a perceptual learning task, whereas alcoholics invoke higher-order cognitive processes (i.e., frontal executive systems) to perform the same task at normal levels. Use of more demanding cognitive systems by the alcoholics may be less efficient and more costly to processing capacity than those invoked by controls.	
15528882	Delirium may be a presenting feature in acute subarachnoid haemorrhage (SAH). The aim of this study was to investigate the risk factors for delirium in acute SAH and to analyse the relation between delirium and location and amount of haematic densities and hydrocephalus.We assessed delirium in a sample of 68 consecutive patients with acute (< or =4 days) SAH (33 aneurysmal, 33 non-aneurysmal, including 9 with perimesencephalic haemorrhage), before aneurysmal treatment, using DSM-IV-R criteria and the Delirium Rating Scale (DRS). DRS scores were related to: (1) the total amount of haematic densities at 10 basal cisterns/fissures and in the 4 ventricles, using a validated rating scale, (2) the haematic densities in the prepontine cistern and the convexity of the brain and (3) hydrocephalus, using the bicaudate index, obtained from a review of admission CT scans.	Eleven acute SAH patients presented with delirium. Older age (U = 316.5, p = 0.04), alertness disturbance (chi(2) = 5.1, p = 0.02, OR = 7.6, 95% CI = 1.5-37.3), aphasia (U = 61.5, p = 0.007) and a Hunt and Hess score >2 (U = 362.5, p = 0.02) were associated with delirium. Higher amounts of intraventricular haematic densities (chi(2) = 4.43, p = 0.04, U = 158, p = 0.001) and hydrocephalus (U = 215, p = 0.009) were also associated with higher DRS scores. Two delirious patients had basofrontal haematomas.	Delirium was detected in 16% of acute SAH patients. Intraventricular bleeding, hydrocephalus and basofrontal haematomas contribute to the pathogenesis of delirium, through damage to anatomical networks subserving sustained attention, declarative memory and the expression of emotional behaviour.	
15525784	In humans, weak transcranial direct current stimulation (tDCS) modulates excitability in the motor, visual, and prefrontal cortex. Periods rich in slow-wave sleep (SWS) not only facilitate the consolidation of declarative memories, but in humans, SWS is also accompanied by a pronounced endogenous transcortical DC potential shift of negative polarity over frontocortical areas. To experimentally induce widespread extracellular negative DC potentials, we applied anodal tDCS (0.26 mA) [correction] repeatedly (over 30 min) bilaterally at frontocortical electrode sites during a retention period rich in SWS. Retention of declarative memories (word pairs) and also nondeclarative memories (mirror tracing skills) learned previously was tested after this period and compared with retention performance after placebo stimulation as well as after retention intervals of wakefulness. Compared with placebo stimulation, anodal tDCS during SWS-rich sleep distinctly increased the retention of word pairs (p < 0.005). When applied during the wake retention interval, tDCS did not affect declarative memory. Procedural memory was also not affected by tDCS. Mood was improved both after tDCS during sleep and during wake intervals. tDCS increased sleep depth toward the end of the stimulation period, whereas the average power in the faster frequency bands (,alpha, and beta) was reduced. Acutely, anodal tDCS increased slow oscillatory activity <3 Hz. We conclude that effects of tDCS involve enhanced generation of slow oscillatory EEG activity considered to facilitate processes of neuronal plasticity. Shifts in extracellular ionic concentration in frontocortical tissue (expressed as negative DC potentials during SWS) may facilitate sleep-dependent consolidation of declarative memories.
15525766	Recent accounts suggest that the hippocampal system critically supports two central characteristics of episodic memory: the ability to establish and maintain representations for the salient relationships between experienced events (relational representation) and the capacity to flexibly manipulate memory (flexible memory expression). To test this proposal in monkeys, intact controls and subjects with bilateral aspiration lesions of the entorhinal cortex were trained postoperatively on two standard memory tasks, delayed nonmatchingto-sample (DNMS) and two-choice object discrimination (OD) learning, and three procedures intended to emphasize relational representation and flexible memory expression: a paired associate (PA) task, a transitive inference (TI) test of learning and memory for hierarchical stimulus relationships, and a spatial delayed recognition span (SDRS) procedure. The latter assessments each included critical "probe" tests that asked monkeys to evaluate the relationships among previously learned stimuli presented in novel combinations. Subjects with entorhinal cortex lesions scored as accurately as controls on all phases of DNMS and OD, procedures that can be solved on the basis of memory for individual stimuli. In contrast, experimental monkeys displayed deficits relative to controls on all phases of the PA, TI, and SDRS tasks that emphasized the flexible manipulation of memory for the relationships between familiar items. Together, the findings support the conclusion that the primate hippocampal system critically enables the relational organization of declarative memory.
15523609	We examined new semantic learning in two profoundly amnesic patients (E.P. and G.P.) whose lesions involve virtually the entire medial temporal lobe (MTL) bilaterally. The patients were given five tests of semantic knowledge for information that could only have been acquired after the onset of their amnesia in 1992 and 1987, respectively. Age-matched and education-matched controls (n = 8) were also tested. On tests of recall, E.P. and G.P. each scored 10% correct on a test of 20 easy factual questions (controls = 90%), 2% and 4% correct on 55 questions about news events (controls = 85%), and 0% and 4% correct on a test of 24 famous faces. On three tests of recognition memory for this same material, the patients scored at chance levels. Similarly, the patients were unable to judge whether persons who had been famous for many decades were still living or had died during the past 10 years (E.P. = 53%; G.P. = 50%; controls = 73%; chance = 50%). Lastly, neither patient E.P. nor patient G.P. could draw an accurate floor plan of his current residence, despite having lived there for 10 years and 1 year, respectively. The results demonstrate that the capacity for new semantic learning can be absent, or nearly absent, when there is virtually complete damage to the MTL bilaterally. Accordingly, the results raise the possibility that the acquisition of conscious (declarative) knowledge about the world cannot be supported by structures outside the MTL, even with extended exposure. Published 2004 Wiley-Liss, Inc.
15518984	Depending on task demands, there is a growing body of evidence suggesting that the dorsal striatum plays a critical role in not only learning new response strategies but also in the inhibition of pre-existing strategies when a shift in strategy is required. The present experiment examined the effects of lesions of the dorsal striatum or dorsal hippocampus on acquisition of a response-learning rule and a place-learning rule in a Greek Cross version of the Morris water maze. Specifically, adult Long-Evans rats were prepared with either sham lesions or lesions to one of two subcortical areas of the brain considered necessary for processing nondeclarative or declarative memories, the dorsal striatum or the hippocampus, respectively. An analysis of the trial 2 performance pooled across reversals revealed hippocampus lesions induced accelerated acquisition when a response-learning rule was required. A much smaller enhancement effect was observed in dorsal striatum-lesioned animals in the place-learning paradigm. Dorsal hippocampus- and dorsal striatum-lesioned animals were highly impaired on place learning and response learning, respectively. The present results are congruent with a growing body of literature suggesting that different anatomical substrates are involved in the acquisition and maintenance of different types of information, that these processes can occur simultaneously and in parallel, and that the dorsal striatum is necessary for the mediation of stimulus-response learning, while the hippocampus is necessary to mediate the expression of place learning.
15506830	Patients with schizophrenia (n = 41) and healthy comparison participants (n = 46) completed neuropsychological measures of intelligence, memory, and executive function. A subset of each group also completed magnetic resonance diffusion tensor imaging (DTI) studies (fractional anisotropy and cross-sectional area) of the uncinate fasciculus (UF) and cingulate bundle (CB). Patients with schizophrenia showed reduced levels of functioning across all neuropsychological measures. In addition, selective neuropsychological-DTI relationships emerged. Among patients but not controls, lower levels of declarative-episodic verbal memory correlated with reduced left UF, whereas executive function errors related to performance monitoring correlated with reduced left CB. The data suggested abnormal DTI patterns linking declarative-episodic verbal memory deficits to the left UF and executive function deficits to the left CB among patients with schizophrenia.
15505185	Repetitive transcranial magnetic stimulation (rTMS) may temporarily accelerate knowledge acquisition by neural networks, possibly by promoting rapid Hebbian learning. The authors tested this hypothesis in 20 normal subjects by comparing the impact of 25 minutes of high-frequency left dorsolateral prefrontal rTMS with that of sham rTMS on subsequent knowledge acquisition in several procedural and declarative memory domains. No significant group effects, positive or negative, were noted for any memory acquisition test, but prefrontal rTMS did reduce motor evoked potential threshold.
15503591	This study investigated the relationship between working memory (WM), declarative strategy knowledge, and math achievement in children with and without mathematical disabilities (MD). Experiment 1 examined the relationship between strategy knowledge, verbal WM, and visual-spatial WM in children with MD as a function of initial, gain, and maintenance conditions. The results showed that after partialing the influence of reading, stable strategy choices rather than specific strategy knowledge was related to verbal and visual-spatial WM span in high demand (maintenance) conditions. Experiment 2 compared children with MD to a group of chronological age-matched children and a group of math ability-matched children on the same conditions as Experiment 1. Age-matched children's verbal and visual-spatial WM performance was superior to that of children with MD, whereas WM performance was statistically comparable between children with MD and younger children matched on math ability. The selection of expert strategies was related to high WM span scores in the initial conditions. After controlling for reading achievement in a regression analysis, verbal and visual-spatial WM, stable verbal strategy choices, and expert strategy choices related to visual-spatial processing all contributed independent variance to math achievement. Overall, these results suggest that WM and math achievement are related to strategy knowledge.
15501585	Consolidation is a process through which labile memories are made persistent [Science 287 (2000) 248]; [Annu Rev Psychol 55 (2004) 51]. When retrieved, a consolidated memory is rendered labile again and undergoes reconsolidation [Learn Mem 7 (2000) 73]; [Trends Neurosci 26 (2003) 65]). Reconsolidation thus offers the opportunity to manipulate memory after it is formed, and may therefore provide a means of treating intrusive memories associated with post-traumatic stress disorder (PTSD). Reconsolidation is most usually studied using protein synthesis inhibitors, which is not practical in humans. However, the beta adrenergic receptor antagonist propranolol impairs consolidation of declarative memory in humans [Science 287 (2000) 248]; [Nature 371 (1994) 702] and consolidation and reconsolidation of inhibitory avoidance learning in rats [Brain Res 368 (1986) 125]; [J Neurosci 19 (1999) 6623]. Here, we show that systemic or intra-amygdala infused propranolol blocks reconsolidation but not consolidation. If the effects on reconsolidation are verified in humans, the results would suggest the possibility that propranolol after memory retrieval might be an effective way of treatment of intrusive memories in PTSD. That the systemic effects of propranolol on reconsolidation are achieved via an action in the amygdala is especially important in light of the fact that PTSD involves alterations in the amygdala [Arch Gen Psychiatry 53 (1996) 380].
15490462	Medial temporal lobe (MTL) structures often respond to stimulus repetition with a reduction in neural activity. Such novelty/familiarity responses reflect the mnemonic consequences of initial stimulus encounter, although the aspects of initial processing that lead to novelty/familiarity responses remain unspecified. The current functional magnetic resonance imaging (fMRI) experiment examined the sensitivity of MTL to changes in the semantic representations/processes engaged across stimulus repetitions. During initial study blocks, words were visually presented, and participants made size, shape, or composition judgments about the named referents. During repeated study blocks, the initial words were visually re-presented along with novel words, and participants made size judgments for all items. Behaviorally, responses were faster to repeated words in which the same task was performed at initial and repeated exposure (i.e., size-->size) relative to repeated words in which the tasks differed (i.e., composition-->size and shape-->size). fMRI measures revealed activation reductions in left parahippocampal cortex following same-task and different-task repetition; numerically, the effect was larger in the same-task condition. Accordingly, left parahippocampal cortex demonstrates sensitivity to perceptual novelty/familiarity, and it remains unclear whether this region also is sensitive to novelty/familiarity in the conceptual domain. In left perirhinal cortex, a novelty/familiarity effect was observed in the same-task condition but not in the different-task condition, thus revealing sensitivity to the degree of semantic overlap across exposures but insensitivity to perceptual repetition of the visual word form. Perirhinal sensitivity to semantic repetition and insensitivity to perceptual repetition suggests that human perirhinal cortex receives conceptual inputs, with perirhinal contributions to declarative memory perhaps partially stemming from its role in processing semantic aspects of experiences.
15482072	Adaptive control of thought-rational (ACT-R; J. R. Anderson & C. Lebiere, 1998) has evolved into a theory that consists of multiple modules but also explains how these modules are integrated to produce coherent cognition. The perceptual-motor modules, the goal module, and the declarative memory module are presented as examples of specialized systems in ACT-R. These modules are associated with distinct cortical regions. These modules place chunks in buffers where they can be detected by a production system that responds to patterns of information in the buffers. At any point in time, a single production rule is selected to respond to the current pattern. Subsymbolic processes serve to guide the selection of rules to fire as well as the internal operations of some modules. Much of learning involves tuning of these subsymbolic processes. A number of simple and complex empirical examples are described to illustrate how these modules function singly and in concert.
15467969	The temporal course of recovery of depressed patients' cognitive impairment is not fully understood.We used the California Verbal Learning Test (CVLT) to test declarative memory in 24 depressed patients before and after 35 days of antidepressive treatment as well as after long-term follow-up (> 12 months) in order to relate improvement of depression to recovery of cognitive impairment.	Patients with complete remission after 35 days had generally been less impaired at baseline. The disturbance of declarative memory in treatment responders as well as in non-responders did not change from baseline to end of treatment (day 35). However, our results revealed normal values in the CVLT sum score as well as in measures of short- and long-delay free-recall measures in both groups after long-term full remission.	We conclude that clinical response to antidepressive treatment precedes improvement of declarative memory. A low degree of impairment of declarative memory is associated with early complete remission of depression.	
15464403	Should the medial temporal lobe (MTL) of primates--which includes allocortical structures such as the hippocampus, neocortical structures such as the parahippocampal cortex, and nuclear structures such as the basolateral amygdala--be considered a single "thing"? According to the prevailing view, here termed the reification theory, the answer is yes. According to this theory, the MTL functions as an amalgamated entity that provides the neuronal mechanisms for declarative memory; the greater the damage to the MTL or any of its components, the greater the deleterious effects on declarative memory. A countervailing view, here called the balkanization theory, holds that the various components of the MTL process and store different kinds of information. According to this theory, damage to each part of the MTL causes a unique set of behavioral deficits-some involving memory, others involving perception, and yet others involving response selection. The empirical neuropsychological evidence favors the balkanization theory, as do some new concepts in theoretical neuroanatomy.
15458855	Cognitive impairments such as memory deficits and sleep disturbances are common clinical features of schizophrenia. Since sleep plays an important role in consolidation of memory, we hypothesize, that there is an interrelationship between distinct alterations in sleep and memory performance in schizophrenia. We studied 17 patients with schizophrenia on stable antipsychotic medication with amisulpride (age range 22-44 years; 7 women) and 17 healthy controls (matched for age, gender and educational level). Sleep was recorded and scored according to the standard criteria by Rechtschaffen and Kales. Immediately before polysomnography and the morning after we performed neuropsychological tasks including Rey-Osterrieth Complex Figure Test and a test for recall of spatial location for testing aspects of declarative memory and a mirror tracing skill for procedural memory. In comparison to healthy controls, the patients showed a significant increase in sleep onset latency and a significant decrease in sleep efficiency and amount of slow wave sleep (SWS). Furthermore, the patients' performance in recall of the Rey-figure and of spatial location the next morning was significantly impaired. These impairments in the tests for visuospatial memory were positively correlated with reduction in the amount of SWS and in sleep efficiency. These results point to a functional interrelationship between regulation of SWS and performance in visuospatial memory in schizophrenia. If these results of our pilot study hold true, they will allow the development of innovative treatment strategies for neuropsychological deficits in patients with schizophrenia.
15457106	Several studies have shown deficits in verbal declarative memory function in posttraumatic stress disorder (PTSD). Most of these studies have been performed in men with combat-related PTSD compared with healthy subjects; relatively little is known about memory function in women with abuse-related PTSD, or whether these effects are specific to PTSD or are a nonspecific outcome of exposure to early abuse. The purpose of this study was to assess declarative memory function in women with and without a history of early childhood sexual abuse and PTSD. Forty-three women with and without a history of early childhood sexual abuse and PTSD underwent neuropsychological testing with subtests of the Wechsler Memory Scale--Revised for measurement of verbal and visual memory and subtests of the Wechsler Adult Intelligence Scale for measurement of IQ, and behavioral ratings of PTSD and other psychiatric symptoms. Abused women with PTSD had deficits in verbal declarative memory as measured with the subtests of the Wechsler Memory Scale--Revised compared with women with early abuse without PTSD and nonabused women without PTSD. There were no significant differences in IQ. These findings suggest that early abuse with PTSD is associated with deficits in verbal declarative memory, and that these effects are not related to the nonspecific effects of childhood abuse.
15453514	To assess the effect of ischemic infarctions affecting the basal ganglia (BG) region on a series of procedural learning tasks.The basal ganglia hypothesis of procedural learning is a matter of debate. As most of the relevant research so far is based on examination of patients suffering from Parkinson disease, this inconsistency might reflect either lesion heterogeneity existing in this pathologic group or the heterogeneity of the procedural learning tasks.	Twelve patients with lesions confined to the right (BGr), 10 to the left (BGI) BG region, and 15 matched controls participated in the study. Three procedural learning tasks were used: Tower of Hanoi Puzzle, Mirror Reading, and Porteus Mazes. Declarative memory and general intelligence were also tested.	Verbal declarative memory was impaired in the BG1 group. For each procedural learning task, baseline performance and learning rate were analyzed. Tower of Hanoi Puzzle: Baseline performance of the BG1 group was impaired compared with the other groups. The BGr group was the only group that did not improve over learning trials. MR: Baseline performance of the BGr group was impaired compared with the other groups. The groups' learning rate did not differ significantly. Porteus Mazes: Baseline performance of both patient groups was impaired compared with that of the control group. Learning rate over repetitive trials of the same maze was impaired in the BGr group. However, the transfer of procedural learning to a newly exposed maze was impaired in the BG1 group.	First, right and left basal ganglia play different roles in different procedural learning tasks. Second, procedural learning is not a unitary capacity subserved by any single neural mechanism.	
15450166	We discuss several lines of evidence refuting the hypothesis that procedural or declarative memories are processed/consolidated in sleep. One of the strongest arguments against a role for sleep in declarative memory involves the demonstration that the marked suppression or elimination of REM sleep in subjects on antidepressant drugs or with brainstem lesions produces no detrimental effects on cognition. Procedural memory, like declarative memory, undergoes a slow, time-dependent period of consolidation. A process has recently been described wherein performance on some procedural tasks improves with the mere passage of time and has been termed "enhancement." Some studies, but not others, have reported that the consolidation/enhancement of perceptual and motor skills is dependent on sleep. We suggest that consolidation or enhancement, initiated in waking with task acquisition, could in some instances extend to sleep, but sleep would serve no unique role in these processes. In sum, there is no compelling evidence to support a relationship between sleep and memory consolidation.
15450164	The hippocampus serves a critical role in declarative memory--our capacity to recall everyday facts and events. Recent studies using functional brain imaging in humans and neuropsychological analyses of humans and animals with hippocampal damage have revealed some of the elemental cognitive processes mediated by the hippocampus. In addition, recent characterizations of neuronal firing patterns in behaving animals and humans have suggested how neural representations in the hippocampus underlie those elemental cognitive processes in the service of declarative memory.
15447639	Priming is an unconscious (nondeclarative) form of memory whereby identification or production of an item is improved by an earlier encounter. It has been proposed that declarative memory and priming might be related-for example, that conceptual priming results in more fluent processing, thereby providing a basis for familiarity judgments. In two experiments, we assessed conceptual priming and recognition memory across a 5-min interval in 5 memory-impaired patients. All patients exhibited fully intact priming in tests of both free association (study tent; at test, provide an association to canvas) and category verification (study lemon; at test, decide: Is lemon a type of fruit?). Yet the 2 most severely amnesic patients performed at chance on matched tests of recognition memory. These findings count against the notion that conceptual priming provides feelings of familiarity that can support accurate recognition judgments. We suggest that priming is inaccessible to conscious awareness and does not influence declarative memory.
15382260	The human medial temporal lobe (MTL) is known to be involved in declarative memory, yet the exact contributions of the various MTL structures are not well understood. In particular, the data as to whether the hippocampal region is preferentially involved in the encoding and/or retrieval of associative memory have not allowed for a consensus concerning its specific role. To investigate the role of the hippocampal region and the nearby MTL cortical areas in encoding and retrieval of associative versus non-associative memories, we used functional magnetic resonance imaging (fMRI) to measure brain activity during learning and later recognition testing of novel face-name pairs. We show that there is greater activity for successful encoding of associative information than for non-associative information in the right hippocampal region, as well as in the left amygdala and right parahippocampal cortex. Activity for retrieval of associative information was greater than for non-associative information in the right hippocampal region also, as well as in the left perirhinal cortex, right entorhinal cortex, and right parahippocampal cortex. The implications of these data for a clear functional distinction between the hippocampal region and the MTL cortical structures are discussed.
15381017	Previous research indicates that amnesic subjects tested on sequential learning or serial reaction time tasks can learn a repeated procedural sequence but are unable to explicitly recall the correct sequence when asked to generate the sequence. Rats with hippocampal lesions are also able to learn and remember procedural or implicit sequences but were impaired for declarative sequences. We used analogous procedures used in rats to assess the role of the hippocampus in the acquisition of declarative and procedural sequences in amnesic and control participants. Amnesic participants with damage restricted to the hippocampus and control participants were administered analogous tasks of declarative and procedural sequential learning using a computer version of the radial arm maze. The amnesic participants had slower response times during the acquisition of procedural sequences, but were not impaired compared to controls when switched to a random sequence, suggesting that both groups learned the sequence. Alternatively, the amnesic but not control participants were significantly impaired in the declarative sequence task. Our findings provide support for evolutionary continuity in cognitive function of the hippocampus in rats and humans and the dissociation between the declarative and procedural sequential learning. The performance differences on the two sequence learning tasks are likely due to the use of different strategies associated with learning sequences based on procedural versus declarative knowledge.
15378250	Synthetic glucocorticosteroids can induce various severe mental disorders. Persisting cognitive disorder represents a rare complication of corticoid therapy involving memory, concentration, attention, or occupational performance. We observed the effects of a 20-day self-induced high-dose corticosteroid treatment on the cognitive functions in a 54-year-old patient. Having excluded dementia due to other organic causes, we examined the patient neuropsychologically immediately at the end of the steroid therapy and at follow-up (1, 2, 4, and 6 months). The initial tests showed seriously impaired functioning of concentration, attention, learning, and memory as well as of common ability to solve problems. The follow-up tests up to 6 months revealed an improvement of concentration and attention, but there were still serious deficits of the declarative memory with a high confabulating tendency. Our results confirm those of human experimental studies that exogenous steroids can cause serious persisting specific cognitive disorders especially of the declarative, hippocampus-dependent memory.
15355134	Forty participants assigned artificial creatures to categories after explicit rule instruction or feedback alone. Stimuli were typical and atypical exemplars of 2 categories with independent prototypes, conflicting exemplars sharing features of both categories, and "Others" with only 1 or 2 features of the well-defined categories. Ten feedback-only participants spontaneously adopted a unidimensional rule; 10 used a multidimensional similarity strategy. Event-related potentials (ERPs) recorded during the transfer phase showed a commonality between multidimensional rule and similarity strategies in late frontal brain activity that differentiated both from unidimensional rule use. Multidimensional rule users alone showed an earlier prefrontal ERP effect that may reflect inhibition of responses based on similarity. The authors also discuss the role of declarative memory for features and exemplars.
15327712	Obsessive-compulsive disorder (OCD) has been associated with frontostriatal abnormality. This has led to the hypothesis that the disorder is characterized by abnormality of procedural memory. However, evidence for either procedural or declarative memory disturbance has been mixed, and few studies have directly assessed both of these forms of memory in the same patient group. In the present study, we assessed encoding and retrieval in declarative memory using the Rey Auditory Verbal Learning Test (RAVLT), and procedural memory using the Pursuit Rotor Task, in 27 adults with OCD and 29 matched healthy controls. Groups did not differ with respect to salient demographic characteristics or memory on the RAVLT. In contrast, patients with OCD performed significantly better than controls during the early, but not later trial blocks of the Pursuit Rotor Task. This pattern of results indicates intact encoding and retrieval in declarative memory, but abnormally enhanced procedural memory during the early course of learning in OCD. These findings may be consistent with striatal overactivation observed in neuroimaging studies of OCD, as well as the prominent role of the striatum during early stages of procedural memory.
15319576	Variation in memory performance is to a large extent explained by genes. In the prefrontal cortex, the catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine, a neurotransmitter implicated in cognitive functions. The present study examined the effect of a polymorphism in the COMT gene on individual differences and changes in memory in adulthood and old age. Tests assessing episodic and semantic memory were administered to 286 men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula prospective cohort study) at two occasions followed over a 5-year period. Carriers of the Met/Met genotype (with low enzyme activity) performed better on episodic and semantic memory, as compared to carriers of the Val allele (with higher enzyme activity). Division of episodic memory into its recall and recognition components showed that the difference was specific to episodic recall, not recognition tasks; an effect that was observed across three age groups (middle-age, young-old, and old-old adults) and over a 5-year period. The COMT gene is a plausible candidate gene for memory functioning in adulthood and old age.
15310427	The concept of trauma currently occupies a central position in interdisciplinary dialogue. Using the concept of psychical trauma as a bridge, the author attempts an interdisciplinary dialogue with psychiatry, biology and neuroscience. Beginning with the concept of psychical trauma in Freud, the author reviews the evolution of Freud's thinking, and links it with the ideas of Ferenczi and post-Freudian psychoanalytical authors. From a different framework, he considers the present state of research on post-traumatic stress disorder in current psychiatric nosography and attempts an interdisciplinary approximation to the concept of psychical trauma. Interesting ideas like the traumatic situation, trauma spectrum and psychopathological spectrum emerge, which enable a better understanding of the concept of psychical trauma through its relatedness, as a bridge connecting a broad psychopathological range extending from normality to psychosis. The ensuing possible relative loss of nosographical rigour is more than compensated by the resulting increased understanding and enlarged therapeutic possibilities. In the second part of the paper, the author attempts a dialogue with neuroscience, taking into account new advances in current research on emotion and memory, and making them compatible with the psychoanalytical concept of trauma. In this sense, the paper underlines the importance of emotion and crucially of memory, regarded as a fundamental axis of the subject explored in this paper. Here a substantial distinction which is pertinent for analytical work appears: declarative memories versus non-declarative or procedural memories. In a concluding discussion the author argues that, taking into account the implications of these current notions regarding a number of theoretical and technical aspects, psychoanalysis currently holds a privileged position, both in its potential for prevention and regarding the treatment of patients, in so far as, through interdisciplinary dialogue, psychoanalysis can be receptive to and be enriched by the contributions of other disciplines, just as it enriches them with its own contributions.
15288712	Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92 +/- 1.00, Insulin 6.20 +/- 1.03, p < 0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger (p < 0.02) and enhanced self-confidence (p < 0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer's disease.
15269259	Understanding how the hippocampus processes information critical for establishing spatial and declarative memories will benefit greatly from determining not only what kind of information the hippocampus registers, but also how this information is processed across the different hippocampal subfields. We addressed this question using a novel immediate-early gene-based brain-imaging method (Arc/H1a catFISH) that allows comparisons of neuronal ensembles activated by two experiences separated by approximately 30 min. Rats exposed to the same environment twice activated CA3 and CA1 ensembles with a similarly high degree of overlap. Changing the identity or configuration of local cues, or changing distal cues, activated CA3 and CA1 ensembles with reduced overlap. Yet, the overlap was greater in CA3 than in CA1. In contrast, rats exposed to two completely different environments activated CA3 and CA1 ensembles with low overlap, and this overlap was even lower in CA3 compared with CA1. Thus, CA3 has a discontinuous, whereas CA1 has a graded, population response to alterations of an environment. Additionally, as indicated by the percentage of active neurons, the context representation was more sparse in CA3 (approximately 18%) than in CA1 (approximately 35%). Finally, CA3 and CA1 activity levels were not correlated within a session, arguing against a simple coactivation of these regions. Instead, the within-rat ratio of CA3/CA1 cell activity was correlated across sessions, suggesting that the balance of CA3/CA1 activity is individual specific. Taken together, these findings suggest that CA3 and CA1 neuronal ensembles perform distinct, yet complementary, functions in the processing of spatial and contextual information.
15257527	In amnesic syndromes, it's usually to see dissociation between episodic, semantic and procedural memory. However, a few reports have been found about musical memory's processing and the relation with classic memory systems.To describe the musical's abilities preserved in a patient with amnesic syndrome and discuss possible neuropsychological and neurobiological bases implicated.	A 28-years-old woman presenting with amnesic syndrome is reported. Following a carbon monoxide encephalophaty and subsequent hypoxia she remained in coma for 10 days with evidence of bilateral temporal changes, mainly affecting basal ganglia areas. The patient showed anterograde amnesia and semantic memory impairment, with disproportionately spared musical abilities' performance, either music perception (discrimination and recognition of tonal melodies, musical sight-reading) or music production (song and instrumental performance) or musical memory.	This case suggests that the music require elaborate bihemispheric processing and may implicate different forms of information processing. The neural network involved in musical memory can be different that the declarative memory systems (episodic and semantic).	
15249108	Sleep has been implicated in the plastic cerebral changes that underlie learning and memory. The scientific investigation of people with exceptional memory has been relatively neglected. We report the results of a polysomnographic investigation of an individual with superior memory performance. The sleep structure, in terms of sleep induction and maintenance, as well as non-REM and REM sleep percentages, were normal. The main finding was an increased number of periodic arousal fluctuations during non-REM sleep (measured as cyclic alternating pattern, CAP) during two consecutive nights (7-8 S.D. units above that observed in age-matched controls). Since CAP rate reflects the structural organization of non-REM sleep, this observation supports the hypothesis of a link between non-REM sleep and declarative memory performance.
15242692	Now that the human genome has been sequenced there exists the possibility of identifying specific genes that affect human cognition. In this article, recent studies that have found associations between common gene variants and specific cognitive processes are reviewed. Several principles for evaluating this new field are also discussed. The interpretation of results is far from simple because a single gene can affect multiple processes, multiple genes can impact on a single process, and multiple cognitive processes are intercorrelated. In general, functional neuroimaging has been a more sensitive assay of cognitive processing than behavioral measures used alone, although there are important caveats regarding its use. Replicated findings so far involve associations between a COMT polymorphism and prefrontally-based executive functions and neurophysiology, and a BDNF polymorphism and medial-temporal-cortex based declarative memory processes. Implicit in this review is a concern that many of the cognitive paradigms used evolved for purposes well outside those described here. As such it may be necessary to view cognition in novel ways, based on constraints imposed by genomics and neurobiology, in order to increase the effect size of genotypic influences on cognition.
15242413	Transient global amnesia (TGA) is an episodic dysfunction of declarative memory, which is assumed to be a benign disorder. Brain perfusion single photon emission computed tomography (SPECT) was shown to be abnormal during the acute stage and to become normal with normalization of memory function. No data are known about the brain perfusion pattern among these patients with recurrent TGA.Sixteen patients with TGA were studied with an initial brain imaging during the acute stages of their attack, and a second imaging was performed after 3 months. In the event of a patients having a second abnormal brain perfusion HMPAO SPECT, a third imaging was performed after 1 year.	Hypofusion perfusion was demonstrated in all cases during the acute stage. In all patients who had a first TGA, a normal SPECT was demonstrated after 3 months. In three patients with recurrent TGA, the brain perfusion remained abnormal after 3 months and after 1 year.	A normal perfusion in TGA after 3 months can be expected in a patient with a first attack. In patients with recurrent TGA attacks, a persistent focal hypoperfusion can be expected. This subgroup of patients may demonstrate a non-benign type of TGA, eventually due to a different etiology of event.	
15231442	Depression has been linked to stress, memory deficits, and hypercortisolemia. However, the relationships between depression, hippocampal structure and function, and cortisol levels are unclear and the effects of antidepressant treatment on the measures are not well studied.Whole hippocampal volume, performance on verbal and visual declarative memory function and cortisol status was evaluated in 38 subjects with major depressive disorder (MDD) and 33 healthy subjects. All measures were repeated in a subgroup (n = 22) of depressed patients after successful selective serotonin reuptake inhibitor (SSRI) treatment.	Hippocampal volume was not significantly different between patients with untreated MMD and healthy subjects, after controlling for whole brain volume, age and gender. However, depressed subjects had significantly greater deficits in delayed memory and percent retention on the verbal portion of the Wechsler Memory Scale-Revised (WMS-R) compared with healthy subjects, without significant differences in visual memory, attention, vigilance, or distractibility. Baseline plasma or urinary free cortisol (UFC) was not related to either hippocampal volume or memory deficits. Successful treatment with antidepressants did not change hippocampal volume but did result in a significant improvement in memory function and a reduction in UFC excretion.	Medication-free nonelderly depressed outpatients without alcohol dependence or adverse experiences in childhood had normal hippocampal volume. Focal declarative memory deficits in depression supported localized hippocampal dysfunction in depressed patients. Treatment with antidepressants significantly improved memory and depression but did not alter hippocampal volume, suggesting that antidepressants may improve hippocampal function in the absence of detectable structural changes.	
15229237	It is widely believed that declarative memory is mediated by a medial temporal lobe memory system consisting of several distinct structures, including the hippocampus and perirhinal cortex. The strong version of this view assumes a high degree of functional homogeneity and serial organization within the medial temporal lobe, such that double dissociations between individual structures should not be possible. In the present study, we tested for a functional double dissociation between the hippocampus and peri-postrhinal cortex in a single experiment. Rats with bilateral excitotoxic lesions of either the hippocampus or peri-postrhinal cortex were assessed in tests of spatial memory (radial maze) and object recognition memory. For the latter, the spontaneous object recognition task was conducted in a modified apparatus designed to minimize the potentially confounding influence of spatial and contextual factors. A clear functional double dissociation was observed: rats with hippocampal lesions were impaired relative to controls and those with peripostrhinal cortex lesions on the spatial memory task, whereas rats with peri-postrhinal lesions were impaired relative to the hippocampal and control groups in object recognition. These results provide strong evidence in favor of heterogeneity and independence of function within the temporal lobe.
15225150	Patients with remitted bipolar disorder (BD) have persistent impairments in neuropsychological function, particularly in the domains of executive control and declarative memory [Br J Psychiatry 180 (2002) 293]. If these were the phenotypic expression of genetic vulnerability to BD, then healthy subjects with a genetic predisposition to BD would be expected to display the same deficits. This study, therefore, examined neuropsychological function in healthy first-degree relatives of patients with BD.A cross-sectional design was employed to compare the performance of 17 unaffected first-degree relatives of BD patients and 17 demographically matched controls on a range of neuropsychological tests.	Relatives were significantly impaired on Backward Digit Span, Spatial Span and on tasks of visuospatial declarative memory in comparison with controls. Psychomotor performance and verbal declarative memory were intact, as were non-working memory aspects of executive performance.	The selective deficits in executive control and declarative memory exhibited by relatives in this study have previously been reported in euthymic BD patients suggesting they may be useful endophenotypic markers of genetic vulnerability to BD.	
15219255	Children's memories of painful experiences can have long-term consequences for their reaction to later painful events and their acceptance of later health care interventions. This review surveys research on children's memory for pain, emphasizing implications for clinical practice. Topics reviewed include consequences of children's memories of pain; the development of memory; differences between explicit (declarative, verbal, autobiographic) memory and implicit (nondeclarative, nonverbal) memory; and individual differences, situational, and methodologic factors affecting memories of pain. Methods to prevent the adverse consequences of remembered pain are addressed with reference to current research on editing or reframing memories.This review covers topics of value to clinicians providing care to children undergoing painful procedures. Specific recommendations are offered regarding the importance of acknowledging and assessing children's previous memories of painful experiences, the type of information that benefits children before and after procedures, and the most appropriate questioning strategies. It might be possible to prevent or reduce the adverse effects of memories of pain.	
15217334	The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). The system consists of the hippocampal region (CA fields, dentate gyrus, and subicular complex) and the adjacent perirhinal, entorhinal, and parahippocampal cortices. Here, we review findings from humans, monkeys, and rodents that illuminate the function of these structures. Our analysis draws on studies of human memory impairment and animal models of memory impairment, as well as neurophysiological and neuroimaging data, to show that this system (a) is principally concerned with memory, (b) operates with neocortex to establish and maintain long-term memory, and (c) ultimately, through a process of consolidation, becomes independent of long-term memory, though questions remain about the role of perirhinal and parahippocampal cortices in this process and about spatial memory in rodents. Data from neurophysiology, neuroimaging, and neuroanatomy point to a division of labor within the medial temporal lobe. However, the available data do not support simple dichotomies between the functions of the hippocampus and the adjacent medial temporal cortex, such as associative versus nonassociative memory, episodic versus semantic memory, and recollection versus familiarity.
15215216	The finding that patients with amnesia retain the ability to learn certain procedural skills has provided compelling evidence of multiple memory systems in the human brain, but the scope, defining features and ecological significance of the preserved mnemonic abilities have not yet been explored. Here, we tested the hypothesis that subjects with amnesia would be able to learn and retain a broad range of procedural skills, by examining their acquisition and retention performance on five novel experimental tasks. The tasks are based on real-world activities and encompass a broad range of perceptual-motor demands: (i) the weaving task involves weaving pieces of fabric from woollen strings, using a manual weaver's loom; (ii) the geometric figures task consists of tracing geometric figures with a stylus as they move horizontally across a touch screen monitor; (iii) the control stick task involves tracking a sequence of visual target locations using a joystick control; (iv) the pouring task consists of pouring 200 ml of water from a watering can into a series of graduated cylinders, from a point 20 cm above the cylinders; and (v) the spatial sequence task involves learning an ordered sequence of pushing five spatially distributed buttons without visual guidance. Ten chronic and stable amnesic subjects (nine with bilateral medial temporal lobe damage due to herpes simplex encephalitis or anoxia, and one with thalamic stroke) and 25 matching normal comparison subjects were tested on three occasions: initial learning at time 1; retention at time 2 (24 h later); and retention at time 3 (2 months later). Despite impaired declarative memory for the tasks, the amnesic subjects demonstrated acquisition and retention of the five skills; their learning slopes over repeated trials were comparable with those of comparison subjects. These findings indicate that preserved learning of complex perceptual-motor skills in patients with amnesia is a robust phenomenon, and that it can be demonstrated across a variety of conditions and perceptual-motor demands. The comparability of the tasks employed in this study with real-world activities highlights the potential application of this memory dissociation in the rehabilitation of patients with amnesia.
15212996	The spatial properties of the firing of hippocampal neurons have mainly been studied in (a) freely moving rodents, (b) non-human primates seated in a moveable primate chair with head fixed, and (c) epileptic patients subjected to virtual navigation. Although these studies have all revealed the ability of hippocampal neurons to generate spatially selective discharges, the detected firing patterns have been found to be considerably different, even conflicting, in many respects. The present cellular electrophysiological study employed squirrel monkeys (Saimiri sciureus), which moved freely on the walls and floor of a large test chamber. This permitted the examination of the spatial firing of hippocampal neurons in nearly ideal conditions, similar to those used in rodents, yet in a species that belongs to the primate Suborder Anthropoidea. The major findings were that: (1) a group of slow-firing complex-spike cells increased their basal, awake firing rate more than 20-fold, often above 30 spikes/s, when the monkey was in a particular location in the chamber, (2) these location-specific discharges occurred consistently, forming 4-25 s action potential volleys, and (3) fast-firing cells displayed no such electrical activity. Thus, during free movement in three dimensions, primate hippocampal complex-spike cells do generate high-frequency, location-specific action potential volleys. Since these cells are components of the medial temporal lobe memory system, their uncovered firing pattern may well be involved in the formation of declarative memories on places.
15203289	Previous research demonstrated that depression is associated with hyperactivity of the hypothalamus-pituitary-adrenocortical (HPA) system after stimulation. There is also strong evidence that the modulation of corticosteroids in the brain induces memory dysfunction which represents core features of depression. Antidepressant treatment with serotonin reuptake inhibitors (SSRIs) alleviates both dysfunctions. Thus, these previous observations propose a correlation between treatment induced changes of the endocrinological response of the HPA system to challenge with dexamethasone and CRH and changes of memory functions during antidepressant treatment. This study explores the relationship between depression, memory functions and the responsiveness of the HPA system as assessed by the combined DEX/CRH test during antidepressant treatment in n = 64 patients with major depression during a four weeks treatment with citalopram. We found that treatment induced changes of the cortisol response pattern in the DEX/CRH test were correlated with improvement of working memory but not so with episodic memory, sustained attention or global severity of depression. We suggest that improvement of working memory is more sensitive to the changes of hormones of the HPA system (e.g. cortisol) than other cognitive functions and the global severity of depression.
15202829	To present a case of permanent global amnesia related to hippocampal damage. Permanent global amnesia is a very rare condition of unknown etiology; lesions restricted to the hippocampus are uncommon, which hinders investigations of this pattern of memory loss. This case is unusually well documented, as the patient underwent extensive neuropsychological evaluations.A cheerful right-handed, 83-year-old retired electrician was first evaluated in 1990 for progressive difficulty in learning new information and in recalling events over the preceding 3-4 years. Tests over the next 5 years showed that the impairment was confined to episodic declarative memory. New verbal information could be stored only in episodic memory in a restricted manner, limited by short-term memory capacity. A relatively mild retrograde amnesia was detected. Semantic and implicit memory was spared, as were other functions evaluated. The patient's language and executive function were strikingly efficient. Magnetic resonance imaging of the brain showed bilateral atrophy of the hippocampi and amygdalae, ruling out conditions such as tumour growth. A diagnosis of permanent global amnesia was made. In the ensuing years, the retrograde amnesia worsened, but no new deficits were identified.	This case, the first with a detailed cognitive examination, is evidence of a relatively pure hippocampal pattern for memory loss in permanent global amnesia.	
15183507	The neuropathology of Alzheimer's disease (AD) reflects a precarious balance between neurodegenerative phenomena and reactive events of neuroplasticity. This latter aspect of AD neuropathology has received less attention than it deserves and its contribution to memory loss is therefore not well understood. To monitor neuroplastic-related events we studied the distribution of the plasticity-associated, brain growth protein GAP-43 in AD subjects and age-matched controls. In tissue from AD patients, we observed a consistent elevation of GAP-43 in a subfield of the hippocampus, stratum lacunosum moleculare. This subfield contains inputs from multiple brain regions and is known to regulate declarative memory function. Levels of potentially aberrant sprouting, as marked by elevated growth protein, were positively correlated with the severity of AD suggesting that increased expression of GAP-43 leads to a miswiring of circuits critical for memory function. Our findings suggest a mechanism, aberrant neuroplasticity, that in concert with neurodegeneration may importantly contribute to the memory loss in AD.
15181406	Auditory evoked potentials (AEPs) are an electrical manifestation of the brain response to an auditory stimulus. Mid-latency auditory evoked potentials (MLAEPs) and the coherent frequency of the AEP are the most promising for monitoring depth of anaesthesia. MLAEPs show graded changes with increasing anaesthetic concentration over the clinical concentration range. The latencies of Pa and Nb lengthen and their amplitudes reduce. These changes in features of waveform are similar with both inhaled and intravenous anaesthetics. Changes in latency of Pa and Nb waves are highly correlated to a transition from awake to loss of consciousness. MLAEPs recording may also provide information about cerebral processing of the auditory input, probably because it reflects activity in the temporal lobe/primary cortex, sites involved in sounds elaboration and in a complex mechanism of implicit (non declarative) memory processing. The coherent frequency has found to be disrupted by the anaesthetics as well as to be implicated in attentional mechanism. These results support the concept that the AEPs reflects the balance between the arousal effects of surgical stimulation and the depressant effects of anaesthetics. However, AEPs aren't a perfect measure of anaesthesia depth. They can't predict patients movements during surgery and the signal may be affected by muscle artefacts, diathermy and other electrical operating theatre interferences. In conclusion, once reliability of the AEPs recording became proved and the signal acquisition improved it is likely to became a routine feature of clinical anaesthetic practice.
15178170	Monkeys with crossed unilateral excitotoxic lesions of the anterior thalamus and unilateral inferotemporal cortex ablation were severely impaired at learning two tasks which required the integration of information about the appearance of objects and their positions in space. The lesioned monkeys were also impaired at learning a spatial task and a task which required the integration of information about the appearance of objects and the background on which the objects were situated. Monkeys with only one of the unilateral lesions were not impaired and previous work has shown that monkeys with bilateral lesions of the anterior thalamus were not impaired on these tasks. These results indicate that the whole of the inferotemporal cortex-anterior thalamic circuit, which passes via the hippocampus, fornix, mamillary bodies and mamillothalamic tract, is essential for the topographical analysis of information about specific objects in different positions in space. Together with previous work, the results show that a unilateral lesion may affect cognition in the presence of other brain damage when an equivalent bilateral lesion alone does not. The tasks required the slow acquisition of information into long term memory and therefore assessed semantic knowledge although other research has shown impairment on topographical processing within working or episodic memory following lesions of the hippocampal-diencephalic circuit. It is argued that the hippocampal-diencephalic circuit does not have a role in a specific form of memory such as episodic memory but rather is involved in topographical analysis of the environment in perception and across all types of declarative memory.
15177088	The hippocampal formation, a structure involved in declarative, spatial and contextual memory, undergoes atrophy in depressive illness along with impairment in cognitive function. Animal model studies have shown that the hippocampus is a particularly sensitive and vulnerable brain region that responds to stress and stress hormones. Studies on models of stress and glucocorticoid actions reveal that the hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes remodeling of dendrites in the CA3 region, a region that is particularly important in memory processing. Both forms of structural remodeling of the hippocampus are mediated by adrenal steroids working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, head trauma, and ischemia, and alterations of calcium homeostasis that accompany age-related cognitive impairment. Tianeptine (tianeptine) is an effective antidepressant that prevents and even reverses the actions of stress and glucocorticoids on dendritic remodeling in an animal model of chronic stress. Multiple neurotransmitter systems contribute to dendritic remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working synergistically with glucocorticoids. This review summarizes findings on neurochemical targets of adrenal steroid actions that may explain their role in the remodeling process. In studying these actions, we hope to better understand the molecular and cellular targets of action of tianeptine in relation to its role in influencing structural plasticity of the hippocampus.
15176723	Neuropsychological research has permitted different cognitive profiles among subjects with intellectual disabilities (ID) of different etiology to be defined. For example, numerous authors have stressed that the typical language profile for people with Down's syndrome (DS) consists of poor production with greater compromise of morphosyntax than of lexical abilities, but relatively preserved comprehension. Children with Williams' syndrome (WS) often show marked impairment in certain visuospatial abilities (especially praxic-constructive) and relative preservation of both productive and receptive language, at least concerning the phonological elements. These observations seem to support a theoretical approach that considers ID not as a mere slowing of normal cognitive development, but as distinct, individual profiles that can be qualitatively specified. The importance of this approach was shown in several recent studies of memory, especially implicit memory in subjects with ID. Neuropsychological studies suggest insufficient development of the mnemic function in ID at different levels of articulation. Long-term memory has been extensively investigated in people with ID both in the explicit and in the implicit component. According to recent studies, people with ID should show a diffuse impairment of declarative mnesic abilities and a relative preservation of implicit memory. The focus of this study is on the characteristics of long- and short-term memory in children with ID and, particularly, with DS and WS. The results are relevant to knowledge on the qualitative aspects of the anomalous cognitive development in mentally retarded people and the neurobiological substrate underlying this development.

15165527	Since the seminal research by Jenkins and Dallenbach in the 1920s, it has been well proven that sleep has a major effect on the memory of pre-sleep material. However, there is still sparse knowledge about exactly which features of sleep have the most impact. Studies which examined separately the role of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep provided largely controversial results and aroused harsh scientific debate, and the investigation of the link of specific sleep patterns to different memory systems (e.g. declarative vs. procedural) did not fully reconcile these inconsistencies. New research perspectives have been proposed in recent years to overcome the limits of the previous 'single state' approach. Psychological, neurophysiological and neuroanatomical data have recently suggested that NREM and REM sleep both play a part in memory consolidation. We here present the hypothesis that NREM and REM are complementary for memory processes during sleep, thanks to their close interaction within the NREM-REM cycle, and discuss experimental data which prove the critical role of the sleep cycle for the morning recall of verbal material.
15161409	Effective computer skill training is vital to organizational productivity. Two experiments (N = 288) demonstrated that the behavior modeling approach to computer skill training could be substantially improved by incorporating symbolic mental rehearsal (SMR). SMR is a specific form of mental rehearsal that establishes a cognitive link between visual images and symbolic memory codes. As theorized, the significant effects of SMR on declarative knowledge and task performance were shown to be fully mediated by changes in trainees' knowledge structures. The mediational role of knowledge structures is expected to generalize to other training interventions and cognitive skill domains. Our findings have the immediate implications that practitioners should use SMR for improving the effectiveness of computer skill training.
15159600	To investigate the association between APOE-epsilon4 allele and memory phenotype in the preclinical stage of Alzheimer's disease (AD). We compared an extensive preclinical memory profile at the baseline evaluation of 2 AD genotype groups: APOE-epsilon4 allele carriers and patients with APOE-epsilon3 homozygosity. Baseline memory performance was carried out at least 2 years (interval of 27.7 +/- 4 months) before AD diagnosis was established, and analysis included different modalities of working memory (visuoperceptive, visuospatial, digit span and processing speed), of declarative memory (recent, verbal learning, prospective and semantic) and of nondeclarative memory (procedural, incidental and priming). We found no significant differences: memory performance was similar in both genotype groups. The presence of the APOE-epsilon4 allele does not seem to be sufficient to cause a distinctive preclinical memory phenotype in AD patients.
15147595	We sought to identify magnetic resonance- (MR)-imaged structures associated with declarative memory in a community-dwelling sample of elderly Mexican-American individuals with a spectrum of cognitive decline. Measured structures were the hemispheric volumes of the hippocampus (HC), parahippocampal gyrus, and remaining temporal lobes, as well as severity of white matter signal hyperintensities (WMH). Participants were an imaged subsample from the Sacramento Area Latino Study of Aging (SALSA), N = 122. Individuals were categorized as normal, memory impaired (MI), cognitively impaired non-demented (CIND), or demented. We show that WMH was the strongest structural predictor for performance on a delayed free-recall task (episodic memory) in the entire sample. The association of WMH with delayed recall was most prominent in elderly normals and mildly cognitively impaired individuals with no dementia or impairment of daily function. However, the left HC was associated with verbal delayed recall only in people with dementia. The right HC volume predicted nonverbal semantic-memory performance. We conclude that WMH are an important pathological substrate that affects certain memory functions in normal individuals and those with mild memory loss and discuss how tasks associated with WMH may rely upon frontal lobe function.
15146011	Specific cognitive impairments have been found in association with mesial temporal lobe epilepsy (TLE), such as deficits in declarative memory or verbal abilities. No attention has been paid so far to possible deficits in number processing.To investigate deficits in number processing in patients with TLE.	Numerical abilities were assessed in 28 right handed patients with medically intractable unilateral TLE and in a control group.	No differences between patients and controls were found in analogue number processing with Arabic input, in a comparison task, or in simple addition and simple subtraction; however, there were significant group differences in tasks with verbal input, in simple division, in complex mental calculation, in a semantic knowledge task, and in conceptual tasks. Only minor differences were found between patients with right and left TLE.	While numerical deficits may be expected in patients with left sided TLE, it is open for discussion why patients with right sided TLE also show numerical deficits.	
15135882	Neuropsychological deficits were investigated with respect to regional distribution of cerebral atrophy as assessed by volumetric magnetic resonance imaging (MRI) in 50 patients with Alzheimer's dementia (AD; NINCDS-ADRDA criteria) and 20 healthy volunteers. When compared between groups, test performance of all investigated neuropsychological domains including declarative memory, language, praxia, psychomotor speed, as well as attention and concentration was significantly impaired. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex correlated with declarative memory performance, whereas volumes of the left temporo-parietal regions correlated with performance in naming and praxia. Furthermore, left frontal lobe atrophy was associated with verbal fluency. Our data confirm the central role that medial temporal atrophy plays for declarative memory deficits in AD and indicate that additional changes in the parietal, temporal and frontal lobes are responsible for further neuropsychological deficits characteristic of this disorder.
15118359	The aim of this study was to investigate the impact on several forms of memory and metabolism of a 5-day combat course including heavy and continuous physical activities and sleep deprivation. Mnemonic performance and biochemical parameters of 21 male soldiers were examined before and at the end of the course. Our results showed that short-term memory (memory span, visual memory, audiovisual association) and long-term memory were significantly impaired, whereas short-term spatial memory and planning tasks were spared. Parallel biochemical analysis showed an adaptation of energy metabolism. The observed decrease in glycaemia may be partly responsible for the long-term memory impairment, whereas the decreases in plasma cholinesterases and choline may be involved in the short-term memory deterioration. However, there are also many other reasons for the observed memory changes, one of them being chronic sleep deprivation.
15118016	Structural stability and change in semantic and episodic memory performance as well as interindividual differences in 5-year changes in these constructs are examined within a sample of older adults (age rangeT1 = 60-80; n = 361). Interindividual differences in change were limited but significant. Stability coefficients were higher for semantic memory (.95) than for episodic memory (.87). Changes in episodic and semantic memory performance were strongly associated (r =.68). Across time, variances and covariances increased, and a tendency toward dedifferentiation in terms of increasing correlations was found. Chronological age was related to both level and change, but gender and education were only related to level of memory performance. Collectively, these results depict relatively high degrees of structural stability and stability of interindividual differences in declarative memory in old age.
15117396	Efforts to identify genetic loci for bipolar disorder (BPD) have thus far proved elusive. The identification of processes mediating between genotype and phenotype (endophenotypes) may help resolve the carrier status of family members in genetic studies of polygenetic disorders with imperfect penetrance, such as BPD. We reviewed the literature to determine if neuropsychological measures could be used as effective endophenotypes to aid molecular genetic studies searching for genes predisposing to BPD.Four prerequisites for endophenotypic markers are described, and a critical review of relevant literature was undertaken to determine if neurocognitive measures satisfy these four requirements in BPD.	We found evidence that executive functions and declarative memory may be candidate neurocognitive endophenotypes for BPD. However, we cannot exclude other areas of cognition as being affected by BPD susceptibility genes, given the limits of the current knowledge of the neuropsychology of BPD. In particular, the paucity of studies measuring cognition in healthy relatives of BPD patient limits conclusion regarding familial aggregation of particular neurocognitive deficits (i.e. attention). Furthermore, the effects of clinical state and/or medication usage on cognitive functioning in BPD probands should be further explored.	Molecular genetic studies of BPD may benefit from the application of select neuropsychological measures as endophenotypic markers. The use of these markers, once defined, may improve power for detecting genes predisposing to BPD and may help to better define diagnostic criteria.	
15113271	Recent studies provide evidence for an interaction between a declarative memory system, dependent on the medial temporal lobe (MTL), and a habit memory system, dependent on the basal ganglia. Using functional MRI, the authors studied this interaction when 1 system was compromised by neurological disease. Neural activity when performing a habit-learning task was compared in normal controls and subjects with Parkinson's disease (PD). Patients with PD showed less activation in the caudate nucleus and greater activation in a region of prefrontal cortex that has been associated with explicit memory retrieval. Patients with PD also showed activation of the MTL during the weather-prediction task. These findings are consistent with an interaction between memory systems of the MTL and the striatum.
15113269	The effects of adrenergic and corticosteroid hormonal systems on emotional memory were measured in 64 young men. Placebo, propranolol (40 or 80 mg; beta blocker), or metyiapone (corticosteroid synthesis inhibitor) was administered before the viewing of a story composed of emotional and neutral segments. Short- and long-term declarative memory for the story was assessed. Propranolol 40 mg had no effects on declarative memory. Propranolol 80 mg impaired short- and long-term declarative memory for emotionally arousing material. Metyrapone did not impair short-term declarative memory but impaired long-term declarative memory for emotionally arousing and neutral material. Results demonstrate that adrenergic and corticosteroid hormonal systems differentially affect declarative memory for emotionally arousing and neutral material, and suggest that interactions between adrenal hormonal systems modulate emotionally arousing declarative memory in humans.
15110920	The effects of corticosteroids on memory performance have been the subject of some controversy. Whilst many studies have shown that high levels of corticosteroids can impair memory performance, others have shown they can facilitate it. One explanation for these discrepant effects arises from the differential activation of the two types of corticosteroid receptor--the mineralocorticoid receptor (MRs) and the glucocorticoid receptor (GRs), and the function each subserves during memory formation. Studies in rats and chickens suggest that activation of the MRs is essential during sensory storage (i.e. encoding), whereas normal levels of activation of the GRs (in addition to the already activated MRs) is essential during memory consolidation and retrieval. By using a repeated measures design with nine people with Addison's disease (mean age, 37.9 years), the effects following activation of the MRs only, GRs only, and a combination of MRs/GRs, on working memory and the episodic and semantic components of declarative memory were investigated. MRs and GRs were activated using either MR specific (9 alpha fluorohydrocortisone) or GR specific (dexamethasone) exogenous steroids, respectively. The results showed that participants performed better in the Digits Backward task when both receptors were activated compared to when GRs only were activated (P<0.01). They also performed better in recall in the Hopkins Verbal Learning Test when both receptors were activated compared to when MRs only were activated (P<0.05) and GRs only were activated (P<0.01). Whilst significant effects were not consistent across memory tasks, these results lend further support to the view that balanced activation of MRs and GRs is necessary for optimal memory function in humans.
15107182	There is converging evidence that brain serotonin and dopamine may selectively modulate learning and memory in humans. However, this has not been directly demonstrated. In the current study, we used the method of amino acid precursor depletion to explore the effects of low serotonin and catecholamine function on memory in healthy female volunteers. Participants completed three experimental sessions: (i) tryptophan depletion (TD to lower 5-HT); (ii) tyrosine and phenylalanine depletion (TPD to lower catecholamines); and (iii) a balanced control condition (Bal). All testing was conducted in a double-blind, placebo-controlled, crossover design. Cognitive and mood assessments were performed at baseline and 5 h after ingesting the amino acid mixture. Consistent with previous studies, TD impaired declarative memory consolidation on a structured word-learning task, while TPD, acting to lower brain dopamine availability, impaired spatial working memory. No secondary deficits were observed on measures of attention, short-term memory or subjective mood state. These findings suggest that low brain serotonin versus dopamine selectively impairs memory performance in humans. This may shed light on the role of these neurotransmitters in disorders that are characterized by significant memory impairment.
15103264	The perirhinal cortex is a structure that lies within the medial temporal lobe. In the present paper, we review current knowledge of the anatomical boundaries and functional correlates of this structure. In the past decade, numerous animal studies have attempted to understand the contribution of the perirhinal cortex to memory. Taken together, they suggest that the perirhinal cortex is crucially involved in recognition memory. This function appears to be independent from those assumed to be subserved by the hippocampus. In humans, data are scarce but tend to corroborate results found in the animal literature. The perirhinal cortex appears to support context-free (non-episodic) knowledge, such as general knowledge about the world and "item-specific" memories. Models of declarative memory that take into account the specific contribution of the perirhinal cortex are discussed, along with their potential application to early cortical neurodegenerative disorders.
15099696	This study investigated event-related potential (ERP) effects when judgments about temporal context (recency judgments) required the retrieval of different amount of information. Subjects studied two consecutively presented word lists and at test made recency judgments to word pairs composed of two previously studied words, one drawn from each list ('Old + Old different' pairs), both drawn from the same list ('Old + Old same' pairs), or two unstudied words ('New + New' pairs). A frontopolar old/new effect was elicited by correct recency judgments which did not differ between both 'Old + Old' pairs. This finding suggests that the generators of the frontopolar old/new effect are not sensitive to the differing retrieval demands required here. However, an old/new effect over left inferior temporal electrodes was larger for 'Old + Old same' than for 'Old + Old different' pairs. The significance of these old/new effects are discussed in relation to the broader pattern of old/new effects seen in standard tests of declarative memory retrieval.

15095176	This study aims to systematically analyze the relationship between neuropsychological deficits and regional cerebral atrophic changes in Alzheimer's dementia (AD). As an extension of previous studies we not only investigated substructures of the medial temporal lobe but also included other relevant cerebral regions such as frontal, temporal, and parietal lobes. This approach was based on the assumption that morphological correlates of global and specific cognitive dysfunction might reflect to a certain degree the neuronal basis of the respective function. Accordingly, the functional role assigned to a certain cerebral structure or region can be further elucidated which might lead to a better understanding of the clinical and neuropsychological heterogeneity of AD. Fifty patients with AD (NINCDS-ADRDA criteria) and 20 healthy elderly control subjects were included. All patients and controls were examined on a standardized neuropsychological test battery. In addition, magnetic resonance imaging (MRI) of the brain was performed. Volumes of the whole brain, CSF-spaces, amygdala-hippocampus complex, frontal lobes, temporal lobes, and parietal lobes were measured using a standardized protocol. AD-patients were characterized by neuropsychological deficits with respect to memory, language, praxia, cognitive speed as well as attention and concentration. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex were correlated with declarative memory performance in the non-verbal visual domain. Furthermore, an association between left temporo-parietal regions and aspects of semantic memory, as well as verbal recall and left frontal regions could be established. The validity of our results is supported by recent findings from neuropathological and functional neuroimaging studies. In conclusion, our data indicate that MRI-based volumetry can be successfully used to detect morphological correlates of neuropsychological heterogeneity in AD and that this methodological approach allows to fruitfully study the neuronal basis of cognitive functions.
15094519	Declarative memory has been reported to rely on the medial temporal lobe system, whereas non-declarative memory depends on basal ganglia structures. We investigated the functional role of the subthalamic nucleus (STN), a structure closely connected with the basal ganglia for both types of memory. Via deep brain high frequency stimulation (DBS) we manipulated neural activity of the STN in humans. We found that DBS-STN differentially modulated memory performance: declarative memory was impaired, whereas non-declarative memory was improved in the presence of STN-DBS indicating a specific role of the STN in the activation of memory systems.
15091333	Hippocampal representations of the environment are thought to play a fundamental role in the encoding, storage, and retrieval of declarative memory. In this issue of Neuron, Kentros and coworkers show that new hippocampal representations stabilize only when animals are attentive.
15090653	Semantic knowledge (e.g., long-established knowledge about objects, facts, and word meanings) is known to be severely impaired by damage to the anterolateral temporal lobe. For example, patients with semantic dementia have prominent atrophy in anterolateral temporal cortex and also have significant damage within the medial aspect of the temporal lobe. However, there is uncertainty about the contribution of medial temporal lobe damage, including perirhinal cortex damage, to impaired semantic knowledge. Drawing largely on published material from multiple sources, we compared the performance of severely amnesic patients with large medial temporal lobe lesions and patients with semantic dementia on nine tests of semantic knowledge and two tests of new learning ability. On the tests of semantic knowledge, the amnesic patients performed markedly better than the patients with semantic dementia. By contrast, on the tests of new learning, the patients with semantic dementia performed markedly better than the amnesic patients. We conclude that medial temporal lobe damage impairs the formation of declarative memory, and that semantic knowledge is impaired to the extent that damage extends laterally in the temporal lobe. Reports that the extent of atrophy in perirhinal cortex correlated with the severity of impaired semantic knowledge may be understood by supposing that the extent of damage in many temporal lobe areas is intercorrelated in this progressive disease, and that the extent of atrophy in perirhinal cortex is a proxy for the overall severity of dementia.
15089020	A conception of insight is proposed, based on a systems and information-processing framework and using current neuroscience concepts, as an integration of information that results in a new symbolization of experience with a significant change in self-image and a transformation of non-declarative procedural knowledge into declarative knowledge. Since procedural memory and knowledge, seen to include emotional and relationship issues, is slow to change, durable emotional and behavioral change often requires repeated practice, a need not explicitly addressed in standard psychoanalytic technique. Working through is thus seen as also encompassing nondynamic factors. The application of these ideas to therapeutic technique suggests possible therapeutic interventions beyond interpretation. An illustrative clinical vignette is presented.
15079141	Traumatic amnesia has been amply documented in the psychoanalytic literature but inconsistently in the research literature.Six trauma were followed prospectively. Survivors were interviewed 7, 30, and 120 days following the traumatic event. Each interview documented in detail their recollections of the day of their trauma.	In four subjects who did not develop posttraumatic stress disorder (PTSD), we found brief, stable, and persistent memory gaps, which coincided with the moment of greatest emotional intensity. In two subjects who developed PTSD, we found, in addition to the previous form of amnesia, longer, progressive, and unstable memory gaps.	Neurobiological research offers two explanatory mechanisms for the observations: A failure of acquisition of episodic memories may account for the stable deficits seen in all subjects. This could coincide with stress-induced malfunction of the hippocampal declarative memory system. A failure of spontaneous recall may account for the more extended traumatic amnesia that was observed in PTSD patients. This resembles the psychoanalytic description of repression.	These preliminary findings suggest that brief, irreversible memory gaps are common in trauma survivors, whereas longer, progressive, and potentially reversible amnesia occurs among survivors who develop PTSD.	
15062861	In a previous study [Cogn. Brain Res. 16 (2003) 325], we found that letter knowledge did not evolve from implicit training on whole-word recognition in an artificial Morse-like script, although the participants were adults, experienced in alphabetical reading. Here we show minimal conditions in which letter knowledge may evolve in some individuals from training on whole-word recognition. Participants received multi-session training in reading nonsense words, written in an artificial script, in which each phoneme was represented by two discrete symbols. Three training conditions were compared: alphabetical whole words with letter decoding instruction (Explicit), alphabetical whole words (Implicit), and non-alphabetical whole words (Arbitrary). Subjects were assigned to training either on the explicit and arbitrary or on the implicit and arbitrary conditions. Our results show that: (a) Letter-decoding knowledge evolved implicitly from training on alphabetical whole-word recognition, in some individuals. However, (b) a clear double dissociation was found between effectively applied implicit letter knowledge and declarative letter knowledge. (c) There was no advantage of the implicitly derived over the explicitly instructed letter knowledge. (d) Long-term retention was more effective in the explicit compared to the arbitrary condition. (e) Word-specific recognition contributed significantly to performance in all three training conditions, i.e. even under conditions that presumably afford advantage for word segmentation. Altogether, our results suggest that both declarative and procedural knowledge contributed to letter decoding as well as to word-specific recognition performance. Moreover, a greater dependency on declarative knowledge may not be an inherent characteristic of word-specific recognition, but rather that both letter decoding and word-recognition routines can become proceduralized given sufficient practice.
15058477	Neuroscientific research has established that the hippocampal formation, a structure within the medial temporal lobe (MTL), plays a critical role in memory for facts and events (declarative memory) (Milner et al., 1998). However, its precise role remains unclear. According to one view, the hippocampus has a special role in relating or binding together previously unrelated pieces of information, while another view proposes that the hippocampus is equally involved in all forms of declarative memory, regardless of their demands on relational processing. Using functional magnetic resonance imaging (fMRI), we show that hippocampal activation is modulated by the extent to which a retrieval task depends on relational processing.
15056509	Prior studies showed that subjects with major depression have deficits in hippocampal-based verbal declarative memory (e.g., recall of a paragraph) and in hippocampal and prefrontal cortical functioning and structure. The purpose of the present study was to assess hippocampal and prefrontal functioning during performance of a verbal declarative memory task in subjects with midlife major depression.Subjects with midlife major depression (N=18) and healthy subjects (N=9) underwent positron emission tomography imaging during a control task and verbal encoding of a paragraph.	During the verbal memory encoding task the comparison subjects, but not the subjects with depression, activated the right hippocampus and prefrontal cortex (anterior cingulate), as well as the cuneus and cerebellum.	These results are consistent with a failure of hippocampal and anterior cingulate activation in depression, and they support the hypothesis of deficits in hippocampal and anterior cingulate functioning in depression.	
15050862	Major depression has been associated with hypercortisolemia in a subset of patients with depression. Administration of exogenous cortisol and other glucocorticoids to healthy human subjects has been observed to result in a transient impairment in verbal declarative memory function. The purpose of this study was to assess the effects of the glucocorticoid, dexamethasone, on verbal declarative memory function in patients with untreated unipolar major depressive disorder (MDD).Fifty two men and women with (n = 28) and without (n = 24) MDD received placebo or dexamethasone (1 mg and 2 mg on 2 successive days) in a double-blind, randomized fashion. Declarative memory was assessed with paragraph recall at baseline (day 1) and day 3.	There was a significant interaction between diagnosis and drug (dexamethasone vs. placebo) on paragraph recall. In the healthy subjects, memory improved from baseline to day 3 with placebo and was unchanged with dexamethasone, whereas in MDD patients memory function showed a pattern of decreasing with placebo and improving with dexamethasone from baseline to day 3.	These findings are consistent with an altered sensitivity of declarative memory function in MDD to regulation by glucocorticoids. Possible explanations of the findings include alterations in glucocorticoid receptors in the hippocampus or other brain regions mediating declarative memory, or differential sensitivity to dexamethasone-induced reductions in cortisol, in patients with MDD.	
15038994	Patients with schizophrenia have smaller hippocampal volumes and perform abnormally on most declarative memory tasks. Although these findings are likely related, the impact of hippocampal pathology on cognitive performance in schizophrenia remains unclear. This study examined this relationship by measuring the volume of the hippocampus and its activation during memory task performance.Participants included 15 patients with schizophrenia and 16 age-matched control subjects. Hippocampal volume was determined via three-dimensional volumetric analysis of high-resolution magnetic resonance images. Hippocampal activity was assessed by measuring changes in blood oxygen level-dependent signal during a recognition memory task.	Patients with schizophrenia had smaller hippocampal volumes bilaterally and demonstrated poorer performance on the recognition memory task, largely because of a heightened rate of false alarms to novel stimuli. Both groups showed robust hippocampal activity to old and new items when compared with a low-level baseline task; however, direct comparison of hippocampal activity during recognition task performance revealed that healthy control, but not the schizophrenia, subjects showed significant right anterior hippocampal activation during the evaluation of novel items.	The impaired ability to classify new items as previously not experienced is associated with decreased recruitment and smaller volume of the hippocampus in schizophrenia.	
15037131	The structure of the brain and the nature of evolution suggest that, despite its uniqueness, language likely depends on brain systems that also subserve other functions. The declarative/procedural (DP) model claims that the mental lexicon of memorized word-specific knowledge depends on the largely temporal-lobe substrates of declarative memory, which underlies the storage and use of knowledge of facts and events. The mental grammar, which subserves the rule-governed combination of lexical items into complex representations, depends on a distinct neural system. This system, which is composed of a network of specific frontal, basal-ganglia, parietal and cerebellar structures, underlies procedural memory, which supports the learning and execution of motor and cognitive skills, especially those involving sequences. The functions of the two brain systems, together with their anatomical, physiological and biochemical substrates, lead to specific claims and predictions regarding their roles in language. These predictions are compared with those of other neurocognitive models of language. Empirical evidence is presented from neuroimaging studies of normal language processing, and from developmental and adult-onset disorders. It is argued that this evidence supports the DP model. It is additionally proposed that "language" disorders, such as specific language impairment and non-fluent and fluent aphasia, may be profitably viewed as impairments primarily affecting one or the other brain system. Overall, the data suggest a new neurocognitive framework for the study of lexicon and grammar.
15027792	This study compared attention and declarative memory in a sample of combat veterans with posttraumatic stress disorder (PTSD, n = 24) previously reported to have reduced concentrations of the hippocampal neuronal marker N-acetyl aspartate (NAA), but similar hippocampal volume compared to veteran normal comparison participants (n = 23). Healthy, well-educated males with combat-related PTSD without current depression or recent alcohol/drug abuse did not perform differently on tests of attention, learning, and memory compared to normal comparison participants. Further, hippocampal volume, NAA, or NAA/Creatine ratios did not significantly correlate with any of the cognitive measures when adjustments for multiple comparisons were made. In this study, reduced hippocampal NAA did not appear to be associated with impaired declarative memory.
15027040	Based on the hypothesis that declarative memory and navigation ability depend on hippocampal integrity, and the fact that declarative memory declines early in Alzheimer's disease (AD), the authors suggest that topographical disorientation (TD) will be an early manifestation of AD.Patients diagnosed with AD based on DSM-IV criteria, residing at home, were studied in a clinic at a 1000-bed referral medical center. Patient characteristics, disease condition, performance on neuropsychological tests, and navigation function were compared between patients with and without current TD. Information regarding the extent and duration of TD and the level of current navigational function were collected during a clinical interview.	112 patients (61 males and 51 females) with mean age of 74 years and disease duration of 37 months completed the study. Among them, 61 currently experienced TD, 20 had required an escort to their home by others, and 28 had TD as an incipient symptom. Those with current TD tended to have a longer disease duration, required an escort to their home by others, and reported a history of repeated change of residence, TD as an incipient symptom, a restricted spatial range within which they felt comfortable (safety range), and disorientation when they were out of familiar territory. In addition, care-givers reported a high level of concern for the safety of those with TD when he or she traveled alone.	TD in community-dwelling AD patient is common. Caregivers should pay attention to those with longer disease duration and try to avoid changing residence. Developing a brief and valid test for topographical orientation will be helpful for the early detection of TD.	
15023583	Hippocampal volume reduction, declarative memory deficits, and cortisol elevations are reported in persons with major depressive disorder; however, data linking cortisol elevations with hippocampal atrophy are lacking. Prescription corticosteroid-treated patients offer an opportunity to examine corticosteroid effects on hippocampal volume and biochemistry and memory in humans.Seventeen patients on long-term prescription corticosteroid therapy and 15 controls of similar age, gender, ethnicity, education, height, and medical history were assessed with magnetic resonance imaging and proton magnetic resonance spectroscopy, the Rey Auditory Verbal Learning Test, Stroop Color Word Test and other neurocognitive measures, the Hamilton Rating Scale for Depression, Young Mania Rating Scale, and Brief Psychiatric Rating Scale.	Compared with controls, corticosteroid-treated patients had smaller hippocampal volumes and lower N-acetyl aspartate ratios, lower scores on the Rey Auditory Verbal Learning Test and Stroop Color Word Test, and higher Hamilton Rating Scale for Depression and Brief Psychiatric Rating Scale scores.	Patients receiving chronic corticosteroid therapy have smaller hippocampal volumes, lower N-acetyl aspartate ratios, and declarative memory deficits compared with controls. These findings support the idea that corticosteroid exposure appears to be associated with changes in hippocampal volume and functioning in humans.	
15014624	Physicians in the United States write approximately 10 million new prescriptions for oral corticosteroids each year. Common side effects of corticosteroids include weight gain, osteoporosis, and diabetes mellitus. This article reviews the available literature on psychiatric and cognitive changes during corticosteroid therapy.A search of the MEDLINE and psycINFO databases was conducted to find clinically relevant articles on psychiatric and cognitive side effects with corticosteroids using search terms including corticosteroid, prednisone, mania, depression, psychosis, mood, memory, and cognition.	Symptoms of hypomania, mania, depression, and psychosis occur during corticosteroid therapy as do cognitive changes, particularly deficits in verbal or declarative memory. Psychiatric symptoms appear to be dose-dependent and generally occur during the first few weeks of therapy. Patients who must remain on corticosteroids may benefit from pharmacotherapeutic approaches, such as lithium and the new antipsychotic medications.	Mood and cognitive changes with corticosteroids appear to be common but generally mild and reversible side effects. More studies are needed to determine effective treatment for steroid-induced psychiatric disorders.	
15013823	Much evidence indicates that emotional arousal generally improves memory and that the amygdala is responsible for this effect. The available data suggest that stress hormones and neuromodulators released in emotionally arousing conditions alter the activity of basolateral amygdala (BLA) neurons in the hours after the learning episode. In turn, these changes would facilitate synaptic plasticity elsewhere in the brain; however, the biological mechanisms underlying the facilitation of memory consolidation by the BLA remain unknown. This article focuses on data suggesting that synchronized oscillatory BLA activity promotes synaptic plasticity by facilitating interactions between neocortical and temporal lobe areas involved in declarative memory.
15013575	Pentyl-4-yn-valproic acid (VPA), a cognition-enhancing agent whose mode of action has been attributed to cell adhesion molecule-mediated neuritogenesis, has been shown to enhance hippocampus-dependent spatial learning. Here, we investigated its potential to reverse age-related memory impairment that relates mainly to declarative memory. Aged spatial learning deficits in the water maze paradigm were demonstrated by swim angle analysis, the angle between axes of start-to-platform and start-to-animal position, and latency to reach a submerged platform. Chronic pentyl-4-yn-VPA administration mediated a significant improvement in both search strategy and latency to find the submerged platform in aged animals. Pentyl-4-yn-VPA also facilitated task recall in aged animals as evidenced by increased time in the target quadrant during a probe trial 3 days following the final training session. The action of pentyl-4-yn-VPA on platform latency, search strategy and task recall suggests that this agent may have great benefit in the treatment of age-dependent cognitive decline.
15011158	Apart from chronic motor disorder and the possible sensory deficits (visual, propioception) associated to periventricular leukomalacia (PVL), disorders involving the integration of higher functions due to bilateral injury to the occipital parietal junction are relatively common.Our aim was to further our knowledge of the neuropsychological characteristics of this non progressive cerebral motor disorder. Patients and methods. We analysed a sample of 15 patients with spastic diplegia due to PVL who did not present mental retardation (verbal IQ> 75 and mean verbal IQ= 91, WISC R) in order to evaluate their visual gnosis praxis, verbal and visual memory, psycholinguistic and attentional capabilities.	Disorders involving visuospatial integration and visual constructive memory are frequent. Long term verbal memory is poor (in fact in some cases it is clearly deficient), but can be improved with associative learning. They do not present any difficulties regarding attention and some subjects display deficiencies in the pragmatic use of language. This research is still underway and the findings presented here are preliminary.	The neuropsychological profile of the diplegic children who were studied shares the characteristics of non verbal learning disorder. The declarative memory disorder observed in several of the subjects in our sample, who were all born premature and below weight, can be accounted for by a bihippocampal pathology or by a dysexecutive disorder.	
14989416	A central question in schizophrenia research is which brain abnormalities are independent of psychosis and which evolve before and after psychosis begins. This question can be addressed by longitudinal neuroimaging studies beginning in the prodrome, but at present there is only one published study. We reviewed the literature on structural brain imaging in persons with chronic and first episode schizophrenia, nonpsychotic persons at genetic high risk, and persons thought to be at risk for imminent psychosis ("prodromal" persons). Medial temporal lobe (MTL), especially hippocampal, volume alterations are among the most robust brain vulnerabilities for schizophrenia. Because verbal declarative memory (VDM) deficits are prominent and the parahippocampal gyrus (PHG) is considered to be centrally involved with the hippocampus in VDM processing, we analyzed PHG data from a family study of schizophrenia. Patients with schizophrenia and nonpsychotic relatives from "multiplex" families (families with multiple persons with schizophrenia) had significantly smaller right parahippocampal anterior (PHa) volumes than controls. Marginally significant findings were observed for the left PHa. Unexpectedly, relatives from "simplex" families (families with only one person with schizophrenia) had significantly larger PH posterior volumes than controls and did not differ from controls on PHa. Results provide some support for the hypothesis that the vulnerability to schizophrenia includes abnormal volumes of the PHG. These data provide additional support for the hypothesis that some MTL abnormalities in schizophrenia are independent of psychosis, at least in families with presumably high genetic loading. Implications of genetic risk studies for prodromal research are discussed.
14984329	To identify the key components of executive functions (EFs) in children following traumatic brain injury (TBI), data from a series of EF tests administered to 286 pediatric TBI patients at least 3 years postinjury were subjected to an exploratory factor analysis. A 5-factor model included discourse, EFs (e.g., problem solving, planning), processing speed (e.g., coding), declarative memory, and motor speed. Confirmatory factor analysis based on data obtained from 265 pediatric TBI patients at 3 months postinjury disclosed that the 5-factor model provided a good fit to the data. A second exploratory analysis of the 3-month postinjury data disclosed a 4-factor model in which processing speed and motor speed measures loaded on a common factor. Severity of TBI and age at test had significant effects on all factors in both the 5- and 4-factor models. Adaptive functioning, as measured by the Vineland Adaptive Behavioral Scale-Revised, was moderately related to factor scores at 3 years or longer postinjury, but weakly related to factor scores obtained at 3 months postinjury. The factor scores could be used in clinical trials to facilitate data reduction and appear to have validity as indicators of TBI outcome.
14983183	During sleep, neural activity in the hippocampus and neocortex seems to recapitulate aspects of its earlier, awake form. This replay may be a substrate for the consolidation of long-term declarative memories, whereby they become independent of the hippocampus and are stored in neocortex. In contrast to storage, other crucial facets of competent long-term memory, such as maintenance of access to stored traces and preservation of their correct interpretation, have received little attention. We investigate long-term episodic and semantic memory in a theoretical model of neocortical-hippocampal interaction. We find that, in the absence of regular hippocampal reactivation, even supposedly consolidated episodic memories are fragile in the face of cortical semantic plasticity. Replay allows access to episodes stored in the hippocampus to be maintained, by keeping them in appropriate register with changing neocortical representations. Hippocampal storage and replay also has a constructive role in the recall of structured, semantic information.
14872023	To investigate the heritability of memory and other cognitive measures in families with multiple individuals with Alzheimer disease (AD) to determine if neuropsychological measures can be used to better understand genetic contributions to AD.The genetic contributions to the variation in declarative memory, attention, abstract reasoning, language, and visuospatial function using a variance component method were estimated. For memory scores, the proportion of genetic contribution was estimated, controlling for APOE.	The unadjusted heritability estimates for the declarative memory tasks ranged from 0.47 for delayed recall to 0.25 for delayed recognition, where a heritability estimate of 1 indicates that genetic factors explain all of the phenotypic variance and a heritability score of 0 indicates that genetic factors explain none. When adjusted for sex, age, education, and general intelligence, the heritability estimates increased to 0.60 for delayed recall and 0.41 for delayed recognition. None of the other cognitive tests showed heritability estimates as high as that observed for memory. When the influence of APOE was taken into account, the heritability estimates changed modestly for delayed recall and consistent long-term retrieval, whereas the estimates for other memory scores did not change, suggesting that APOE contributes little to these memory scores.	Declarative memory in familial AD is under strong genetic influence, only part of which is attributable to APOE. Memory performance should prove to be a useful phenotypic component in the investigation of the genetic basis of AD.	
14766981	The neurotransmitter acetylcholine is considered essential for proper functioning of the hippocampus-dependent declarative memory system, and it represents a major neuropharmacological target for the treatment of memory deficits, such as those in Alzheimer's disease. During slow-wave sleep (SWS), however, declarative memory consolidation is particularly strong, while acetylcholine levels in the hippocampus drop to a minimum. Observations in rats led to the hypothesis that the low cholinergic tone during SWS is necessary for the replay of new memories in the hippocampus and their long-term storage in neocortical networks. However, this low tone should not affect nondeclarative memory systems. In this study, increasing central nervous cholinergic activation during SWS-rich sleep by posttrial infusion of 0.75 mg of the cholinesterase inhibitor physostigmine completely blocked SWS-related consolidation of declarative memories for word pairs in human subjects. The treatment did not interfere with consolidation of a nondeclarative mirror tracing task. Also, physostigmine did not alter memory consolidation during waking, when the endogenous central nervous cholinergic tone is maximal. These findings are in line with predictions that a low cholinergic tone during SWS is essential for declarative memory consolidation.
14754866	Using event-related fMRI, we scanned young healthy subjects while they memorized real-world photographs and subsequently tried to recognize them within a series of new photographs. We confirmed that activity in the medial temporal lobe (MTL) and inferior prefrontal cortex correlates with declarative memory formation as defined by the subsequent memory effect, stronger responses to subsequently remembered than forgotten items. Additionally, we confirmed that activity in specific regions within the parietal lobe, anterior prefrontal cortex, anterior cingulate and cerebellum correlate with recognition memory as measured by the conventional old/new effect, stronger responses for recognized old items (hits) than correctly identified new items (correct rejections). To obtain a purer measure of recognition success, we introduced two recognition effects by comparing brain responses to hits and old items misclassified as new (misses). The positive recognition effect (hits > misses) revealed prefrontal, parietal and cerebellar contributions to recognition, and in line with electrophysiological findings, the negative recognition effect (hits < misses) revealed an anterior medial temporal contribution. Finally, by inclusive masking, we identified temporal and cerebellar brain areas that support both declarative memory formation and retrieval. For matching operations during recognition, these areas may re-use representations formed and stored locally during encoding.
14754864	The parahippocampal gyrus, located at the medial temporal lobe, is a key structure in declarative memory processing. We have analyzed the general organization of the parahippocampal gyrus in the baboon, a nonhuman primate species relatively close to human. This region is rostrocaudally made up of the temporopolar, perirhinal, entorhinal (divided into seven subfields) and posterior parahippocampal (areas TH and TF) cortices. The basic analysis has been performed in three brains, serially sectioned and stained with thionin, myelin stain, acetylcholinesterase and parvalbumin, to determine cytoarchitectonic boundaries. Borders of all subfields were charted onto camera lucida drawings, and two-dimensional maps of the surface and topography of the parahippocampal gyrus were made. Finally, the limits of each parahippocampal area were then transposed on corresponding MR images (commonly used for in vivo PET or functional MRI activation studies) of two animals for precise identification. The general cytoarchitectonic features of the baboon parahippocampal gyrus are similar to macaques, but the size of temporopolar cortex and the laminar organization of perirhinal and posterior parahippocampal cortices resemble humans more than macaque species. In conclusion, the size and structure of the baboon parahippocampal cortex makes this species very appropriate for experimental studies on memory function.
14749440	Lesions in the hippocampus (HC), the entorhinal cortex (EC), and the prefrontal cortex (PFC) are associated with impairment of episodic memory; reduced HC volume is linked to memory declines in dementia; and decline in EC volume predicts progression from mild cognitive impairment to dementia. However, in healthy adults, the relationship between memory and regional volumes is unclear, and no data are available on the relationship of longitudinal regional shrinkage to memory performance in a cognitively intact population. The objective of this study was to examine whether shrinkage of the EC, HC, and PFC over a 5 year period can predict declarative memory performance in healthy adults. The volumes of three brain regions were measured on magnetic resonance images that were acquired twice, 5 years apart. Multiple measures of episodic memory were administered at follow-up. Results indicated that the volume of HC and PFC (but not EC) correlated with age at baseline and follow-up. However, after age differences in memory were taken into account, none of the regional volumes was associated with memory performance at follow-up. In contrast, greater annual rate of shrinkage in EC (but not HC or PFC) predicted poorer memory performance. Thus, in a healthy and educated population, even mild age-related shrinkage of the EC may be a sensitive predictor of memory decline.
14728998	Mild cognitive impairment (MCI) is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss. MCI is important as it often precedes Alzheimer's disease (AD). Recognizing MCI may lead to preventive strategies that can delay the onset of AD. Many patients who transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. The improvement in cognitive function with hormones is subtle and often not measurable on standard neuropsychological batteries. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement. Functional changes and vascular changes can be detected after hormonal replacement with more sophisticated imaging of the brain like PET scans. We hypothesize androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males.
14728917	Recognition memory performance reflects two distinct processes or types of memory referred to as recollection and familiarity. According to theoretical claims about the two types of memory, single item and associative recognition tasks can be used as an experimental method to distinguish recollection and familiarity processes. Associative recognition decisions can be used as an index of recollection while memory for single items is mostly based on familiarity judgement. We employed this procedure to examine a possible dissociation in the memory performance of amnesic patients between spared single item and impaired associative recognition. Twelve amnesic patients, six with damage confined to the hippocampus proper, and six with damage elsewhere in the brain, were recruited for the present study. The findings showed that hippocampal amnesics exhibit relative sparing of single item learning but are consistently deficient in the learning of all kinds of between-item associations. These results are consistent with the view that hippocampal formation contributes differently to declarative tasks that require recollective or familiarity processes.
14725804	To test theories of explicit memory in amnesia, we examined the effect of hypoxia on memory performance in a group of 56 survivors of sudden cardiac arrest. Structural equation modeling revealed that a single-factor explanation of recall and recognition was insufficient to account for performance, thus contradicting single-process models of explicit memory. A dual-process model of recall in which two processes (e.g., declarative memory and controlled search) contribute to recall performance, whereas only one process (e.g., declarative memory) underlies recognition performance, also failed to explain the results adequately. In contrast, a dual-process model of recognition provided an acceptable account of the data. In this model, two processes--recollection and familiarity--underlie recognition memory, whereas only the recollection process contributes to free recall. The best-fitting model was one in which hypoxia and aging led to deficits in recollection, but left familiarity unaffected. Moreover, a controlled search process was correlated with recollection, but was not associated with familiarity or the severity of hypoxia. The results support models of explicit memory in which recollection depends on the hippocampus and frontal lobes, whereas familiarity-based recognition relies on other brain regions.
14720229	How the implicit/non-declarative and explicit/declarative cognitive domains interact is centrally important in the consideration of effecting change within the psychoanalytic arena. Stern et al. (1998) declare that long-lasting change occurs in the domain of implicit relational knowledge. In the view of this author, the implicit and explicit domains are intricately intertwined in an interactive dance within a psychoanalytic process. The author views that a spirit of inquiry (Lichtenberg, Lachmann & Fosshage 2002) serves as the foundation of the psychoanalytic process. Analyst and patient strive to explore, understand and communicate and, thereby, create a 'spirit' of interaction that contributes, through gradual incremental learning, to new implicit relational knowledge. This spirit, as part of the implicit relational interaction, is a cornerstone of the analytic relationship. The 'inquiry' more directly brings explicit/declarative processing to the foreground in the joint attempt to explore and understand. The spirit of inquiry in the psychoanalytic arena highlights both the autobiographical scenarios of the explicit memory system and the mental models of the implicit memory system as each contributes to a sense of self, other, and self with other. This process facilitates the extrication and suspension of the old models, so that new models based on current relational experience can be gradually integrated into both memory systems for lasting change.
14702259	The authors' goals were 1) to establish a clinically useful standard index of the relative anticholinergic potency of psychiatric medications; 2) to determine which cognitive functions are most affected by the administration of anticholinergic medications to patients with schizophrenia; and 3) to compare in vitro and clinically derived indexes of anticholinergic load in predicting these cognitive impairments.One hundred six clinically stable patients with schizophrenia were given a brief neuropsychological battery and evaluated on a standard symptom rating scale. The anticholinergic load associated with their psychiatric medications was estimated by using 1) a pharmacological index, calculated from a compilation of published studies reporting in vitro brain muscarinic receptor antagonism, and 2) a clinical index, based on clinician ratings of the anticholinergic side effects of medications. The authors analyzed the correlations of both indexes with the neuropsychological measures and with summary neuropsychological factor scores.	The clinical and pharmacological anticholinergic indexes were highly correlated with each other and showed virtually identical associations with neuropsychological measures. Anticholinergic load was associated with lower scores on measures of attention and declarative memory, including several measures of auditory and visual memory and two tests of complex attention, but was unrelated to intelligence, simple attention, working memory, executive functions, conceptual fluency, or motor speed.	This pattern of cognitive impairment with central cholinergic antagonism is consistent with emerging models of the functional anatomy of ascending forebrain cholinergic subsystems. Both pharmacological and clinical indexes show utility in predicting the effects of anticholinergic load on cognition in schizophrenia. Doses of psychiatric medication within the range of routine pharmacotherapy practice may have clinically significant effects on memory and complex attention in patients with schizophrenia; these effects may contribute as much as one-third to two-thirds of the memory deficit typically seen in patients with schizophrenia.	
14694035	To examine whether the amnesic syndrome of alcoholic Korsakoff's syndrome (KS) originates from pathology of the hippocampus and not solely the diencephalon.The authors studied 5 patients with KS and two comparison groups: 20 patients with Alzheimer's disease (AD) with known bilateral hippocampal volume loss and 36 healthy control subjects. The authors used quantitative MRI to characterize the hippocampus and comparison brain structures (temporal cortex, lateral ventricles, temporal horns, and third ventricle).	Relative to healthy control subjects, the KS and AD groups had comparable, significant bilateral hippocampal volume deficits. Although both patient groups also had extensive volume abnormalities in temporal lobe cortical gray matter, temporal horns, and lateral and third ventricles, declarative memory test performance was selectively related to hippocampal volumes in KS and not to any of the comparison volumes.	The characteristic memory deficit of Korsakoff's syndrome involves hippocampal and diencephalic pathology.	
14674372	The adaptive and maladaptive roles of the hypothalamic-pituitary-adrenal (HPA) axis in stressful conditions and in disorders such as major depression, posttraumatic stress disorder, and Cushing's syndrome, have been the subject of substantial, ongoing study. In particular, HPA disturbances have been associated with memory impairments, and hypercortisolemic conditions with atrophy of the hippocampus, a limbic structure closely associated with declarative memory. Recent discoveries support a more complicated picture of HPA axis function and pathology in acquiring, retrieving, and consolidating new memories. These findings include: the existence of an 'inverted U-shaped relationship" between stimulation of brain glucocorticoid receptors and memory performance; that distinct areas of the hippocampus have been found to respond differently to cortisol stimulation; and that hippocampal atrophy has been found to be potentially reversible in some conditions, although whether such atrophy is a cause or effect of these pathological conditions is currently unclear. More longitudinal studies of HPA axis function in aging normal individuals, those with mild cognitive impairment,and individuals with Alzheimer' disease, examining pertinent variables such as APOEe-4 status, are needed to help clarify these new findings. Antiglucocorticoid agents appear to have therapeutic value in particular conditions. These results are relevant for understanding and treating memory dysfunction in individuals with Alzheimer's disease, a disorder prominently and invariably characterized by early hippocampal lesions and memory impairment. Given the burden of this disease, we feel it timely to encourage controlled trials of antiglucocorticoid agents in the treatment of mild cognitive impairment and Alzheimers disease.
14660056	Although a strong psychoneuroendocrine linkage exists between stress, glucocorticoids and memory, the relationship is not always straightforward. Eighty-eight effect sizes and 1642 participants from 28 studies were meta-analyzed for the effects of stress on memory performance and glucocorticoid activation. Analyses showed that stress was associated with glucocorticoid activation and declarative memory decline. In animal studies, predator stress affected memory performance more than physical stress. In human studies, males showed higher cortisol levels than females in response to stress. Further, the correlation between cortisol levels and memory deficits was stronger in studies using laboratory stressors than those examining long term effects of chronic exposure to rising basal levels of glucocorticoids and chronic life stressors. It was concluded that, although the relationship between stress, glucocorticoids, and memory loss was empirically supported, there were other factors, such as stress condition and gender, as well as individual differences within groups, that influenced the association between these variables, and warrant further examination.
14657256	Classical conditioning of the eyeblink reflex to a neutral stimulus that predicts an aversive stimulus is a basic form of associative learning. Acquisition and retention of this learned response require the cerebellum and associated sensory and motor pathways and engage several other brain regions including the hippocampus, neocortex, neostriatum, septum, and amygdala. The cerebellum and its associated circuitry form the essential neural system for delay eyeblink conditioning. Trace eyeblink conditioning, a learning paradigm in which the conditioned and unconditioned stimuli are noncontiguous, requires both the cerebellum and the hippocampus and exhibits striking parallels to declarative memory formation in humans. Identification of the neural structures critical to the development and maintenance of the conditioned eyeblink response is an essential precursor to the investigation of the mechanisms responsible for the formation of these associative memories. In this review, we describe the evidence used to identify the neural substrates of classical eyeblink conditioning and potential mechanisms of memory formation in critical regions of the hippocampus and cerebellum. Addressing a central goal of behavioral neuroscience, exploitation of this simple yet robust model of learning and memory has yielded one of the most comprehensive descriptions to date of the physical basis of a learned behavior in mammals.
14656505	Prior research suggests that the action system is responsible for creating an immediate sense of self by determining whether certain sensations and perceptions are the result of one's own actions. In addition, it is assumed that declarative, episodic, or autobiographical memories create a temporally extended sense of self or some form of identity. In the present article, we review recent evidence suggesting that action (procedural) knowledge also forms part of a person's identity, an action identity, so to speak. Experiments that addressed self-recognition of past actions, prediction, and coordination provide ample evidence for this assumption. The phenomena observed in these experiments can be explained by the assumption that observing an action results in the activation of action representations, the more so, when the action observed corresponds to the way in which the observer would produce it.
14645987	Endotoxin stimulation of the immune system produces marked alterations in memory functioning. However, molecular links between this cognitive response and infection-responding neurotransmission pathways are still unknown. The cytokine and memory responses of volunteers injected with 0.8 ng/kg Salmonella endotoxin were compared with changes in plasma levels and integrity of the stress-induced acetylcholinesterase variant, AChE-R. Vascular endothelial cells were found to express AChE-R messenger RNA and protein both in healthy and inflamed human tissues. Plasma AChE activity was reduced after endotoxin treatment, but not placebo treatment, parallel to the decline in cortisol after the endotoxin-induced peak and inversely to the accumulation of a C-terminal immunopositive AChE-R peptide of 36 amino acid residues. AChE-R cleavage coincided with significant endotoxin-induced improvement in working memory and impairment in declarative memory. By 3 h posttreatment, working memory improvement was negatively correlated with AChE-R cleavage, which showed association to proinflammatory cytokine levels. By 9 h posttreatment, declarative memory impairment was negatively correlated with AChE-R cleavage and positively correlated with the suppressed AChE activity. Endotoxin-induced peripheral cholinergic stress responses are hence associated with greater impairment in declarative memory and lower improvement in working memory, pointing at AChE-R as a surrogate marker of psychoneuroimmunological stress.
14640856	Fibromyalgia is a stress-related disorder characterized by chronic pain, memory impairment, and neuroendocrine aberrations. With the hypothesis that biological and psychological symptoms may underlie the cognitive problems, the relative influences of neuroendocrine function and psychological factors on declarative memory were examined among 50 women with fibromyalgia. This within-group analysis controlled for age, education, pain, and relevant medications. Neuroendocrine function and depression had significant independent associations with memory function. Higher log-transformed mean salivary cortisol levels were associated with better performance on both immediate and delayed visual recall and with delayed verbal recall. Depressive symptoms were negatively associated with verbal recall. These findings suggest that a basic disorder of endocrine stress responses may contribute to the cognitive symptoms experienced by fibromyalgia patients.
14622164	Spatial knowledge of an environment involves two distinct competencies: declarative spatial knowledge, linked to where environmental cues are and where the subject is with respect to the cues, and, at the same time, procedural spatial knowledge, linked to how to move into the environment. It has been previously demonstrated that hemicerebellectomized (HCbed) rats are impaired in developing efficient exploration strategies, but not in building spatial maps or in utilizing localizing cues. The aim of the present study was to analyse the relationships between spatial procedural and declarative knowledge by using the open field test. HCbed rats have been tested in two different protocols of the open field task. The results indicate that HCbed animals succeeded in moving inside the arena, in contacting the objects and in habituating to the new environment. However, HCbed animals did not react to environmental changes, when their impaired explorative pattern was inappropriate to the environment, suggesting that they were not able to represent a new environment because they were not able to explore it appropriately. Nevertheless, when their altered procedures were favoured by object arrangement, they detected environmental changes as efficiently as did normal rats. This finding suggests that no declarative spatial learning is possible without appropriate procedural spatial learning.
14590190	Despite the emergence of a number of new classification systems, the diagnosis of cerebrovascular dementia remains controversial. Also controversial is the significance of periventricular and deep white matter alterations (WMA) as seen on magnetic resonance imaging (MRI). To further clarify this issue, MRI scans were used to regroup patients clinically diagnosed with Alzheimer's disease (AD) or subcortical ischemic vascular dementia (IVD) into cohorts presenting with either little versus significant WMA on MRI. These two groups were then compared to demented patients diagnosed with idiopathic Parkinson's disease (PD) using a comprehensive neuropsychological protocol. Neuropsychological assessment failed to distinguish between patients with PD and significant WMA. By contrast, both of these patient groups exhibited disproportionate impairment on tests of executive systems functioning, whereas patients with little WMA showed greater impairment on tests of declarative memory and semantic knowledge. These findings constitute further evidence that the pattern of cognitive impairment associated with significant WMA is distinctly different when compared to AD. These results are discussed within the context of a growing body of literature suggesting that elements of the underlying neuropathologies in AD and IVD are linked. Implications for the diagnosis of dementia are also discussed.
14584566	In spite of the acknowledged role that the thalamus plays in declarative memory, details about the precise memory processes it is involved in and which are the structures of the thalamus that contribute to these processes remain unknown. An overview is presented of human clinical and animal experimental findings showing the involvement of the thalamus, at the level of white matter tracts and separate nuclei, in aspects of memory functioning. The region in the thalamus that contributes to declarative memory is the anterior and medial division, containing the anterior nuclei, the medial dorsal nucleus and the intralaminar and midline nuclei. A lesion to the anterior nuclei or their afferent white matter tract, the mammillothalamic tract, results in deficits of encoding of new stimuli. Lesions to the medial dorsal nucleus affect executive processes pertaining to declarative memory, such as the use of memory strategies for retrieval; damage to the intralaminar and midline nuclei results in decreased arousal and thus affects the declarative memory process. Based on anatomical and functional data, a theory is proposed of how the thalamus might play a role at different levels of declarative memory functioning. Firstly, the anterior and mediodorsal nucleus are involved in processing the contents of the stimuli for storage and recall. The anterior nuclei influence the selection of material to be stored and remembered, whereas the mediodorsal nucleus is involved in the coordination and selection of the strategies used to retrieve material. Secondly, the intralaminar and midline nuclei and specifically the lateral and ventral components, maintain a necessary state of the cortical regions involved in the ongoing memory processes. The two types of function subserved by these groups of thalamic nuclei, focussing on contents vs. state, need to work in parallel to mediate and allow memory functioning, respectively.
14584545	A dissociation between short- and long-term memory (LTM) and between the episodic and the semantic component of LTM is reported in a young girl who became amnesic at the age of 6 after an episode of acute encephalopathy resulting in bilateral frontal, insular, thalamic, ponto-mesencephalic, hippocampal and temporal lesions, as documented by MRI. The girl became amnesic a few months after starting school. A follow-up investigation showed that she was able to learn to read, write and acquire number facts and procedures and to improve her semantic knowledge. Our results show that the features of adult amnesia can also be found in children and that new semantic knowledge can be acquired in spite of an anterograde memory deficit. This dissociation does not agree with theories viewing long-term declarative memory as a unitary process mediated by the hippocampal system, but supports recent hypotheses that the acquisition of semantic knowledge is independent from episodic memory processes, and takes place through spared cortical regions subjacent to the hippocampi (Vargha-Khadem et al., 1997).
14574410	In the brain, hippocampal pyramidal cells use temporal as well as rate coding to signal spatial aspects of the animal's environment or behaviour. The temporal code takes the form of a phase relationship to the concurrent cycle of the hippocampal electroencephalogram theta rhythm. These two codes could each represent a different variable. However, this requires the rate and phase to vary independently, in contrast to recent suggestions that they are tightly coupled, both reflecting the amplitude of the cell's input. Here we show that the time of firing and firing rate are dissociable, and can represent two independent variables: respectively the animal's location within the place field, and its speed of movement through the field. Independent encoding of location together with actions and stimuli occurring there may help to explain the dual roles of the hippocampus in spatial and episodic memory, or may indicate a more general role of the hippocampus in relational/declarative memory.
14521867	The hypothesis that cortical cholinergic inputs mediate attentional functions and capacities has been extensively substantiated by experiments assessing the attentional effects of specific cholinotoxic lesions of cortical cholinergic inputs, attentional performance-associated cortical acetylcholine release, and the effects of pharmacological manipulations of the excitability of basal forebrain corticopetal cholinergic projections on attentional performance. At the same time, numerous animal experiments have suggested that the integrity of cortical cholinergic inputs is not necessary for learning and memory, and a dissociation between the role of the cortical cholinergic input system in attentional functions and in learning and memory has been proposed. We speculate that this dissociation is due, at least in part, to the use of standard animal behavioral tests for the assessment of learning and memory which do not sufficiently tax defined attentional functions. Attentional processes and the allocation of attentional capacities would be expected to influence the efficacy of the acquisition and recall of declarative information and therefore, persistent abnormalities in the regulation of the cortical cholinergic input system may yield escalating impairments in learning and memory. Furthermore, the cognitive effects of loss of cortical cholinergic inputs are augmented by the disruption of the top-down regulation of attentional functions that normally acts to optimize information processing in posterior cortical areas. Because cortical cholinergic inputs play an integral role in the mediation of attentional processing, the activity of cortical cholinergic inputs is hypothesized to also determine the efficacy of learning and memory.
14512209	Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD.Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging.	Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume.	These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.	
14511350	The deficiency of declarative memory compared with waking state is an often overlooked characteristic of sleep. Here, we investigated whether rhinal-hippocampal coherence, an electrophysiological correlate of declarative memory formation, is significantly altered during sleep as compared with waking state. For this purpose, we analysed recordings of intracranial EEG activity during sleep obtained directly from within the medial temporal lobe in patients with unilateral temporal lobe epilepsy. We found a general reduction of rhinal-hippocampal EEG coherence during sleep compared with waking state, which was most pronounced within the upper gamma bands (average decrease up to 56%). The observed coherence changes clearly differ from findings reported for surface EEG data and thus appear to be specific for the medial temporal lobe. The decrease of rhinal-hippocampal EEG coherence from waking state towards sleep may yield an electrophysiological explanation for the sleep-related deficiency of declarative memory.
14498794	Emotion has been shown to have a modulatory effect on declarative memory. Normal aging is associated with a decline in declarative memory, but whether aging might affect the influence of emotion on memory has not been established. To investigate this, we administered a task that provides a detailed assessment of emotional memory to 80 neurologically normal adults ranging in age from 35 to 85 years. Across ages, memory performance was found to be modulated by the emotional significance of stimuli in a comparable manner (improved memory for gist, compromised memory for visual detail), despite an overall decline in memory performance with increasing age. The results raise the interesting possibility that aging has a differential effect on hippocampal versus amygdala function.
13680460	Previous neuropsychological research suggests that psychometrically defined subclinical obsessive-compulsive (OC) individuals perform worse than non-OC controls on specific tests of executive functioning. This study aimed to extend these findings by comparing the performance of 25 subclinical OC and 28 non-OC control subjects on measures of declarative learning (Rey Auditory Verbal Learning Test), motor procedural learning (star maze), spatial problem solving (single administration of the 3-disk version of the Tower of Hanoi; TH3), and "cognitive" procedural learning (repeated administrations of the 4-disk version of the Tower of Hanoi; TH4). In addition, the subjects were administered measures of general intelligence, anxiety and depression. No between-group differences were observed on measures of declarative and motor procedural learning. Subclinical OC subjects needed significantly more moves than controls to solve TH3, suggesting poorer spatial problem solving ability. A significant group x trial interaction on the TH4 suggested reduced cognitive skill acquisition in the subclinical OC group. However, performance on TH3 and TH4 was significantly correlated in the OC group but not in the control group, suggesting that the suboptimal acquisition of cognitive skills among subclinical OC subjects is more likely to be related to inefficient spatial problem solving strategies than to a cognitive procedural learning deficit per se. These results replicate and expand upon previous findings and support a dimensional model of Obsessive-Compulsive Disorder.
13680442	Verbal declarative memory deficits in schizophrenia are well documented whereas visual declarative memory is less studied. Moreover, there are limited data on whether organizational and visual memory deficits are specific to schizophrenic psychoses. We compared visual memory and organizational function in patients with chronic schizophrenia (n=79) and chronic bipolar psychotic disorder (n=14), and in healthy controls (n=84) using the Rey-Osterrieth Complex Figure (ROCF), testing whether organizational impairments (i.e., executive dysfunctions) account for the visual memory deficit. Groups were comparable on age, handedness and expected intellectual ability (based on single word reading). Using analyses of covariance with sex, parental SES and ethnicity as co-variates, patients with schizophrenia were significantly more impaired than controls on copy accuracy, on recall accuracy, and on percent accuracy of recall. Patients with schizophrenia used a more detail-oriented style on copy and recall and had significantly worse recognition memory. After co-varying IQ, copy organization was also significantly different between the groups. Results for accuracy of copy and recall were not significantly attenuated when controlling for copy organization. Duration of illness was associated with visual memory. Bipolar patients performed at an intermediate level between controls and patients with schizophrenia. The data suggest that in schizophrenia, patients have a visual memory disorder characterized by both organizational processing impairments and retention difficulties, and that there is a decline in visual memory functions with duration of illness. Further research is required to determine whether similar mechanisms underlie the neurocognitive deficits in these psychotic disorders.
13678499	The author notes that neuropsychological research has discovered the existence of two long-term memory systems, namely declarative or explicit memory, which is conscious and autobiographical, and non-declarative or implicit memory, which is neither conscious nor verbalisable. It is suggested that pre-verbal and pre-symbolic experience in the child's primary relations is stored in implicit memory, where it constitutes an unconscious nucleus of the self which is not repressed and which influences the person's affective, emotional, cognitive and sexual life even as an adult. In the analytic relationship this unconscious part can emerge essentially through certain modes of communication (tone of voice, rhythm and prosody of the voice, and structure and tempo of speech), which could be called the 'musical dimension' of the transference, and through dream representations. Besides work on the transference, the critical component of the therapeutic action of psychoanalysis is stated to consist in work on dreams as pictographic and symbolic representations of implicit pre-symbolic and pre-verbal experiences. A case history is presented in which dream interpretation allowed some of a patient's early unconscious, non-repressed experiences to be emotionally reconstructed and made thinkable even though they were not actually remembered.
13129657	The effect of familial loading on neurocognitive deficits in relatives of schizophrenia patients has been detected in family and twin studies. The present study examined this effect among healthy siblings of schizophrenia patients in a Finnish isolate with high prevalence of schizophrenia.We assessed performance in verbal and visual span tasks, in tests measuring intelligence, and in declarative verbal memory and learning tasks in 31 and 67 healthy siblings from families with one schizophrenia patient, or with two or more patients, respectively. The differences between the groups were tested using linear mixed effects models.	An effect of familial loading was detected in the backward visual span task, measuring immediate visual memory with requirements from the visual domain of working memory. In this task, the healthy siblings from multiply affected families performed worse than those from the singleton families.	The finding that the multiplex vs. singleton differences were selective to the backward visual span task, strengthens the view that the visual domain of working memory may provide a valuable endophenotypic marker for genetic schizophrenia studies.	
12943329	Patients with early Alzheimer's disease (AD) exhibit impaired declarative memory although some forms of nondeclarative memory are intact. Performance on perceptual nondeclarative memory tasks is often preserved in AD, whereas conceptual nondeclarative memory is often impaired. A conceptual nondeclarative learning task that has been studied in amnesic patients is the artificial grammar learning (AGL) task. Healthy participants and patients with impaired declarative memory both acquire information about an underlying rule structure in this task and exhibit the ability to identify rule-conforming items, despite the subjective experience of guessing at the response. In this study, 12 patients diagnosed with early AD were tested on the AGL task and a matched recognition task. The patients were able to reliably distinguish rule-conforming items from others, indicating successful AGL. Performance of the AD patients was impaired, relative to controls, on a similar recognition task, although they were found to use information about the grammaticality of study items in an attempt to improve their recognition performance. The AD patients showed a dissociation similar to that seen in anterograde amnesia: impaired recognition memory in conjunction with successful AGL. This finding suggests that the brain areas that support AGL are not compromised early in the course of AD. In addition, the nondeclarative memory of the AD patients acquired during AGL appeared to influence their performance on a declarative memory task, suggesting an interaction between this nondeclarative memory task and declarative memory.
12941284	Three experiments explore the role of working memory in motor skill acquisition and performance. Traditional theories postulate that skill acquisition proceeds through stages of knowing, which are initially declarative but later procedural. The reported experiments challenge that view and support an independent, parallel processing model, which predicts that procedural and declarative knowledge can be acquired separately and that the former does not depend on the availability of working memory, whereas, the latter does. The behaviour of these two processes was manipulated by providing or withholding visual (and auditory) appraisal of outcome feedback. Withholding feedback was predicted to inhibit the use of working memory to appraise success and, thus, prevent the formation of declarative knowledge without affecting the accumulation of procedural knowledge. While the first experiment failed to support these predictions, the second and third experiments demonstrated that procedural and declarative knowledge can be acquired independently. It is suggested that the availability of working memory is crucial to motor performance only when the learner has come to rely on its use.
12928061	In this functional MRI (fMRI) study, we investigated ageing effects on motor skill learning. We applied an adapted version of the serial reaction time (SRT) task to extensive groups of young (N=26) and elderly (N=40) subjects. Since indications have been provided for age-related shrinkage of brain regions assumed to be critical to motor skill learning, we tested the hypothesis that age effects on implicit sequence learning are larger on a neurofunctional level than on a behavioural level. The SRT task consisted of two identical scan sessions, in which subjects had to manually trail an asterisk appearing serially in one of four spatial positions by means of button-pressing. Reliable response time reductions were already found in the first session for both the young and the elderly groups, when comparing a fixed sequence condition to a random sequence, but the learning effect was greater for the young subjects. In the second session, though, both groups showed a similar degree of learning. This indicates that implicit sequence learning is still intact in elderly adults, but that the rate of learning is somewhat slower. Reliable learning-related changes in brain activity were also observed. A similar network of brain regions was recruited by both groups during the fixed compared to the random sequence, involving several regions that have been previously associated with implicit sequence learning, including bilateral parietal, and frontal regions, the supplementary motor area (SMA), cerebellum and the basal ganglia. The direct group comparison did not reveal any differences in brain activity. In addition, we did not observe any significant differences in activity when comparing the different sessions either, neither for the young nor for the elderly subjects. Hence, we did not find indications for an age-related functional reorganisation of neural networks involved in motor sequence learning. In view of earlier reports of pronounced ageing effects on the performance on declarative memory tasks, our finding of age-related sparing of processes that sustain motor skill learning, provides further support for the proposition of different memory systems relying on different brain substrates.
12928059	Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiological consequences including neuropathy, retinopathy and incidence of vascular disease. Recently, several authors reviewed studies that suggested that NIDDM is associated with cognitive impairments leading to a higher incidence of dementia. In the present experiment, we measured cognitive function in 57 healthy male and female non-diabetic older participants who ranged in age from 55 to 84. Various biological measures were obtained including a glucose tolerance test during which glucose and insulin were measured. Participants were separated into better and poorer glucoregulatory groups on the basis of their blood glucose levels during the tolerance test. Participants were evaluated twice, once after drinking a saccharin solution and on another occasion after drinking a glucose solution (50 g). Older participants (72 years and over) with poorer glucoregulation had the worse performance in tests evaluating working memory, verbal declarative memory and executive functions. Glucose administration appeared to only attenuate the decrements observed in the saccharin condition in the older participants for some of the tests. These results suggest that cognitive functions may be impaired before glucoregulatory impairment reaches levels consistent with a type II diabetes diagnosis.
12927943	In recent years, researchers have provided data to show that individuals with Alzheimer's disease (AD) can learn new information and functional behaviors, despite significant declarative memory deficits. However, clinicians in long-term care frequently have difficulty justifying and providing needed services to persons with Alzheimer's disease in LTC settings. In this paper, implicit learning will be discussed as a theoretical rationale to support rehabilitation along with practical issues related to the provision of speech-language pathology services for residents with Alzheimer's disease in LTC settings.After reading this article, learners will be able to: (1) Define implicit learning; (2) discuss evidence for implicit learning in Alzheimer's disease; (3) describe how to capitalize on implicit learning during rehabilitation for individuals with Alzheimer's disease; (4) explain how to justify and provide interventions for individuals with Alzheimer's disease in LTC settings.	
12921408	Two imaging experiments were performed--one involving an algebraic transformation task studied by Anderson, Reder, and Lebiere (1996) and the other an abstraction symbol manipulation task studied by Blessing and Anderson (1996). ACT-R models exist that predict the latency patterns in these tasks. These models require activity in an imaginal buffer to represent changes to the problem representation, in a retrieval buffer to hold information from declarative memory, and in a manual buffer to hold information about motor behavior. A general theory is described about how to map activity in these buffers onto the fMRI blood oxygen level dependent (BOLD) response. This theory claims that the BOLD response is integrated over the duration that a buffer is active and can be used to predict the observed BOLD function. Activity in the imaginal buffer is shown to predict the BOLD response in a left posterior parietal region; activity in the retrieval buffer is shown to predict the BOLD response in a left prefrontal region; and activity in the manual buffer is shown to predict activity in a motor region. More generally, this article shows how to map a large class of information-processing theories (not just ACT-R) onto the BOLD response and provides a precise interpretation of the cognitive significance of the BOLD response.
12902389	In understanding the brain's response to extensive practice and development of high-level, expert skill, a key question is whether the same brain structures remain involved throughout the different stages of learning and a form of adaptation occurs, or a new functional circuit is formed with some structures dropping off and others joining. After training subjects on a set of complex motor tasks (tying knots), we utilized fMRI to observe that in subjects who learned the task well new regional activity emerged in posterior medial structures, i.e. the posterior cingulate gyrus. Activation associated with weak learning of the knots involved areas that mediate visual spatial computations. Brain activity associated with no substantive learning indicated involvement of areas dedicated to the declarative aspects learning such as the anterior cingulate and prefrontal cortex. The new activation for the pattern of strong learning has alternate interpretations involving either retrieval during episodic memory or a shift toward non-executive cognitive control of the task. While these interpretations are not resolved, the study makes clear that single time-point images of motor skill can be misleading because the brain structures that implement action can change following practice.
12890761	BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val66met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.
12887039	The recent literature on the neuropsychology of schizophrenia has emphasized memory deficits as a key area of impairment. Abnormalities in the medial temporal lobe, a brain region crucial for long-term memory formation, have also consistently been reported. We conducted a comprehensive review of verbal declarative memory (VDM) in schizophrenia with the aim of systematically addressing the nature of this impairment. We conclude that verbal declarative memory is significantly impaired in schizophrenia and is largely accounted for by deficits in the encoding stage. Subtle impairments in increased rates of forgetting are present, but are mild compared with those in amnestic disorders. Impairment in other cognitive domains studied thus far (e.g., attention), medication effects, or fluctuations in symptoms do not completely account for the deficit. VDM is among the most impaired neurocognitive domains in schizophrenia (along with attention and executive functions). Milder encoding deficits are present in high-risk subjects and non-psychotic relatives of individuals with schizophrenia suggesting that components of the deficit are associated with a genetic vulnerability to the illness, and are independent of the frank psychotic illness. Furthermore, VDM is observed in individuals experiencing their first-psychotic episode and it remains fairly consistent over time. Preliminary imaging studies and other work suggest abnormalities in prefrontal-hippocampal processing networks. Future work should emphasize delineating specific information processing components contributing to the deficit. This would allow imaging studies to determine which brain regions contribute to specific information processing deficits in schizophrenia.
12880920	Practice makes perfect, but the role of repetitions in skill learning is not yet fully understood. For example, given a similar number of trials on a given task, it is debated whether repeating and non-repeating items are learned by the same neural process. When one is given training with both types of items--does one learn two separate skills, or only one? Here we show, using a mirror reading task, that practice trials with trial-unique words, and practice trials with repeated words, count towards learning to a different degree. There was no interaction between the time-course of learning repeated and unique words even within the same individuals given mixed training. While repeated words were learned faster than unique words, the repetitions-dependent gains diminished with training beyond a small number of repetitions. Moreover, the gains in performance could not be accounted for solely by the number of repetitions, as assumed by power-law models of learning; rather, the passage of time was a critical factor. Finally, our results suggest that although both repeated and new words were learned by both declarative and procedural memory mechanisms, even a single repetition of specific words could lead to the establishment of a selective differential representation in memory. The results are compatible with the notion of a repetition-sensitive process, triggered by specific repeating events. This 'repetition counter' may be a critical trigger for the effective formation of procedural as well as some type of declarative memory.
12849517	The practice of neurorehabilitation in the clinic has undergone a paradigm shift as a result of influences from basic and clinical research. I have identified six areas of knowledge that by advancing so rapidly have brought about this paradigm shift: first, the increased understanding of how the CNS is reorganised after training or injury; second, the knowledge of how declarative and procedural memory operates and how this can influence rehabilitation therapy; third, a greater appreciation of the chemical factors that promote learning and neural remodelling; fourth, the fact that computational neuroscience can teach us how complex behaviour can emerge from the interaction of thousands of neurons; fifth, the influence of evidence-based medicine on neurorehabilitation; and sixth, the importance of reliable outcome measures for both injury and treatment. These are young scientific disciplines that offer great opportunities for further research. The complexity of neurorehabilitation will also require greater attention to a substantially neglected problem, the incorporation of techniques that have been proven effective in clinical trials into routine and effective clinical practice.
12836912	In studies with brain-damaged patients and experimental animals, the medial temporal lobe, including the hippocampus and parahippocampal gyrus, has been found to play a critical role in establishing declarative or episodic memory. We measured the neural response in these structures, using event-related functional magnetic resonance imaging, while six healthy subjects performed the retrieval task for facial identity and emotion, respectively. Under the identity condition, the subjects participated in a yes/no recognition test for neutral faces learned before the scanning. Under the emotion condition, the subjects learned the faces with positive or negative expression and retrieved their expressions from neutral cue faces. The results showed that the left hippocampus is primarily involved in the identification of learned faces, and that the adjacent parahippocampal gyrus responds more to target than to distracter events. These results indicate a specific engagement of the left hippocampal regions in conscious recollection and identification of physiognomic facial features. The activity in the right hippocampus increased under both the identity and emotion conditions. The present results may relate with the functional model of face recognition in which the left hemisphere contributes to the processing of detailed features and the right hemisphere is efficient in the processing of global features.
12832296	Memory impairment is observed in adults with type 2 diabetes. The focus of this study was to determine whether acute carbohydrate consumption contributes to or exacerbates memory dysfunction.The impact of consuming 50 g of rapidly absorbed carbohydrate (one half bagel and white grape juice) at breakfast was examined in 19 adults with type 2 diabetes. Subjects (mean age 63 +/- 9 years, mean BMI 26.1 +/- 4.5 kg/m(2)) were tested, under fed and fasted conditions, on verbal declarative memory using both word list and paragraph recall tests (immediate and delayed [7-min] recall), Trails Test Part B as a measure of general brain function, and mood (subjectively monitoring global vigor and affect).	Under baseline (fasting) conditions, elevated blood HbA(1c) was negatively associated with immediate and delayed paragraph recall performance (R(2) = 0.30; P = 0.024) and higher fasting blood glucose trended toward poorer word list recall (R(2) = 0.09; P = 0.102). Carbohydrate ingestion influenced measures of delayed, but not immediate, recall in a time-dependent fashion (time x food) (word list, P = 0.046; paragraph, P = 0.044) such that delayed recall was improved at 15 min postingestion but was impaired at 30 min. Neither Trails Test scores (P = 0.17) nor mood (affect, P = 0.68 and vigor, P = 0.45) were influenced by food ingestion.	In adults with type 2 diabetes, poorer glycemic control is associated with lower performance on tests of declarative memory. Acute ingestion of high glycemic index carbohydrate foods further contributes to the underlying memory impairment.	
12821730	Abnormal insulin metabolism may contribute to the clinical symptoms and pathophysiology of AD. In vitro studies show that insulin enhances the release of beta-amyloid protein (Abeta) or inhibits its degradation, either of which might increase amyloid burden.On separate mornings, 16 healthy older adults (10 women, 6 men; mean age 68.7 years, SD 8.6 years) each underwent two infusions consisting of either saline (placebo) or insulin (1.0 mU x kg(-1) x min(-1)) plus dextrose to maintain euglycemia. After 120 minutes of infusion, blood, CSF, and cognitive measures were acquired.	As expected, insulin infusion produced an increase in CSF insulin concentration. Insulin infusion also led to an increase in CSF Abeta42 levels, most notably in older subjects. As has been observed previously, insulin infusion facilitated declarative memory, but such facilitation was attenuated in the subjects with the greatest increase in CSF Abeta42 levels.	These findings are consistent with recent in vitro studies of insulin effects on Abeta and support the notion that insulin may modulate Abeta42 levels acutely in humans.	
12815709	Many members of the forkhead/winged helix transcriptional factors are known to be regulators of embryogenesis. Mutations of the Fox gene family have been implicated in a range of human developmental disorders. Foxp2, a member of the Fox gene family, has recently been identified as the first gene that is linked to an inherited form of language and speech disorder. To elucidate the anatomical basis of language processing in the brain, we have examined the expression pattern of Foxp2 gene and its homologous gene, Foxp1, in the rat brain through development. Expression of Foxp2 mRNA was detected in the ventral telencephalon as early as embryonic day 13. Foxp2 mRNA was expressed primarily in differentiated cells of the lateral ganglionic eminence (striatal primordium). Of particular interest was that the developmental expression of Foxp2 followed a compartmental order in the striatum. Patches containing high levels of Foxp2 were aligned with patches enriched in mu-opoid receptor, a marker for striosomal cells, in the striatum through postnatal development. Conversely, Foxp2-positive patches were devoid of calbindin-D28k, a maker for striatal matrix cells. Therefore, Foxp2 was preferentially expressed in striosomal compartment in the striatum during development. In the mature striatum, Foxp2 expression was maintained in striosomes, although its expression level was reduced. In contrast to Foxp2, Foxp1 was expressed in both the striosomal and matrix compartments in the striatum through development. The striatum is known to be involved in the process of procedural memory, and mutation of Foxp2 results in neurological disorders of language and speech. Given the preferential expression of Foxp2 in the striosomal compartment, the striatum, particularly the striosomal system, may participate in neural information processing for language and speech. Our suggestion is consistent with the declarative/procedural model proposed by Ullman and colleagues (Ullman et al. [1997] J. Cogn. Neurosci. 9:266-276; Ullman [2001] Nat. Rev. Neurosci. 2:717-726), in which the procedural memory-dependent mental grammar is rooted in the basal ganglia and the frontal cortex and the declarative memory-dependent mental lexicon is rooted in the temporal lobe.
12791995	The medial temporal lobe is crucial for the ability to learn and retain new declarative memories. This form of memory includes the ability to quickly establish novel associations between unrelated items. To better understand the patterns of neural activity during associative memory formation, we recorded the activity of hippocampal neurons of macaque monkeys as they learned new associations. Hippocampal neurons signaled learning by changing their stimulus-selective response properties. This change in the pattern of selective neural activity occurred before, at the same time as, or after learning, which suggests that these neurons are involved in the initial formation of new associative memories.
12787857	Major depressive disorder (MDD) and alcohol dependence (AD) frequently occur together. However, MDD clinical trials generally exclude patients with alcohol-related disorders.A 12-week, open-label trial of nefazodone in a group of people (n=13) with both a current major depressive episode and current AD was conducted to examine the effect of this antidepressant on depressive symptoms, alcohol use, and cognition.	Scores on the Hamilton Rating Scale for Depression (HRSD) and Hamilton Rating Scale for Anxiety (HRSA) significantly decreased from baseline to exit. In addition, significant reduction in alcohol craving, drinks/week, and days of alcohol use/week was found. Scores on the Rey Auditory Verbal Learning Test (RAVLT) did not significantly improve during the study. Changes in mood/anxiety and memory did not correlate with changes in alcohol use.	Thus, nefazodone therapy was associated with improvement in mood/anxiety and alcohol use, which seem to be independent of each other in this patient sample. However, declarative memory, which was low average at baseline, did not show statistically significant improvement during the 12 weeks of the study.	
12765749	Clozapine has been shown to improve verbal declarative memory and other cognitive functions in chronic schizophrenia. This raises the possibility that additional adjunctive manipulations might improve memory further. In this study, we hypothesized that glucose, which improves memory in a variety of conditions, including schizophrenia, would improve memory more than saccharin in a group of patients stabilized on clozapine. Twelve outpatients with schizophrenia who received treatment with clozapine participated in a double-blind, counterbalanced, crossover study. Subjects received beverages containing either glucose or saccharin on one occasion, and then the other beverage about a week later. Fifteen minutes after ingesting the beverage, subjects received a brief battery of neuropsychological tests to assess verbal declarative memory, attention, and executive functions. Blood glucose levels were assessed at baseline, and at 15 and 50 min after beverage ingestion. The main findings were that retention of a list of words was improved in the glucose condition, while performance on a complex test of sustained vigilance declined after glucose ingestion. These findings provide evidence that glucose improves declarative memory in patients with schizophrenia who were treated with clozapine, and underscore the possibility of developing effective protocols to reduce cognitive dysfunctions in the disorder. They also highlight the need to explore the extent to which glucose modulates nonmemory cognitive functions such as attention, and to understand more generally how glucose availability and regulation influence cognition.
12757886	The positive influence of sleep on memory may partly depend on the processing which transforms items of declarative knowledge into contents of mental sleep experience (MSE). This view implies that the consolidation level should be more enhanced for those items which have been repeatedly processed and transformed into identical or very similar (so-called interrelated) contents of distinct MSEs in the same night. We examined here the occurrence of interrelated contents in the MSEs reported after an awakening provoked in stage 2 at sleep onset and the spontaneous awakening in the morning. Interrelated contents resulted much more frequently than the chance occurrence of contents with the same semantic features, regardless of the sleep stage in which morning awakening occurred. The accessibility of given items for transformation into MSE contents over the night makes it plausible that they are reprocessed, and thus further consolidated, during various stages and cycles of sleep.
12747526	The authors theorize that 2 neurocognitive sequence-learning systems can be distinguished in serial reaction time experiments, one dorsal (parietal and supplementary motor cortex) and the other ventral (temporal and lateral prefrontal cortex). Dorsal system learning is implicit and associates noncategorized stimuli within dimensional modules. Ventral system learning can be implicit or explicit It also allows associating events across dimensions and therefore is the basis of cross-task integration or interference, depending on degree of cross-task correlation of signals. Accordingly, lack of correlation rather than limited capacity is responsible for dual-task effects on learning. The theory is relevant to issues of attentional effects on learning; the representational basis of complex, sequential skills; hippocampal-versus basal ganglia-based learning; procedural versus declarative memory; and implicit versus explicit memory.
12742675	Animal studies have shown that early stressors result in lasting changes in structure and function of brain areas involved in memory, including hippocampus and frontal cortex. Patients with childhood abuse-related posttraumatic stress disorder (PTSD) have alterations in both declarative and nondeclarative memory function, and imaging studies in PTSD have demonstrated changes in function during stimulation of trauma-specific memories in hippocampus, medial prefrontal cortex, and cingulate. The purpose of this study was to assess neural correlates of emotionally valenced declarative memory in women with early childhood sexual abuse and PTSD.Women with early childhood sexual abuse-related PTSD (n = 10) and women without abuse or PTSD (n = 11) underwent positron emission tomographic (PET) measurement of cerebral blood flow during a control condition and during retrieval of neutral (e.g., "metal-iron") and emotionally valenced (e.g., "rape-mutilate") word pairs.	During retrieval of emotionally valenced word pairs, PTSD patients showed greater decreases in blood flow in an extensive area, which included orbitofrontal cortex, anterior cingulate, and medial prefrontal cortex (Brodmann's areas 25, 32, 9), left hippocampus, and fusiform gyrus/inferior temporal gyrus, with increased activation in posterior cingulate, left inferior parietal cortex, left middle frontal gyrus, and visual association and motor cortex. There were no differences in patterns of brain activation during retrieval of neutral word pairs between patients and control subjects.	These findings are consistent with dysfunction of specific brain areas involved in memory and emotion in PTSD. Regions implicated in this study of emotionally valenced declarative memory are similar to those from prior imaging studies in PTSD using trauma-specific stimuli for symptom provocation, adding further supportive evidence for a dysfunctional network of brain areas involved in memory, including hippocampus, medial prefrontal cortex, and cingulate, in PTSD.	
12727697	Animal studies have suggested that early stress is associated with alterations in the hippocampus, a brain area that plays a critical role in learning and memory. The purpose of this study was to measure both hippocampal structure and function in women with and without early childhood sexual abuse and the diagnosis of posttraumatic stress disorder (PTSD).Thirty-three women participated in this study, including women with early childhood sexual abuse and PTSD (N=10), women with abuse without PTSD (N=12), and women without abuse or PTSD (N=11). Hippocampal volume was measured with magnetic resonance imaging in all subjects, and hippocampal function during the performance of hippocampal-based verbal declarative memory tasks was measured by using positron emission tomography in abused women with and without PTSD.	A failure of hippocampal activation and 16% smaller volume of the hippocampus were seen in women with abuse and PTSD compared to women with abuse without PTSD. Women with abuse and PTSD had a 19% smaller hippocampal volume relative to women without abuse or PTSD.	These results are consistent with deficits in hippocampal function and structure in abuse-related PTSD.	
12724465	The specific effects of visual and verbal memory on the ability of emotional arousal to enhance declarative memory were examined by using multiple linear regression analysis on data from a sample of 56 patients with probable Alzheimer's disease (AD). The enhancing effect of emotion on memory was evaluated by an illustrated story paradigm, and the visual and verbal memory by a standard memory test. In AD, memory enhancement by emotion was significantly correlated with visual memory but not with verbal memory, regardless of age, sex, educational attainment, and severity of dementia, suggesting a close association between memory enhancement by emotion and visual memory.
12716025	The marginal division (MrD) is a spindled-neurons consisted zone at the caudal border of the neostriatum in the mammalian brain and has been verified as contributing to associative learning and declarative memory in the rat and human with behavior and functional magnetic resonance imaging methods. It was proved to have functional connections with the limbic system. Whether the MrD has influence on the hippocampal long-term potentiation (LTP) was investigated in this study. LTP was induced from the dentate gyrus (DG) in the hippocampus by high-frequency stimulation (HFS) to the perforant path (PP). The amplitude of the population spike (PS) and the slope of the excitatory postsynaptic potential (EPSP) increased significantly to form LTP in the DG of the hippocampus after HFS of PP in normal and saline-injected control groups of rats. Lesions introduced in the MrD reduced significantly both the amplitude of PS and the slope of the EPSP following HFS of the PP. The results indicated that lesions in the MrD could attenuate LTP formation in the hippocampus. Our data suggest that the MrD might very possibly have excitatory functional influence on the hippocampus and therefore might influence the function of the hippocampus.
12691658	The question of whether the hippocampus plays a selective role in episodic memory or a more general role in both episodic and semantic memory (together termed declarative memory) is an unresolved and much-debated topic in the current literature. In two back-to-back articles in this issue of Neuron, Squire and his colleagues describe findings from a group of six patients with damage thought to be limited to the hippocampus. The reported findings provide new evidence toward resolving this much-debated controversy.
12690059	Expert opinion remains divided on the issue of whether the hippocampal system functions exclusively in spatial information processing, e.g. in navigation or in understanding spatial relations, or whether it plays a more general role in higher brain function. Previous work on monkeys and rats has tended to support the former view, whereas observations in the clinic point to the latter, including functions as diverse as declarative knowledge, episodic memory, word learning, and understanding relations among objects. One influential theory posits a general role for the hippocampal system in associative learning, with emphasis on associations learned rapidly and recently. The results presented here are consistent with this theory, along with previous clinical and theoretical studies indicating that the hippocampal system is necessary for associative learning even if no component of the association relies on spatial information. In the study reported here, rhesus monkeys learned a series of conditional stimulus-response associations involving complex visual stimuli presented on a video monitor. Each stimulus instructed one of three responses: tapping the stimulus with the hand, steady hand contact with the stimulus for a brief period of time, or steady contact for a longer time. Fornix transection impaired the learning of these associations, even though both the stimuli and the responses were nonspatially differentiated, and this deficit persisted for at least 2 years. This finding indicates that the hippocampal system plays an important role in associative learning regardless of the relevance of spatial information to any aspect of the association. Fornix-transected monkeys were impaired in learning new stimulus-response associations even when the stimuli were highly familiar. Thus, the deficit was one of associating each stimulus with a response, as opposed to problems in distinguishing the stimuli from each other. In contrast to these effects, fornix transection did not impair performance when familiar stimuli instructed a response according to an already-learned association, which shows that the deficit was one of learning new associations rather than one of retention or retrieval of previously learned ones. Taken together, these results show that fornix transection causes a long-lasting impairment in associative learning outside of the spatial domain, in a manner consistent with theories of hippocampal-system function that stress a general role in the rapid acquisition of associative knowledge.
12684487	This experiment measured acetylcholine (ACh) release simultaneously in the hippocampus and striatum while rats were trained in a cross maze. Consistent with past findings, rats initially showed learning on the basis of place (i.e., turning to the correct position relative to the room), but after extensive training, rats shifted to learning on the basis of response (i.e., turning to the right/left to find the food). Profiles of ACh release in the hippocampus and striatum were markedly different during training. In the hippocampus, ACh release increased by approximately 60% at the onset of training and remained at that level of release throughout training, even after the rats began to show learning on the basis of turning rather than place. In the striatum, increases in ACh release occurred later, reaching asymptotic increases of 30-40%, coincident with a transition from expressing place learning to expressing response learning. These findings suggest that the hippocampal and striatal systems both participate in learning in this task, but in a manner characterized by differential activation of the neural systems. The hippocampal system is apparently engaged first before the striatum is activated and, to the extent the hippocampus is important for place learning, promotes the use of a place solution to the maze. Later in training, although the hippocampus remains activated, the striatum is also activated in a manner that may enable the use of a response strategy to solve the maze. These findings may offer a neurobiological marker of a transition during skill learning from declarative to procedural learning.
12683478	The aim of Experiment 1 was to determine if moderate ethanol consumption at bedtime would result in memory loss for recently learned cognitive procedural and declarative tasks. The aim of Experiment 2 was to establish that the memory loss due to alcohol consumption at bedtime was due to the effect of alcohol on sleep states.In Experiment 1, participants were asked to learn a cognitive procedural task and a declarative task in the evening. Then, either the same evening or 2 nights later, they were asked to drink ethanol (0.7g/kg). Sleep was monitored for 3 days and re-testing of the tasks was done on the eighth day after training at the same time of day. In Experiment 2, subjects were asked to learn a cognitive procedural task (Tower of Hanoi) and a motor procedural task (Pursuit Rotor) in the late afternoon. Then one group was asked to drink ethanol (0.9 g/kg) right after task acquisition (5 hours before bed), while the other was asked to drink the same dose of ethanol just prior to bedtime. Re-testing was done 8 days later at the same time of day.	Subjects in Experiment 1 were 15 college students between the ages of 19 and 24 that appeared to be in good health and were relatively naive in terms of drinking alcohol. Subjects in Experiment 2 were 13 college students in the same age range. These subjects were considered to be more experienced drinkers than subjects in Experiment 1 but were not judged to be heavy drinkers.	In Experiment 1, the alcohol ingestion resulted in memory loss for the cognitive procedural task but not the declarative task. Further, the effect was seen when alcohol ingestion occurred the same day or 2 days after the end of acquisition. In Experiment 2, alcohol ingestion at bedtime impaired memory for the cognitive procedural and motor procedural tasks. By contrast, alcohol ingestion in the afternoon, immediately after the acquisition of these two tasks, did not impair memory. There were clear changes in the nature of rapid eye movement (REM) sleep as a result of evening alcohol ingestion. In Experiment 1, the number of REMs and number of minutes of REM in the first half of the night were reduced. In Experiment 2, the reduction was in REM densities in the first half of the night.	Moderate doses of ethanol can modify the REM sleep architecture by reducing the number of REMs and/or REM densities as well as minutes of REM sleep, particularly in the first half of the night. These modifications result in memory impairment for recently learned cognitive procedural material. Alcohol may also have a subtle effect on Stage 2 sleep as well, since memory for a Stage 2 sensitive motor procedural task was also impaired.	
12670318	Previous work indicates that stress levels of circulating glucocorticoids can impair retrieval of declarative memory in human subjects. Several studies have reported that declarative memory retrieval relies on the medial temporal lobe. The present study used H(2)(15)O-positron emission tomography to investigate whether acutely elevated glucocorticoid levels affect regional cerebral blood flow in the medial temporal lobe, as well as in other brain regions, during declarative memory retrieval in healthy male human subjects. When measured over four different declarative memory retrieval tasks, a single, stress-level dose of cortisone (25 mg) administered orally 1 h before retention testing, induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, the left visual cortex and the cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval. Cortisone administration also significantly impaired cued recall of word pairs learned 24 h earlier, while drug effects on performance in the other tasks (verbal recognition, semantic generation and categorization) were not significant. The present results provide further evidence that acutely elevated glucocorticoid levels can impair declarative memory retrieval processes and suggest that such impairments may be related to a disturbance of medial temporal lobe function.
12667523	A successful strategy to memorize unrelated items is to associate them semantically. This learning method is typical for declarative memory and depends on the medial temporal lobe (MTL). Yet, only a small fraction of perceived items emerge into conscious awareness and receive the status of representations in declarative memory. This functional magnetic resonance imaging (fMRI) study tackled the mnemonic fate of unrelated item pairs processed without conscious awareness. Stimuli consisted of a face and a written profession (experimental condition) or of a face (control condition) exposed very briefly between pattern masks. Although the participants were unaware of the stimuli, activity in the hippocampus and perirhinal cortex was changed in the experimental versus the control condition; perirhinal activity changes correlated with the reaction time measure of the later nonconscious retrieval. For retrieval, the previously presented faces were shown again, this time for conscious inspection. The task was to guess the professional category of each face. This task was to induce a nonconscious retrieval of previously formed face-profession associations. Remarkably, activity in the hippocampus and perirhinal cortex was enhanced when subjects were confronted with faces from the experimental versus the control condition. The degree of hippocampal and perirhinal activation changes correlated with the reaction time measure of nonconscious retrieval. Together, our findings suggest that new semantic associations can be formed and retrieved by way of the medial temporal lobe without awareness of the associations or its components at encoding or any awareness that one is remembering at retrieval.
12663082	The relation between individual neurons and neuronal networks in performing brain functions is one of the central questions in modern neuroscience. Most of the current literature suggests that the role of individual neurons is negligible and neural networks play a dominant role in the functioning of the nervous system. Individual neurons are usually viewed as network elements whose functions are limited to generating electrical signals and releasing neurotransmitters. Here I summarize experimental evidence that challenges this concept and argue that the unique, intrinsic properties of highly specialized individual neurons are as important for the functioning of the brain as the network properties. I first discuss the studies of relatively 'simple' functions of the nervous system, such as the control of rhythmic 'automatic' movements and generation of circadian rhythm, which indicate that individual neurons may continue performing their functions after being separated from corresponding networks. I then argue that the complex cognitive functions, such as declarative memory, language processing, and face recognition, are likely to be underlain by the properties of groups of highly specialized neurons. These neurons appear to be genetically predisposed to perform cognitive functions and their dysfunctions cannot be compensated by other elements of the nervous system. Under this concept, the electrical signals circulating within and between neural networks are considered to be a means of forming coordinated dynamic ensembles of neurons involved in performing specific functions. While still speculative, this hypothesis may provoke new approaches to studies of neural mechanisms underpinning cognitive functions of the brain.
12653984	The hippocampus and the rhinal cortex, two substructures of the medial temporal lobe, together play a crucial role in human declarative memory formation. To investigate in detail the mechanism connecting these two structures transiently during memory formation we recorded depth EEG in epilepsy patients from within the hippocampus and the rhinal cortex. During this recording, patients performed a single-trial word list-learning paradigm with a free recall memory test following a distraction task. Rhinal-hippocampal EEG coherence and spectral power at both locations in the time interval up to 2 s after onset of word presentation were analysed in the frequency range 1-19 Hz. Successful as opposed to unsuccessful memory formation was associated with a general rhinal-hippocampal coherence enhancement, but without alterations in spectral power. Coherence increases in the theta range were correlated with the previously reported memory-related changes in rhinal-hippocampal gamma phase synchronization. This correlation may suggest an interaction of the two mechanisms during declarative memory formation. While theta coherence might be associated with slowly modulated coupling related to an encoding state, rhinal-hippocampal gamma synchronization may be more closely related to actual memory processes by enabling fast coupling and decoupling of the two structures.
12651941	A number of studies have shown that the perirhinal (PRh) cortex, which is part of the medial temporal lobe memory system, plays an important role in declarative long-term memory. The PRh cortex contains neurons that represent visual long-term memory. The aim of the present study is to characterize the anatomical organization of forward projections that mediate information flow from visual area TE to memory neurons in the PRh cortex. In monkeys performing a visual pair-association memory task, we conducted an extensive mapping of neuronal responses in the anteroventral part of area TE (TEav) and area 36 (A36) of the PRh cortex. Then, three retrograde tracers were separately injected into A36 and the distribution of retrograde labels in TEav was analyzed. We focused on the degree of divergent projections from TEav to memory neurons in A36, because the highly divergent nature of these forward fiber projections has been implicated in memory function. We found that the degree of divergent projection to memory neurons in A36 was smaller from the TEav neurons selective to learned pictures than from the nonselective TEav neurons. This result demonstrates that the anatomical difference (the divergence) correlates with the physiological difference (selectivity of TEav neurons to the learned pictures). Because the physiological difference is attributed to whether the projections are involved in information transmission required for memory neurons in A36, it can be speculated that the reduced divergent projection resulted from acquisition of visual long-term memory, possibly through retraction of the projecting axon collaterals.
12641319	Confirmatory factor analysis was used to test competing models of declarative memory. Data from middle-aged participants provided support for a model comprised of 2 2nd-order (episodic and semantic memory) and 4 1st-order (recall, recognition, fluency, and knowledge) factors. Extending this model across young-old and old-old participants established support for age invariance. Tests of group differences showed an age deficit in episodic memory that was more pronounced for recall than for recognition. For semantic memory, there was an increase in knowledge from middle to young-old age and thereafter a decrease. Overall, the results support the view that episodic memory is more age sensitive than semantic memory, but they also indicate that aging has differential effects within these 2 forms of memory.
12639264	Beginning with the ways in which the use of the couch lends 'depth to the surface' (Erikson, 1954), I explore the topography of the inter- and intrasubjective psychoanalytic situation and process. I suggest that defences are not by definition unconscious but rather can be observed operating at conscious and preconscious levels, particularly under these conditions. A focus on preconscious disavowal provides a window on what has become unconscious repression. As a result of eliciting and then verbalising the operation of such defences with regard to anxieties in the here-and-now transference, declarative memories of increasingly specific childhood fantasies and events begin to hold sway over unmanageable procedural remnants from the analysand's past. With this may even come the possibility of neuronal regeneration, the more generalisable enhancement of declarative and symbolic functions and the sense of identity with which these are associated. Herein may lie one enduring therapeutic effect of the 'talking cure' - putting feelings into words - as one among a variety of psychotherapeutic modalities.
12625459	It is well established in nonhuman primates that the medial temporal lobe (MTL) structures, the hippocampus and the entorhinal and perirhinal cortices, are necessary for declarative memory encoding. In humans, the neuropathological and neuropsychological changes in early Alzheimer's disease (AD) further support a role for the rhinal cortex in the consolidation of new events into long-term memory. Little is known, however, regarding the function of the rhinal cortex in humans in vivo. To examine the participation of the interconnected MTL structures as well as the whole-brain network of activated brain areas in visual associative long-term memory, functional magnetic resonance imaging (fMRI) was used to determine the brain regions that are activated during encoding and retrieval of paired pictures in 12 young control subjects. The most striking finding in the MTL activation pattern was the consistent activation of the perirhinal cortex in the encoding-baseline and encoding-retrieval comparisons with a strict statistical threshold (P < 0.00001). In contrast, no perirhinal cortex activation was detected in the retrieval-baseline or retrieval-encoding comparisons even with a low statistical threshold (P < 0.05). The location of the perirhinal activation area was in the transentorhinal part of the perirhinal cortex, in the medial bank of the collateral sulcus. The hippocampus and the more posterior parahippocampal gyrus were activated in both encoding and retrieval conditions. During the encoding processing, MTL activations were more consistent and the hippocampal activation area located more anteriorly than during retrieval. The frontal, parietal, temporal, and occipital association cortices were also activated in the encoding-baseline and retrieval-baseline comparisons. The data suggest that encoding, but not retrieval, of novel picture pairs activates the perirhinal cortex. To our knowledge, this is the first fMRI study reporting encoding activation in this transentorhinal part of the perirhinal cortex, the site of the very earliest neuropathological changes in AD.
12617861	The hippocampal formation is known for its importance in conscious, declarative memory. Here, we report neuroimaging evidence in humans for an additional role of the hippocampal formation in nonconscious memory. We maskedly presented combinations of faces and written professions such that subjects were not aware of them. Nevertheless, the masked presentations activated many of the brain regions that unmasked presentations of these stimuli did. To induce a nonconscious retrieval of the faces and face-associated occupational information, subjects were instructed to view the previously masked faces and to guess the professional category of each person--academic, artist, and workman. Guessing the professional category of previously masked versus new faces activated the left and right hippocampal formation and right perirhinal cortex as well as bilateral fusiform areas and fronto-temporal areas known to mediate the retrieval of semantic information. These activations within the semantic processing system suggest that conceptual knowledge acquired during masking was nonconsciously retrieved. Our data provide clues to an analogous role of the hippocampus in conscious and nonconscious memory.
12607174	Fifty-three schizophrenic subjects were compared to 50 patients with major depression and 50 normal controls on measures of working memory, declarative memory and malingering. The schizophrenic group scored 1-2 SDs below controls on all measures, while depressive patients exposed only lesser deficits in working memory and free recall. The memory deficit of the schizophrenic subjects was disproportionately greater than their intellectual decline. Differences between clinical groups could not be explained by differences in IQ, clinical symptom load or demographic characteristics. This indicates that impaired memory is a particular sensitive symptom of schizophrenia and that the impairment is specific to the illness. Working memory failure was prominent in both clinical groups. The schizophrenic subjects displayed primarily an acquisition failure, while the depressed group showed retrieval difficulties.
12584720	The structures associated with learning and memory have been widely studied for over 100 years. The idea of the famous neuropsychologist K.S. Lashley, that learning and memory are stored diffusely in the brain, dominated neuroscience in the early half of Twentieth Century. Since Scoville reported in 1957 a persistent impairment of recent memory caused by bilateral medial temporal lobe resection in a patient, the concept that different brain structures play different roles in learning and memory has been established, but the structures were thought to work separately. The connections and functional influences between hippocampus and prefrontal cortex, thalamus and hippocampus, prefrontal cortex and thalamus, amygdala and hippocampus, basal nucleus of Meynert and medial temporal lobe system, and amygdala and thalamus were successively reported. The marginal division (MrD) is a pan-shaped structure consisting of spindle-shaped neurons at the caudal margin of the neostriatum in the mammalian brain. The MrD has been shown to contribute to associative learning and declarative memory by behavioral study in rats and by functional magnetic resonance image study in humans. Lesions in the MrD influenced the learning and memory function of the basal nucleus of Meynert and attenuated hippocampal long-term potentiation. The MrD is likely, based on its position, advanced development in higher mammalian brains, abundant and swift blood supply, and complex connections, to be an important subcortical memory center in the brain. The above-mentioned studies demonstrated that memory-related centers could influence each other and play different roles. Therefore, we propose that there are very possibly hierachical memory centers in the brain.
12581627	Mild cognitive impairment (MCI) is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss. MCI is important as it often precedes Alzheimer's disease (AD). Recognizing MCI may lead to preventive strategies that can delay the onset of AD. Many patients who transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. The improvement in cognitive function with hormones is subtle and often not measurable on standard neuropsychological batteries. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement. Functional changes and vascular changes can be detected after hormonal replacement with more sophisticated imaging of the brain like positron emission tomography (PET) scans. We hypothesize androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males.
12581183	Two experiments tested the predictions of 'declarative' vs. 'perceptual-mnemonic' views of perirhinal cortex function. The former view predicts that perirhinal cortex lesions should impair rapidly learned, but not more slowly learned, visual discriminations, whereas the latter view predicts that impairments should be related not to speed of learning but to perceptual factors. It was found that monkeys with perirhinal cortex lesions were impaired in the acquisition and performance of slowly learned, perceptually difficult greyscale picture discriminations, but were not impaired in the acquisition of rapidly learned, perceptually easier discriminations. In addition, these same monkeys were not impaired in the acquisition or performance of difficult colour or size discriminations, indicating that the observed pattern of impairments was not due to ceiling effects or difficulty per se. These findings, taken together, are consistent with the 'perceptual-mnemonic' view that the perirhinal cortex is involved in both perception and memory, but are not consistent with the 'declarative' view that the perirhinal cortex is important exclusively for declarative memory, having little or no role in perception. Moreover, the results are consistent with the more specific proposal that the perirhinal cortex contributes to the solution of complex visual discriminations with a high degree of 'feature ambiguity', a property of visual discrimination problems that can emerge when features of an object are rewarded when part of one object, but not when part of another. These and other recent findings suggest the need for a revision of prevailing views regarding the neural organization of perception and memory.
12581181	A two-stage radial arm maze (RAM) task has been designed recently to demonstrate a specific age-related memory deficit in mice. It highlights the contrast between normal and deficient memory expression in a spatial discrimination problem depending on how to-be discriminated arms were presented to the animal. This specific deficit has been interpreted as a preferential loss in a relational/declarative form of memory, thereby implying an underlying hippocampal dysfunction. To test this hypothesis, neuronal activation measured by Fos immunostaining was compared in aged (21-23 months) and adult (4-6 months) mice trained in the aforementioned task and killed after a retention session consisting in age-insensitive probe trials, performed 6 days later (6-day RAM). Two comparison conditions were included: (i) repeated locomotor training on a treadmill (TM); (ii) the same RAM training, except for the use of a longer (30 days instead of six) retention interval (30-day RAM). Although all RAM groups displayed similar levels of performance at the end of the experiment, immediately before the mice were killed, significant between-group differences in brain activation were observed. In adult mice, 6-day RAM testing was associated with greater septal and hippocampal (CA1, CA3, DG) Fos expression than the TM condition. Lengthening the retention interval from 6 days to 30 days resulted in a significant decrease in RAM testing-induced Fos expression in most of the septo-hippocampal regions. With respect to adult mice, aged mice displayed reduced Fos expression (except for DG) and a lack of interrelationships between levels of Fos produced in each of the SH regions, in the 6-day RAM testing condition. Conversely, there was no effect of ageing on Fos expression associated with either TM training or 30-day RAM testing. These results are interpreted as reflecting age- (or time-) related alterations in recruiting of brain structures that underlie a relational/declarative form of memory expression.
12580330	Tennessee Williams called his first great work, The Glass Menagerie, his "memory play." The situation in which Williams found himself when he began writing the play is explored, as are the ways in which he used the declarative memory of his protagonist, Tom Wingfield, to express and deal with his own painful conflicts. Williams's use of stage directions, lighting, and music to evoke memory and render it three-dimensional is described. Through a close study of The Glass Menagerie, the many uses of memory for the purposes of wish fulfillment, conflict resolution, and resilience are examined.
12564756	Here we describe the development of serial expertise in 4 experimentally naive rhesus monkeys that learned, by trial and error, the correct order in which to respond to 3-, 4-, and 7-item lists of arbitrarily selected photographs. The probabilities of guessing the correct sequence on 3-, 4-, and 7-item lists were, respectively, 1/6, 1/24, and 1/5,040. Each monkey became progressively more efficient at determining the correct order in which to respond on new lists. During subsequent testing, the subjects were presented with all possible pairs of the 28 items used to construct the four 7-item lists (excluding pairs of items that occupied the same ordinal position in different lists). Subjects responded to pairs from different lists in the correct order 91% of the time on the first trials on which these pairs were presented. These features of subjects' performance, which cannot be attributed to procedural memory, satisfy two criteria of declarative memory: rapid acquisition of new knowledge and flexible application of existing knowledge to a new problem.
12559839	Drug addiction is characterized by a set of recurring processes (intoxication, withdrawal, craving) that lead to the relapsing nature of the disorder. We have used positron emission tomography to investigate in humans the role of dopamine (DA) and the brain circuits it regulates in these processes. We have shown that increases in DA are associated with the subjective reports of drug reinforcement corroborating the relevance of drug-induced DA increases in the rewarding effects of drugs in humans. During withdrawal we have shown in drug abusers significant reductions in DA D2 receptors and in DA release. We postulate that this hypodopaminergic state would result in a decreased sensitivity to natural reinforcers perpetuating the use of the drug as a means to compensate for this deficit and contributing to the anhedonia and dysphoria seen during withdrawal. Because the D2 reductions are associated with decreased activity in the anterior cingulate gyrus and in the orbitofrontal cortex we postulate that this is one of the mechanisms by which DA disruption leads to compulsive drug administration and the lack of control over drug intake in the drug-addicted individual. This is supported by studies showing that during craving these frontal regions become hyperactive in proportion to the intensity of the craving. Craving is also associated with activation of memory circuits including the amygdala (implicated in conditioned learning), hippocampus (implicated in declarative learning), and dorsal striatum (implicated in habit learning) all of which receive DA innervation. We therefore postulate that dopamine contributes to addiction by disrupting the frontal cortical circuits that regulate motivation, drive, and self-control and by memory circuits that increase the motivational salience of the drug and drug-associated stimuli.
12542259	Human declarative memory formation crucially depends on processes within the medial temporal lobe (MTL). These processes can be monitored in real-time by recordings from depth electrodes implanted in the MTL of patients with epilepsy who undergo presurgical evaluation. In our studies, patients performed a word memorization task during depth EEG recording. Afterwards, the difference between event-related potentials (ERPs) corresponding to subsequently remembered versus forgotten words was analyzed. These kind of studies revealed that successful memory encoding is characterized by an early process generated by the rhinal cortex within 300 ms following stimulus onset. This rhinal process precedes a hippocampal process, which starts about 200 ms later. Further investigation revealed that the rhinal process seems to be a correlate of semantic preprocessing which supports memory formation, whereas the hippocampal process appears to be a correlate of an exclusively mnemonic operation. These studies yielded only indirect evidence for an interaction of rhinal cortex and hippocampus. Direct evidence for a memory related cooperation between both structures, however, has been found in a study analyzing so called gamma activity, EEG oscillations of around 40 Hz. This investigation showed that successful as opposed to unsuccessful memory formation is accompanied by an initial enhancement of rhinal-hippocampal phase synchronization, which is followed by a later desynchronization. Present knowledge about the function of phase synchronized gamma activity suggests that this phase coupling and decoupling initiates and later terminates communication between the two MTL structures. Phase synchronized rhinal-hippocampal gamma activity may, moreover, accomplish Hebbian synaptic modifications and thus provide an initial step of declarative memory formation on the synaptic level.
12542231	This study examined age-dependent deficits in the learning and memory of inferential tasks, using an established senescence-accelerated mouse model in age-related brain dysfunction (SAMP8) and its genetically related inbred strain (SAMR1). The mice learned two sets of nonspatial odor-odor pairs by association learning successively (i.e., A-->B, X-->Y, then B-->C, Y-->Z). They were tested in transitive inference (i.e., A-->C, X-->Z) and symmetrical inference (i.e., C-->B, Z-->Y). In the probe test of A-->C, X-->Z transitive inference, 1-month-old SAMP8 and control SAMR1 at the same age significantly chose the alternative based on transitive inference, but 4- and 7-month-old SAMP8 performed at a random chance level, in comparison with unambiguous inference by control SAMR1 at the same ages. During the test of C-->B, Z-->Y symmetrical inference, SAMP8 at 1 month of age made errors as frequently as control SAMR1 at the same age, but SAMP8 at 4 and 7 months of age made more errors than SAMR1 at the same ages. At 4 and 7 months of age, SAMP8 made more errors than 1-month-old SAMP8. Control SAMR1 did not show such an age-related deficient. These results indicate that SAMP8 mice have age-related learning and memory deficits in the ability to perform inferential tasks. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in old SAMP8 mice during the performance of inferential tasks mediated by declarative memory.
12531156	The present paper focuses on human studies attempting to relate sleep states to memory processes. These studies typically present learning material to participants and then examine their ability to recall this material after intervening post-training sleep or sleep deprivation. Most experiments utilize either sleep recording or sleep deprivation following task acquisition to reach their conclusions, although cueing and position emission tomography (PET) scan studies have also been done. Results strongly suggest that REM sleep is involved with the efficient memory processing of cognitive procedural material but not declarative material. Although there are some data to suggest that stage 3/4 or NREM sleep is necessary for declarative memory consolidation, NREM may in fact simply be occurring at the same time as another factor that is actually involved in the memory processing. Preliminary results suggest that the length of the NREM-REM sleep cycle may be important for declarative memory. Preliminary data also suggest that stage 2 sleep may be involved with the memory for motor procedural but not cognitive procedural tasks. Sleep researchers would do well to capitalize on the latest advancements in memory research by choosing tasks that represent special memory systems and examining their relationships to sleep states.
12526782	The capacity for declarative memory depends on the hippocampal region and adjacent cortex within the medial temporal lobe. One of the most widely studied examples of declarative memory is the capacity to recognize recently encountered material as familiar, but uncertainty remains about whether intact recognition memory depends on the hippocampal region itself and, if so, what the nature of the hippocampal contribution might be. Seven patients with bilateral damage thought to be limited primarily to the hippocampal region were impaired on three standard tests of recognition memory. In addition, the patients were impaired to a similar extent at Remembering and Knowing, measures of the two processes thought to support recognition performance: the ability to remember the learning episode (episodic recollection) and the capacity for judging items as familiar (familiarity).
12499842	Declarative memory declines with age, but there is profound variation in the severity of this decline. Healthy elderly adults with high or low memory scores and young adults viewed words under semantic or non-semantic encoding conditions while undergoing fMRI. Young adults had superior memory for the words, and elderly adults with high memory scores had better memory for the words than those with low memory scores. The elderly with high scores had left lateral and medial prefrontal activations for semantic encoding equal to the young, and greater right prefrontal activation than the young. The elderly with low scores had reduced activations in all three regions relative to the elderly with high memory scores. Thus, successful aging was characterized by preserved left prefrontal and enhanced right prefrontal activation that may have provided compensatory encoding resources.
12475713	Memory is composed of several different abilities that are supported by different brain systems. The distinction between declarative (conscious) and nondeclarative (non-conscious) memory has proved useful in understanding the nature of eyeblink classical conditioning - the best understood example of classical conditioning in vertebrates. In delay conditioning, the standard procedure, conditioning depends on the cerebellum and brainstem and is intact in amnesia. Trace conditioning, a variant of the standard procedure, depends additionally on the hippocampus and neocortex and is impaired in amnesia. Recent studies have sharpened the contrast between delay and trace conditioning by exploring the importance of awareness. We discuss these new findings in relation to the brain systems supporting eyeblink conditioning and suggest why awareness is important for trace conditioning but not for delay conditioning.
12475054	The dorsolateral prefrontal cortex in human and non-human primates functions as the highest-order executor for the perception-action cycle. According to this view, when perceptual stimuli from the environment are novel or complex, the dorsolateral prefrontal cortex serves to set consciously a goal-directed scheme which broadly determines an action repertory to meet the particular demand from the environment. In this respect, the dorsolateral prefrontal cortex is a short-term activation device with the properties of a cognitive switch', because it couples a particular set of perceptual stimuli to a particular set of actions. Here, I suggest that, in order for the organism to react systematically to the environment, neural traces for the switch function must be stored in the brain. Thus, the highest-order, perception-action interface function of the dorsolateral prefrontal cortex per se depends on permanently stored neural traces in the dorsolateral prefrontal cortex and related structures. Such a memory system may be located functionally between two of the well-documented memory systems in the brain: the declarative memory system and the procedural memory system. Finally, based on available neurophysiological data, the possible mechanisms underlying the formation of cognitive switch traces are proposed.
12467104	The context in which events occur can be represented as both (1) a set of independent features, the feature representation view, and (2) a set of features bound into a unitary representation, the conjunction representation view. It is assumed that extrahippocampal (e.g., neocortical) areas provide a basis for feature representations, but the hippocampal formation makes an essential contribution to the automatic storage of conjunctive representations. We develop this dual-representation view and explore its implications for hippocampal contributions to contextual fear conditioning processes. To this end, we discuss how our framework can resolve some of the conflicts in the recent literature relating the hippocampus to contextual fear conditioning. We also present new data supporting the role of a key mechanism afforded by conjunctive representations--pattern completion (the ability of a subset of a memory pattern to activate the complete memory)--in contextual fear conditioning. As is implied by this mechanism, we report that fear can be conditioned to the memory representation of a context that is not actually present at the time of shock. Moreover, this result is predicted by our computational model of cortical and hippocampal function. We suggest that pattern completion demonstrated in animals and by our model provides a mechanistic bridge to human declarative memory.
12457895	What is the interaction between storage and computation in language processing? What is the psychological status of grammatical rules? What are the relative strengths of connectionist and symbolic models of cognition? How are the components of language implemented in the brain? The English past tense has served as an arena for debates on these issues. We defend the theory that irregular past-tense forms are stored in the lexicon, a division of declarative memory, whereas regular forms can be computed by a concatenation rule, which requires the procedural system. Irregulars have the psychological, linguistic and neuropsychological signatures of lexical memory, whereas regulars often have the signatures of grammatical processing. Furthermore, because regular inflection is rule-driven, speakers can apply it whenever memory fails.
12457750	Research of the neurobiological bases of learning and memory suggest that these processes are not unitary in nature, but rather that relatively independent neural systems appear to mediate different types of memory. Neurobiological studies, for instance, have identified separable cognitive or "declarative" and stimulus-response "habit" memory systems that rely upon the medial temporal lobe (e.g. hippocampus) and basal ganglia (e.g. caudate-putamen), respectively. Evidence indicates that multiple memory systems are activated simultaneously and in parallel in various learning tasks, and recent findings suggest that these systems may interact. One form of interaction between medial temporal lobe and basal ganglia memory systems appears competitive in nature, and has been revealed in non-human animal studies in which damage to a given memory system results in enhanced learning. Recent human neuroimaging research has also provided evidence in favor of competition between memory systems. Thus, converging evidence across species supports the hypothesis of interactive multiple memory systems in the mammalian brain. Potential neurobiological mechanisms mediating such interactions include direct anatomical projections between the medial temporal lobe and basal ganglia, indirect neuromodulatory influences of other brain structures (e.g. basolateral amygdala) and activity of neocortical brain regions involved in top-down response selection.
12440578	The conversion of newly formed declarative memories into long-term memories is known to be dependent on the hippocampus. Recent experiments suggest that memory consolidation requires reactivation of the NMDA receptor in CA1 during the initial week(s) after training. This led to the hypothesis that the repeated post-learning reinforcement of synaptic modifications, termed synaptic reentry reinforcement (SRR), is essential for long-term memory consolidation and storage. Based on experimental observations, we have built a computational model to further illustrate and explore the effect of the SRR process on the formation of long-term memory. We show that SRR is capable of strengthening and maintaining memory traces despite inherent variability in the system due to such processes as the turnover of synaptic receptors and their associated signaling and structural proteins. Furthermore, we demonstrate that new rounds of synaptic modification triggered by memory reactivation, either during conscious recall or sleep, could lead to the selective consolidation of a subset of memory traces. Finally, we show why the SRR process in the hippocampus is required during the initial post-training weeks for synaptic reinforcement based memory consolidation in the cortex.
12436375	The reversible electrochemical effects of electroconvulsive therapy (ECT) on specific areas of the brain enable the neuroanatomical bases of some cognitive functions to be studied. In research carried out on memory systems, a selective alteration of the declarative ones has been observed after treatment with ECT. Little work has been done to explore the differential alteration of the memory subsystems in patients with a high number of ECT sessions. AIM. To study the declarative and non declarative memory system in psychiatric patients submitted to maintenance ECT treatment, with a high number of previous ECT sessions.20 patients submitted to treatment with ECT (10 diagnosed as having depression and 10 with schizophrenia) and 20 controls, who were paired by age, sex and psychopathological diagnosis. For the evaluation of the declarative memory system, the Wechsler Memory Scale (WMS) logical memory test was used. The Hanoi Tower procedural test was employed to evaluate the non declarative system.	Patients treated with ECT performed worse in the WMS logical memory test, but this was only significant in patients diagnosed as suffering from depression. No significant differences were observed in the Hanoi Tower test.	A selective alteration of the declarative systems was observed in patients who had been treated with a high number of ECT sessions, while the non declarative memory systems remain unaffected.	
12420895	In schizophrenia, impaired conscious retrieval of past events and facts may represent a selective cognitive deficit of declarative memory against a background of a generalized neuropsychological impairment. We aimed to disentangle the neural subprocesses leading to this deficit applying the 'Remember/Know procedure'.Event-related potentials (ERPs) were recorded as 14 schizophrenic patients and 14 controls recognized an equal mixture of previously presented old and new words. For recognized old words, participants were required to judge whether recognition was associated with recollection ('Remember') or familiarity ('Know'), either reflecting episodic or semantic memory.	Patients showed a lack of 'Remember responses', which led to more opportunities to make 'Know responses'. ERPs for 'Remember' compared to 'New responses' differed consistently in controls over left temporo-parietal and right frontal electrode sites. Although schizophrenic patients showed the same topography for this Remember old/new effect, it was apparent over temporoparietal sites for only 800 ms and over right frontal sites for 1100 ms post-stimulus. For controls, the Know old/new effect was elicited over temporo-parietal sites between 500 and 800 ms. For patients, it showed a widespread maximum over frontal sites between 500 and 1100 ms.	The shorter time course of the left temporo-parietal Remember old/new effect suggests that the patients' episodic memory impairment was possibly mediated by a dysfunction of the mediotemporal regions. The more widespread frontal Know old/new effect in the patients suggests that the prefrontly mediated processes associated with retrieval of semantic memory may be enhanced compensatorily.	
12417640	In Alzheimer's disease (AD), the rhinal cortex is the area earliest and most affected by neurofibrillary tangles, and the degree of temporoparietal glucose hypometabolism and rhinal cortex atrophy are both correlated with dementia severity. In monkeys, damage to the rhinal cortex leads to severe impairment in declarative memory, which is also affected preferentially in early AD. To investigate the contribution of rhinal alterations to the interrelationships between cerebral hypometabolism and declarative memory impairment observed in AD, we studied the effects of excitotoxic bilateral rhinal lesions in baboons on cerebral glucose consumption (CMRglc) as measured by positron emission tomography and performance on a visual recognition memory task as assessed in parallel by a delayed nonmatching-to-sample task. We reported previously that these rhinal lesions induce both a long-lasting hypometabolism in several remote brain regions (Meguro et al., 1999) and impaired memory performance (Chavoix et al., 2002). The present analysis indicates that across lesioned and sham baboons, memory scores were significantly positively correlated (p < 0.05; Spearman) with concomitant CMRglc values of several brain areas, such as neocortical associative and posterior hippocampal regions. These findings, reminiscent of those reported in AD, suggest that the neurodegenerative process that affects the rhinal cortex in early AD plays a crucial role in the pattern of brain hypometabolism and consequently in the declarative memory impairments characteristic of this disease.
12404564	This paper reviews the literature on the relationship between glucocorticoids and cognitive functioning, including memory and selective attention. The main body of evidence suggests that hypothalamic-pituitary-adrenal (HPA) axis dysfunction or a state of hypercortisolaemia can be correlated with cognitive deficits specific to the medial temporal lobe declarative memory system. These impairments are discussed in relation to patients with HPA abnormalities, as seen in a significant number of patients with major depression or Cushing's syndrome, and also in relation to healthy volunteers after administration of glucocorticoids. It remains to be seen whether there are differential effects on acquisition, consolidation or retrieval processes. However, it would seem that glucocorticoids have a preferential effect on recall of information as opposed to recognition, possibly because recognition is more automatic.Type 2 glucocorticoid receptors (GRs), which are occupied by cortisol in humans in times of stress, are thought to be responsible for the glucocorticoid-induced memory impairment. GRs alter the feedback of the HPA axis, which in turn disrupts hippocampal functioning. While this can be reversible, animal studies suggest that chronic elevation of glucocorticoid levels can lead to the loss of hippocampal neurons and irreversible decline in declarative memory. Copyright 2001 John Wiley & Sons, Ltd.
12404531	The hippocampal formation, a structure involved in declarative, spatial and contextual memory, is a particularly sensitive and vulnerable brain region to stress and stress hormones. The hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes atrophy of dendrites in the CA3 region. In addition, ovarian steroids regulate synapse formation during the estrous cycle of female rats. All three forms of structural remodeling of the hippocampus are mediated by hormones working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures and by ischemia and prolonged psychosocial stress. In the human hippocampus, magnetic resonance imaging studies have shown that there is a selective atrophy in recurrent depressive illness, accompanied by deficits in memory performance. Hippocampal atrophy may be a feature of affective disorders that is not treated by all medications. From a therapeutic standpoint, it is essential to distinguish between permanent damage and reversible atrophy in order to develop treatment strategies to either prevent or reverse deficits. In addition, remodeling of brain cells may occur in other brain regions. Possible treatments are discussed. Copyright 2001 John Wiley & Sons, Ltd.
12383228	We examined the performance of Long-Evans rats with 192 IgG-saporin lesions of the medial septum/vertical limb of the diagonal band (MS/VDB) or nucleus basalis magnocellularis/substantia innominata (NBM/SI), which removed cholinergic projections mainly to hippocampus or neocortex, respectively. We studied the effects of these lesions on anterograde and retrograde memory for a natural form of hippocampal-dependent associative memory, the social transmission of food preference. In a study of anterograde memory, MS/VDB lesions did not affect the immediate, 24-h or 3-week retention of the task. In contrast, NBM/SI lesions severely impaired immediate and 24-h retention. In a study of retrograde memory in which rats acquired the food preference 5 days or 1 day before surgery and they were tested 10-11 days after surgery, MS/VDB-lesioned rats showed striking memory deficits for the preference acquired at a long delay (5 days) before surgery, although all lesioned rats exhibited poorer retention on both retest sessions than on their pretest performance. Subsequent testing of new anterograde learning in these rats revealed no disrupting effects of lesions on a standard two-choice test. When rats were administered a three-choice test, in which the target food was presented along with two more options, NBM/SI-lesioned rats were somewhat impaired on a 24-h retention test. These results provide evidence that NBM/SI and MS/VDB cholinergic neurons are differentially involved in a social memory task that uses olfactory cues, suggesting a role for these neurons in acquisition and consolidation/retrieval of nonspatial declarative memory.
12377298	The goal is to review the plasticity and vulnerability of the hippocampus, a brain structure involved in episodic, declarative, contextual and spatial learning and memory, as well as its being a component in the control of autonomic and vegetative functions such as ACTH secretion. It discusses its possible role in the regulation of glucose homeostasis, and the need of hippocampal neurons for glucose because of their high metabolic activity. The hippocampus is also vulnerable to damage by stroke and head trauma and susceptible to damage during aging and repeated stress, and is sensitive to the effects of diabetes.A summary of recent work in the author's laboratory and related work in the field using citations of literature based, in part, on Medline searches.	In addition to its vulnerability, the hippocampus is also a plastic and adaptable brain region that is capable of considerable structural reorganization, including remodeling of dendrites and neurogenesis of dentate gyrus granule neurons in response to repeated stress. Animal models of Type 1 diabetes show accelerated remodeling of dendrites, and Type 2 diabetes remains to be studied in this regard. This is relevant to major depressive illness, in which a progressive atrophy of the hippocampal formation is reported and is accompanied by impairment of cognitive function in those subjects with hippocampal shrinkage. Therefore, hippocampal atrophy in depression, as well as in diabetes, may reflect either damage or plasticity involving structural reorganization that is potentially treatable.	
12372660	Neurocognitive deficits are recognized as a cardinal feature of schizophrenia, but the determinants of these deficits remain unknown. Recent reports have suggested that a functional polymorphism, Val(158)Met in exon III of the catechol-O-methyltransferase gene, shares approximately 4% variance with performance on the Wisconsin Card Sorting Test. These findings led to suggestions that the catechol-O-methyltransferase polymorphism may exert its effects by modulating prefrontal dopamine function, but few other neurocognitive measures have been examined, leaving open questions about phenotypic specificity.We examined the effects of the catechol-O-methyltransferase Val(158)Met polymorphism in 58 individuals with chronic schizophrenia who completed a battery of 15 neurocognitive tests, which were reduced to four reliable neurocognitive domain scores. We examined the effects of genotype on these four domains and on global neurocognitive ability.	The Met allele was associated with better performance in the Processing Speed and Attention domain, but not with other domain scores measuring executive and visuoperceptual functions, declarative verbal learning and memory, simple motor ability, or global neurocognitive function. Genotype shared approximately 11% of variance with Processing Speed and Attention scores, and approximately 2% of variance with Wisconsin Card Sorting Test scores.	The findings provide independent support for the hypothesis that the catechol-O-methyltransferase Val(158)Met polymorphism influences neurocognitive function in schizophrenia, and suggest that the functional effects may be expressed on measures of Processing Speed and Attention. This information may prompt reconsideration of the "prefrontal dopamine" hypothesis and invites examination of a broader range of effects in efforts to refine the neurocognitive phenotype that is most relevant to variation in catechol-O-methyltransferase expression.	
12367592	Functional organization of networks underlying withdrawal, feeding, and respiration in terrestrial gastropod snail Helix are described. Tracking the changes during non-associative and associative modifications of behavior, analysis of plasticity mechanisms in identified neurons involved in these networks allowed to formulate several conceptual principles which are not widely accepted. The review will present data underlying the following principles: 1. Command neuron concept can be applied only to all-or-none behavior. 2. Habituation is an active down-regulation process opposite to up-regulating sensitization. All long-term behavioral changes at least in part are associative. 3. Reinforcement is a motivational state mediated by neuromodulatory neurons and can be produced by activity of a single modulatory neuron. 4. Non-addressed ('soft-wired') neuromodulatory influences are necessary for acquisition of memory, while retention of memory depends mostly on 'hard-wired' local changes in synaptic connectivity. 5. Retrieval of declarative (sensory) and procedural (motor) memory involves different functional classes of neurons.
12232538	Schizophrenic patients are known to feature alterations in their cognitive performances, principally in executive functions, attention and memory. In this last domain, studies have shown a relatively severe and global deficit, which can be assessed in chronic and first episode patients. It seems that the memory dysfunction is independent of age and intellectual level, but does correlate with negative psychopathology and global functioning. In the study of memory dysfunction, attentional capacities, information processing and symptomatology have to be considered as determining factors. It has been shown that patients with schizophrenia perform poorly in selective attention tasks and that this deficit may interfere with learning. In the same way, the slowing of information processing contributes to a superficial and incomplete learning. The impact of symptomatology has also to be considered, as negative and depressive symptoms are linked to mnesic performances. The majority of studies bearing on working memory and schizophrenia show an alteration of performances, but studies on long term memory are more equivocal. Procedural memory seems to be preserved, while declarative memory is impaired. These results support the hypothesis that in schizophrenia, memory processes that are consciously controlled are impaired, contrary to implicit learning which may be intact. Nevertheless, studies bearing on semantic memory and episodic memory show controversial results. Still, many authors argue that schizophrenic patients have difficulties in recalling learned material, specially when a delay or a interfering task are introduced in the test. Besides, the schizophrenic subjects do not use the semantic properties of the words, as well as the control subjects, when they have to learn a words list for example. The main goal of the present study was to examine the auditory-verbal learning capacities of 31 schizophrenic patients (20 men and 11 women, 19-56 years old), compared to 27 healthy subjects (11 men and 16 women, 23-56 years old). All subjects received an evaluation including the Rey Auditory-Verbal Learning Test, used to study the progressive acquisition of 15 disyllabic words which are successively orally presented five times to the subject. About forty-five minutes after the last of the five immediate recalls, the delayed recall is assessed and a percentage of retention is also calculated. Visual reasoning and attention capacities were studied with the Progressive Matrix and the d2 encumbrance test respectively. Global psychiatric symptomatology of the patients group was assessed with the Brief Psychiatric Rating Scale. Considering the literature existing on the verbal learning capacities of schizophrenic patients, it was expected that the patients would perform poorly and learn slower than controls. The initial learning of the material, which is a critical stage for schizophrenic patients, was studied with particular attention as well as the effect of the introduction of a delay upon the recall of the words list. A secondary objective of the study was to investigate the role of visual reasoning and attention upon auditory-verbal learning process. According to published studies, it is expected that schizophrenic patients manifest some impairment in the domains of visual reasoning and attention. The question is to know whether it alters performances in the auditory-verbal learning test or not. Finally, the links between clinical characteristics of the patients, like age and illness duration, and their learning performances were explored. Statistical analysis included first a descriptive analysis of data to examine differences between the two groups. Second, ANCOVAs were used in order to control the respective impact of educational level, attention capacities and verbal reasoning capacities upon learning performances. Third, Spearman's correlations were used to detect links between clinical characteristics of the patients and learning performances. The comparisons between patients and controls confirmed that schizophrenic patients scored less in the attentional and visual reasoning tasks. They also featured a lower educational level compared to the healthy subjects. In the auditory-verbal learning test, the patients showed altered performances in the five recalls, as well as in the delayed recall and for the retention percentage. In order to control the impact of educational level, attentional and visual reasoning capacities, these parameters were introduced in the statistical analyses. Educational level did not influence memory alterations in the schizophrenic group. However, attention and, to a lesser extend, visual reasoning had an impact on the comparison of memory scores: when controlling attention, almost no significant group effect remained. Finally, the exploratory analyses of links between clinical characteristics and memory only revealed the presence of a significant negative correlation between illness duration and learning performances. Thus, the analyze of data showed that schizophrenic subjects featured poor performances in the domains of attention, verbal reasoning and auditory-verbal memory. Further analyses taking into account group differences on attention suggest that the impairment featured by schizophrenic patients in the domain of verbal memory strongly relies on an attentional deficit. These results are discussed according to the existing literature and methodological limitations. Clinical implications are also discussed.
12226560	Many different neural models have been proposed to account for major characteristics of the memory phenomenon family in primates. However, in spite of the large body of neurophysiological, anatomical and behavioral data, there is no direct evidence for supporting one model while falsifying the others. And yet, we can discriminate models based on their complexity and/or their predictive power. In this paper we present a computational framework with our basic assumption that neural information processing is performed by generative networks. A complex architecture is 'derived' by using information-theoretic principles. We find that our approach seems to uncover possible relations among the functional memory units (declarative and implicit memory) and the process of information encoding in primates. The architecture can also be related to the entorhinal-hippocampal loop. An effort is made to form a prototype of this computational architecture and to map it onto the functional units of the neocortex. This mapping leads us to claim that one may gain a better understanding by considering that anatomical and functional layers of the cortex differ. Philosophical consequences regarding the homunculus fallacy are also considered.
12215084	Clues to the causes of schizophrenia can be derived from studying first-degree relatives because they are genetically related to an ill family member. Abnormalities observed in nonpsychotic relatives are indicators of possible genetic vulnerability to illness, independent of psychosis. We tested 4 hypotheses: (1) that hippocampal volume is smaller in nonpsychotic relatives than in controls, particularly in the left hemisphere; (2) that hippocampi will be smaller in multiplex relatives as compared with simplex relatives, and both will be smaller than in controls; (3) that hippocampal volumes and verbal declarative memory function will be positively correlated; and (4) that hippocampi will be smaller in patients with schizophrenia than in their nonpsychotic relatives or in controls.Subjects were 45 nonpsychotic adult first-degree relatives from families with either 2 people ("multiplex," n = 17) or 1 person ("simplex," n = 28) diagnosed with schizophrenia, 18 schizophrenic relatives, and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3-dimensional magnetic resonance images of the brain were acquired on a 1.5-T magnet. Volumes of the total cerebrum and the hippocampus were measured.	Compared with controls, relatives, particularly from multiplex families, had significantly smaller left hippocampi. Verbal memory and left hippocampal volumes were significantly and positively correlated. Within families, hippocampal volumes did not differ between schizophrenic patients and their nonpsychotic relatives.	Results support the hypothesis that the vulnerability to schizophrenia includes smaller left hippocampi and verbal memory deficits. Findings suggest that smaller left hippocampi and verbal memory deficits are an expression of early neurodevelopmental compromise, reflecting the degree of genetic liability to schizophrenia.	
12205165	Procedural learning, such as perceptual-motor sequence learning, has been suggested to be an obligatory consequence of practiced performance and to reflect adaptive plasticity in the neural systems mediating performance. Prior neuroimaging studies, however, have found that sequence learning accompanied with awareness (declarative learning) of the sequence activates entirely different brain regions than learning without awareness of the sequence (procedural learning). Functional neuroimaging was used to assess whether declarative sequence learning prevents procedural learning in the brain. Awareness of the sequence was controlled by changing the color of the stimuli to match or differ from the color used for random sequences. This allowed direct comparison of brain activation associated with procedural and declarative memory for an identical sequence. Activation occurred in a common neural network whether initial learning had occurred with or without awareness of the sequence, and whether subjects were aware or not aware of the sequence during performance. There was widespread additional activation associated with awareness of the sequence. This supports the view that some types of unconscious procedural learning occurs in the brain whether or not it is accompanied by conscious declarative knowledge.
12201636	The medial temporal lobe (MTL) is the core structure of the declarative memory system, but which specific operation is performed by anatomically defined MTL substructures? One hypothesis proposes that the hippocampus carries out an exclusively mnemonic operation during declarative memory formation that is insensitive to content, whereas the rhinal cortex carries out an operation supporting memory formation indirectly. To explore the interaction between a salient item feature and memory formation, we contrasted neural correlates of memory formation of high- and low-frequency words. Event-related potentials (ERPs) were recorded via depth electrodes from within the MTL in nine epilepsy patients while they memorized single words. To assess memory formation, ERPs to words subsequently recalled in a free recall test were contrasted with ERPs to forgotten words. More high- than low-frequency words were remembered. High-frequency words led to distinct ERP subsequent memory effects in rhinal cortex and hippocampus. Low-frequency words, however, were only associated with the hippocampal ERP effect. The anatomically restricted interaction between word frequency and memory formation might indicate a semantically affected operation in the parahippocampal region supporting memory formation indirectly. By contrast, the missing interaction in hippocampal recordings might suggest a direct correlate of declarative memory formation that is insensitive to item properties.
12186310	In humans, anterograde amnesia can result from damage to the medial temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these emerging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.
12183219	According to recent studies, elevated cortisol levels are associated with impaired declarative memory performance. This specific effect of cortisol has been shown in several studies using pharmacological doses of cortisol. The present study was designed to determine the effects of endogenously stimulated cortisol secretion on memory performance in healthy middle-aged women. For psychological stress challenging, we employed the Trier Social Stress Test (TSST). Subjects were assigned to either the TSST or a non-stressful control condition. Declarative and non-declarative memory performance was measured by a combined priming-free-recall-task. No significant group differences were found for memory performance. Post hoc analyses of variance indicated that regardless of experimental condition the subjects with remarkably high cortisol increase in response to the experimental procedure (high responders) showed increased memory performance in the declarative task compared to subjects with low cortisol response (low responders). The results suggest that stress-induced cortisol failed to impair memory performance. The results are discussed with respect to gender-specific effects and modulatory effects of the sympathetic nervous system and psychological variables.
12154156	The authors investigated whether MMSE indices designed to measure temporal and physical orientation, declarative memory, language, working memory, and motor/constructional function could differentiate patients with different dementia diagnoses: Alzheimer's disease (AD), ischemic vascular dementia (IVD), or Parkinson's disease (PD). MMSE summary scores did not differ (AD, 21.4; IVD, 21.1; PD, 22.3). The AD group scored lower than IVD or PD on temporal orientation and declarative memory, IVD lower than AD on motor/ constructional and working memory. The IVD and PD groups made more errors in writing a sentence and copying intersecting pentagons. Significant correlations were found between the orientation indices and neuropsychological tests of naming and memory, and between the working memory and motor/constructional indices and tests of executive control. Such analyses of MMSE performance could assist in formulating referral questions for cognitive assessment and in tracking the course of dementing illnesses.
12151563	Declarative memory consolidation is enhanced by sleep. In the investigation of underlying mechanisms, mainly rapid eye movement (REM) sleep and slow-wave sleep have been considered. More recently, sleep stage 2 with sleep spindles as a most prominent feature has received increasing attention. Specifically, in rats hippocampal ripples were found to occur in temporal proximity to cortical sleep spindles, indicating an information transfer between the hippocampus and neocortex, which is supposed to underlie the consolidation of declarative memories during sleep. This study in humans looks at the changes in EEG activity during nocturnal sleep after extensive training on a declarative learning task, as compared with a nonlearning control task of equal visual stimulation and subjectively rated cognitive strain. Time spent in each sleep stage, spindle density, and EEG power spectra for 28 electrode locations were determined. During sleep after training, the density of sleep spindles was significantly higher after the learning task as compared with the nonlearning control task. This effect was largest during the first 90 min of sleep (p < 0.01). Additionally, spindle density was correlated to recall performance both before and after sleep (r = 0.56; p < 0.05). Power spectra and time spent in sleep stages did not differ between learning and nonlearning conditions. Results indicate that spindle activity during non-REM sleep is sensitive to previous learning experience.
12151126	Temporal lobe epilepsy (TLE) patients are frequently afflicted with deficits in spatial and other forms of declarative memory. This impairment is likely associated with the medial temporal lobe, which suffers widespread damage in the disease. Physiological and lesion studies, as well as examinations of the complex connectivity of the medial temporal lobe in animals and humans, have identified the entorhinal cortex (EC) as a key structure in the function and dysfunction of this brain region. Lesions in EC layer III, which normally provides monosynaptic input to area CA1 of the hippocampus, frequently occur in TLE and may be causally related to the memory impairments seen in the disease. Lesions that are initially largely restricted to EC layer III can be produced in rats by focal intra-entorhinal injections of 'indirect excitotoxins' such as aminooxyacetic acid or gamma-acetylenic GABA. These animals eventually show more extensive neurodegeneration in temporal lobe structures and, after a latent period, exhibit spontaneously recurring seizure activity. These progressive features, which may mimic events that occur in TLE, provide new opportunities to explore the role of the EC in memory deficits associated with TLE. These animals will also be useful for evaluating new treatment strategies that focus on the prevention of pathological events in the EC.
12148936	Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests that measure verbal declarative memory performance in older diabetic patients. The performances of 74 undergraduate students (mean age = 21 years) on several verbal declarative measures, including immediate and delayed paragraph recall, verbal free recall, and order reconstruction tasks, were correlated with glucoregulatory indices. The indices were obtained from glucose and insulin levels after a 75-g glucose load. In general, higher blood glucose levels were associated with poorer performance on all memory tests. Glucose ingestion did not interact with performance except on the most difficult task. Subjects with poorer glucoregulation showed higher evoked glucose and insulin, suggestive of a mild glucose intolerance accompanied by mild insulin insensitivity. Results suggest that poor peripheral glucoregulation has an impact on central nervous system functions.
12143363	Memory is systematically affected by temporal lobe epilepsy. Since surgery is a promising alternative to pharmacological treatment the questions which memory system is affected and what the long-term prognosis of memory is are more relevant than ever. We address these issues by cross-sectional and longitudinal analysis of memory performance in large series of patients with temporal lobe epilepsy (TLE). The findings indicate that episodic memory rather than semantic memory is impaired in TLE, in particular in TLE with mesial temporal pathology. With the exception that mesial functions appear increasingly affected by chronic non-mesial TLE, memory decline in TLE is not different from that observed in healthy control subjects. However, since patients perform poorer than controls at any age, normal senescence brings patients to mnesic disability at a younger age. Semantic memory seems unaffected by this process but early cortical lesions appear to interfere with knowledge acquisition. Longitudinal data come to a different conclusion regarding the contribution of epilepsy/seizures to memory decline. Conservative treatment is associated with significant decline in figural memory and 37% of the patients experience some memory decline in the long run. Surgery partly anticipates the decline observed with conservative treatment, but losses are most marked after left temporal lobe surgery. After surgery, quite stable memory or even late recovery from surgery is indicated. Leaving aside the surgical intervention, the data provide evidence that the longitudinal memory outcome in TLE is determined by seizure control, seizure severity, mental reserve capacities, and the retest interval. Thus early and efficient seizure control and the prevention of any cerebral damage from the beginning of epilepsy are demanded.
12137137	A concert pianist recorded her practice as she learned the third movement, Presto, of J.S. Bach's Italian Concerto. She also described the formal structure of the piece and reported her decisions about basic features (e.g., fingering), interpretive features (e.g., phrasing), and cues to attend to during performance (performance cues). These descriptions were used to identify which locations, features, and cues she practiced most, which caused hesitations when she first played from memory, and which affected her recall 2 years later. Effects of the formal structure and performance cues on all three activities indicated that the pianist used the formal structure as a retrieval scheme and performance cues as retrieval cues. Like expert memorists in other domains, she engaged in extended retrieval practice, going to great lengths to ensure that retrieval was as rapid and automatic from conceptual (declarative) memory as from motor and auditory memory.
12116181	Despite evidence for several chromosomal loci linked to schizophrenia, no susceptibility genes have been identified for the disorder. Using quantitative measures of phenotypic affection in place of clinical diagnostic categories or dichotomous classification of the affection status may be more effective in searching for susceptibility genes. Neurocognitive traits have been suggested as putative quantitative endophenotypes of the disorder, but their heritability estimates are not well known. We investigated the heritability of working memory, verbal declarative memory and its different components, and both verbal and visual ability functions in schizophrenia families with a well-ascertained pedigree structure. We also estimated the number of quantitative trait loci (QTLs) contributing to these neurocognitive functions. Additive genetic heritability of the neurocognitive functions was estimated in a sample of schizophrenia patients and their first-degree relatives (N = 264) from an isolated geographical subregion in Finland. The number of QTLs was analyzed using Markov chain Monte Carlo segregation analysis. Significant heritabilities were found in working memory and ability functions. Furthermore, the working memory functions revealed the most restricted number of QTLs. The mean numbers of loci for verbal and visual working memory were 1.2 and 1.0, respectively, with corresponding posterior probabilities of 73% and 70% for at least one locus. In declarative memory variables, the number of loci was more dispersed. Our results suggest that neurocognitive measures, particularly working memory, may provide valid quantitative phenotypic traits for linkage analyses searching predisposing genes for schizophrenia.
12113915	A model for the posttraumatic stress disorder (PTSD) as a disorder of memory is presented drawing both on psychological and neurobiological data. Evidence on intrusive memories and deficits in declarative memory function in PTSD-patients is reviewed in relation to three brain areas that are involved in memory functioning and the stress response: the hippocampus, amygdala, and the prefrontal cortex. Neurobiological studies have shown that the noradrenergic stress-system is involved in enhanced encoding of emotional memories, sensitization, and fear conditioning, by way of its effects on the amygdala. Chronic stress also affects the hippocampus, a brain area involved in declarative memories, suggesting that hippocampal dysfunction may partly account for the deficits in declarative memory in PTSD-patients. Deficits in the medial prefrontal cortex, a structure that normally inhibits the amygdala, may further enhance the effects of the amygdala, thereby increasing the frequency and intensity of the traumatic memories. Thus, by way of its influence on these brain structures, exposure to severe stress may simultaneously result in strong emotional reactions and in difficulties to recall the emotional event. This model is also relevant for understanding the distinction between declarative and non-declarative memory-functions in processing trauma-related information in PTSD. Implications of our model are reviewed.
12110364	The amygdala receives multi-modal sensory inputs and projects to virtually all levels of the central nervous system. Via these widespread projections, the amygdala facilitates consolidation of emotionally arousing memories. How the amygdala promotes synaptic plasticity elsewhere in the brain remains unknown, however. Recent work indicates that amygdala neurons show theta activity during emotional arousal, and various types of oscillations during sleep. These synchronized neuronal events could promote synaptic plasticity by facilitating interactions between neocortical storage sites and temporal lobe structures involved in declarative memory.
12099492	Intracranial field potentials were recorded from electrodes implanted in the hippocampus in 12 epileptic patients. Potentials were elicited by stimuli presented during a delayed matching-to-sample test. Each trial began with a sample stimulus composed of a 3 x 3 grid of rectangular color patches. The sample was followed by a sequence of similar but task-irrelevant stimuli and the sequential presentation of two test stimuli, one of which was identical to the sample. Patients indicated their recognition of the test stimulus that matched the sample with a button press. High-amplitude negative potentials were consistently elicited by sample and test stimuli. Peak amplitudes occurred 300-500 ms after stimulus onset and were larger for the sample in all cases. The patterns of potential gradients observed between adjacent hippocampal contacts and the locations of maximal amplitudes, as verified by magnetic resonance imaging in seven patients, suggest that these potentials were produced by neuronal activity in posterior hippocampus. These field potentials appear to index a memory storage function engaged in response to events that will later be remembered. The hippocampal contribution to storing declarative memories can thus begin, in some circumstances, within the first half-second after the presentation of a to-be-remembered stimulus.
12099481	The hippocampal formation is essential for forming declarative representations of the relationships among multiple stimuli. The rodent hippocampal formation, including the entorhinal cortex and subicular complex, is critical for spatial memory. Two classes of hippocampal neurons fire in relation to spatial features. Place cells collectively map spatial locations, with each cell firing only when the animal occupies that cell's "place field," a particular subregion of the larger environment. Head direction (HD) cells encode directional heading, with each HD cell firing when the rat's head is oriented in that cell's particular "preferred firing direction." Both landmarks and internal cues (e.g., vestibular, motor efference copy) influence place and HD cell activity. However, as is the case for navigation, landmarks are believed to exert greater influence over place and HD cell activity. Here we show that temporary inactivation of the vestibular system led to the disruption of location-specific firing in hippocampal place cells and direction-specific discharge of postsubicular HD cells, without altering motor function. Place and HD cell activity recovered over a time course similar to that of the restoration of vestibular function. These results indicate that vestibular signals provide an important influence over the expression of hippocampal spatial representations, and may explain the navigational deficits of humans with vestibular dysfunction.
12097527	Most amnesic patients with damage to the medial temporal lobe retain some capacity to learn new information about facts and events. In many cases, the learning appears to depend on a residual ability to acquire conscious (declarative) knowledge. We have studied the capacity for semantic (fact) learning in the profoundly amnesic patient E.P., who has extensive damage limited primarily to the medial temporal lobe. E.P. was presented with factual information (novel three-word sentences) during 24 study sessions across 12 weeks. E.P. performed much more poorly than controls but demonstrated unmistakable improvement across the sessions, achieving after 12 weeks a score of 18.8% correct on a cued-recall test and 64.6% correct on a two-alternative, forced-choice test. Unlike controls, E.P.'s learning was not accompanied by conscious knowledge about which answers were correct. He assigned the same confidence ratings to his correct answers as his incorrect answers. Moreover, on the forced-choice test his response times were identical for correct and incorrect responses. Furthermore, unlike controls, he could not respond correctly when the second word in each sentence was replaced by a synonym. Thus, what E.P. learned was rigidly organized, unavailable as conscious knowledge, and in all respects exhibited the characteristics of nondeclarative memory. Thus, factual information, which is ordinarily learned as declarative (conscious) knowledge and with the participation of the medial temporal lobe, can be acquired as nondeclarative memory, albeit very gradually and in a form that is outside of awareness and that is not represented as factual knowledge. We suggest that E.P.'s learning depended on a process akin to perceptual learning and occurred directly within neocortex.
12052921	Although the mammalian basal ganglia have long been implicated in motor behavior, it is generally recognized that the behavioral functions of this subcortical group of structures are not exclusively motoric in nature. Extensive evidence now indicates a role for the basal ganglia, in particular the dorsal striatum, in learning and memory. One prominent hypothesis is that this brain region mediates a form of learning in which stimulus-response (S-R) associations or habits are incrementally acquired. Support for this hypothesis is provided by numerous neurobehavioral studies in different mammalian species, including rats, monkeys, and humans. In rats and monkeys, localized brain lesion and pharmacological approaches have been used to examine the role of the basal ganglia in S-R learning. In humans, study of patients with neurodegenerative diseases that compromise the basal ganglia, as well as research using brain neuroimaging techniques, also provide evidence of a role for the basal ganglia in habit learning. Several of these studies have dissociated the role of the basal ganglia in S-R learning from those of a cognitive or declarative medial temporal lobe memory system that includes the hippocampus as a primary component. Evidence suggests that during learning, basal ganglia and medial temporal lobe memory systems are activated simultaneously and that in some learning situations competitive interference exists between these two systems.
12017552	Besides affecting the hypothalamus and other brain areas related to reproduction, ovarian steroids have widespread effects throughout the brain, on serotonin pathways, catecholaminergic neurons, and the basal forebrain cholinergic system as well as the hippocampal formation, a brain region involved in spatial and declarative memory. Thus, ovarian steroids have measurable effects on affective state as well as cognition, with implications for dementia. Two actions are discussed in this review; both appear to involve a combination of genomic and nongenomic actions of ovarian hormones. First, regulation of the serotonergic system appears to be linked to the presence of estrogen- and progestin-sensitive neurons in the midbrain raphe as well as possibly nongenomic actions in brain areas to which serotonin neurons project their axons. Second, ovarian hormones regulate synapse turnover in the CA1 region of the hippocampus during the 4- to 5-day estrous cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves N-methyl-D-aspartate (NMDA) receptors, whereas downregulation of these synapses involves intracellular progestin receptors. A new, rapid method of radioimmunocytochemistry has made possible the demonstration of synapse formation by labeling and quantifying the specific synaptic and dendritic molecules involved. Although NMDA receptor activation is required for synapse formation, inhibitory interneurons may play a pivotal role as they express nuclear estrogen receptor-alpha (ERa). It is also likely that estrogens may locally regulate events at the sites of synaptic contact in the excitatory pyramidal neurons where the synapses form. Indeed, recent ultrastructural data reveal extranuclear ERalpha immunoreactivity within select dendritic spines on hippocampal principal cells, axons, axon terminals, and glial processes. In particular, the presence of ER in dendrites is consistent with a model for synapse formation in which filopodia from dendrites grow out to find new synaptic contacts and estrogens regulate local, post-transcriptional events via second messenger systems.
12011554	Recent evidence from animal models has demonstrated that tPA can be neurotoxic to the hippocampus and cerebellum. Since tPA is used in patients with myocardial infarction and has been approved for the treatment of acute ischemic stroke, we carried out a pilot study to investigate whether its administration could result in any clinically relevant neuropsychological dysfunction, with particular attention to those structures most involved in the animal model.Patients with acute myocardial infarction (AMI) who were subjected to thrombolysis with r-tPA and without evidence of prior or concomitant neurological-neuropsychological damage, were eligible. Controls consisted of patients with AMI not candidate for thrombolysis or patients with severe angina admitted to the intensive care unit. A detailed neurological and neuropsychological evaluation was performed, which included mood, visual and verbal memory, psychomotor speed processing and motor dexterity and visuomotor sequence learning.	Ten patients and 13 controls were included. No significant differences between both groups were found, although all the subjects performed in the lower limits of the normal range on the Purdue pegboard test (motor dexterity) and digit-symbol test (psychomotor speed). There was no evidence of depression, as assessed by the Hamilton scale, that could have interfered with performance. Declarative memory (Rey auditory-verbal learning test) as well as visual memory (Rey-Osterrieth figure copy) and visuomotor sequence learning (serial reaction time task) were normal, without between-group differences.	tPA administration at the usual doses did not result in detectable neuropsychological abnormalities in patients with myocardial ischemia.	
12007593	This study was designed to examine whether discrete working memory deficits underlie positive, negative and disorganised symptoms of schizophrenia. Symptom dimension ratings were assigned to 52 outpatients with schizophrenia (ICD-10 criteria), using items drawn from the Positive and Negative Syndrome Scale (PANSS). Linear regression and correlational analyses were conducted to examine whether symptom dimension scores were related to performance on several tests of working memory function. Severity of negative symptoms correlated with reduced production of words during a verbal fluency task, impaired ability to hold letter and number sequences on-line and manipulate them simultaneously, reduced performance during a dual task, and compromised visuospatial working memory under distraction-free conditions. Severity of disorganisation symptoms correlated with impaired visuospatial working memory under conditions of distraction, failure of inhibition during a verbal fluency task, perseverative responding on a test of set-shifting ability, and impaired ability to judge the veracity of simple declarative statements. Severity of positive symptoms was uncorrelated with performance on any of the measures examined. The present study provides evidence that the positive, negative and disorganised symptom dimensions of the PANSS constitute independent clusters, associated with unique patterns of working memory impairment.
12000027	The hippocampus is an important structure for declarative, spatial, and contextual memory and is implicated in the perception of chronic pain. The hippocampal formation is vulnerable to damage from seizures, ischemia, and head trauma and is particularly sensitive to the effects of adrenal glucocorticoids secreted during the diurnal rhythm and chronic stress. Adrenal steroids typically have adaptive effects in the short run, but promote pathophysiology when there is either repeated stress or dysregulation of the HPA axis. The damaging actions of glucocorticoids under such conditions have been termed "allostatic load", referring to the cost to the body of adaptation to adverse conditions. Adrenal steroids display both protective and damaging effects in the hippocampus. They biphasically modulate excitability of hippocampal neurons, and high glucocorticoid levels and severe acute stress impair declarative memory in a reversible manner. The hippocampus also displays structural plasticity, involving ongoing neurogenesis of the dentate gyrus, synaptogenesis under control of estrogens in the CA1 region, and dendritic remodeling caused by repeated stress or elevated levels of exogenous glucocorticoids in the CA3 region. In all three forms of structural plasticity, excitatory amino acids participate along with circulating steroid hormones. Glucocorticoids and stressors suppress neurogenesis in the dentate gyrus. They also potentiate the damage produced by ischemia and seizures. Moreover, the aging rat hippocampus displays elevated and prolonged levels of excitatory amino acids released during acute stress. Our working hypothesis is that structural plasticity in response to repeated stress starts out as an adaptive and protective response, but ends up as damage if the imbalance in the regulation of the key mediators is not resolved. It is likely that morphological rearrangements in the hippocampus brought on by various types of allostatic load alter the manner in which the hippocampus participates in memory functions and it is conceivable that these may also have a role in chronic pain perception.
11992230	The nine-word California Verbal Learning Test (CVLT-9; Libon et al., 1996; Spreen & Strauss, 1998) is a verbal list learning task used to assess declarative memory impairment among dementia patients. The present study sought to investigate the neuro-cognitive mechanisms that underlie the production of intrusions and perseverations on the list A, free recall learning trials, and the false positive responses made on the delayed recognition condition. Patients with probable Alzheimer's disease (AD), Ischaemic Vascular Dementia associated with periventricular and deep white matter changes (IVD), and individuals without dementia (NC) were studied. Between-group analyses showed that AD participants produced more initial intrusion errors, and perseverated on those same intrusion errors across list A learning trials than IVD or NC participants. Also, as participants with dementia produced initial free recall intrusion errors, the semantic organization of their responses on the 'animal' word list generation task declined (Giovannetti-Carew, Lamar, Cloud, Grossman, & Libon, 1997). On the delayed recognition test condition, within-group analyses revealed that the IVD group endorsed more list B interference foils, than other errors. AD participants endorsed semantically related foils and list B interference foils. In addition, as participants with dementia endorsed more list B interference foils, more perseverations were produced on the Graphical Sequence Test - Dementia Version (Lamar et al., 1997). These results were interpreted within the context of the semantic knowledge, and executive functions deficits that typify AD and IVD, respectively.
11985834	In an artificial grammar learning task, subjects were asked to memorise short lists of letter strings formed according to complex rules for letter order. After an interval they were unexpectedly asked to discriminate new grammatical strings from strings which used the same letters but violated the sequential constraints of the grammar. Artificial grammar learning can be mastered successfully by amnesic patients and is considered to be an implicit learning task independent of declarative learning and memory mechanisms. In this study, 10 patients with cerebellar degeneration (CD), 21 Parkinson's disease (PD) and 15 control subjects were tested on artificial grammar learning. Additionally PD patients with advanced disease were examined under adequate medication and dopaminergic withdrawal. All patient groups showed intact artificial grammar learning. Neither cerebellar damage nor basal ganglia dysfunction nor dopaminergic medication impairs or affects artificial grammar learning. Although the patients showed significant executive dysfunction, implicit learning remains intact. The conclusion is that cerebellar and basal ganglia circuits play no essential part in this kind of implicit learning. The results suggest that artificial grammar learning is a cortically mediated function comparable to the mechanism of visual priming.
11983575	Kinder and Shanks report simulations aimed at describing a single-system model of the dissociation between declarative and non-declarative memory. This model attempts to capture both Artificial Grammar Learning (AGL) and recognition memory with a single underlying representation. However, the model fails to reflect an essential feature of recognition memory - that it occurs after a single exposure - and the simulations may instead describe a potentially interesting property of over-training non-declarative memory.
11980044	In this article we discuss the implications of the functional organization and dynamics of the brain for understanding human relationships. In particular, we focus on the brain's multiple memory systems and the various roles they play in organizing the interactions of people as they come to know one another. The distinction between the relatively independent declarative, procedural, and emotional learning systems is especially significant in this regard, as the former mediates what we know about one another, the second mediates what we do with one another, and the third affects behavior by altering our emotional state. Knowledge of the functioning of these dissociable memory systems provides a novel perspective on relationships--both ordinary social relationships and those that develop in psychotherapy--and further illuminates psychotherapeutic transference and countertransference phenomena. We begin with a review of the neural basis of these processes, then turn our attention to the interpersonal level of analysis.
11976194	Glucose administration regulates many neural and behavioral processes in rodents, including learning and memory. Given the important role of glucose in brain function and the safety of glucose as a treatment, we have investigated the effects of glucose administration in humans of different ages. In previous work, we examined the effects of early-morning glucose consumption on cognitive functions in elderly individuals. In this population, glucose enhanced performance on specific measures, particularly on those tasks where mild age-related deficits appear (e.g., verbal declarative memory). Interestingly, glucose failed to enhance cognitive functions in young adults. Our recent work has examined three issues related to glucose enhancement of cognition: First, is glucose effective only in reversing impairments or can it also facilitate performance in highly functioning individuals? Second, are glucose effects dependent either on time of day or on interactions with other meals? Third, are typical breakfast foods as effective as glucose in enhancing cognitive performance? Our findings suggest that glucose can improve memory in highly functioning populations as it does in populations with deficits. However, enhancement by glucose may require sufficient levels of task difficulty and of blood glucose. In addition, like glucose, early morning consumption of cereal can improve performance on some cognitive tests. These results have important implications for the nature of glucose facilitation of memory and for the role of dietary factors in performance of many daily activities.
11970808	Damage to the medial-temporal region is known to result in declarative (explicit) memory deficits but nondeclarative (implicit) memory is largely unaffected by such lesions. Earlier studies have shown that some forms of implicit learning depend on cerebellar circuits but remain preserved following affections of the basal ganglia circuits. It is unknown which forms of implicit learning persist in patients with cerebellar pathology but are affected after basal ganglia lesions. Therefore, we determined if a test sensitive for habit-learning (probabilistic classification task) resulted in normal values for patients with cerebellar disease but resulted in affected results in patients with Parkinson's disease (PD). To this end, 23 patients with PD, 16 patients with familial or idiopathic cerebellar degeneration (CD), and 20 controls were tested for habit-learning. There was no impairment of patients with CD for the early learning period but there was abnormal learning in the PD group. For a later learning period, the patients with the PD showed improved performance. We conclude that the probabilistic learning task is an implicit, nonmotor learning task which is sensitive for basal ganglia pathology but remains unaffected in the case of cerebellar pathology. Such a test may be of special interest for the detection and possible neurobehavioral treatment of cognitive and motor deficits.
11970807	Older people with declining cognitive function typically display deficits in declarative memory processes, often most evident on tests of associative learning (AL). The hippocampal formation (HF) is thought to be critically involved in the encoding and retrieval of such associations, consistent with neuroimaging findings that the HF is damaged in early stages of neurodegenerative disease and in older people with AL impairments. In the clinic, older people with cognitive decline commonly report difficulties associating names with faces. However, we have observed that such people are particularly impaired on tests requiring the association of novel stimuli. In Experiment 1, a series of AL tasks were administered to older people with cognitive decline to determine whether they were impaired at simply making associations, or at making associations between novel stimuli. In Experiment 2, we measured HF function in these subjects by administering an AL task designed to differentiate between HF-damaged and HF-intact individuals. Our experimental protocols were guided by a computational model of HF function in AL described by Gluck and Myers (1997). Older people with cognitive decline displayed impaired performance on tasks designed to be highly dependent upon intact HF function, including a task in which novel patterns and spatial locations were to be associated. These results suggest that the AL impairments observed in older people with cognitive decline may be due to HF dysfunction.
11959362	To date, there have been no formal investigations of neuropsychological performance in patients with obsessive-compulsive disorder (OCD) taking psychotropic medications. The purpose of this study was to determine whether medicated and unmedicated patients with OCD demonstrate differences in neuropsychological functioning. Fifty-two patients with a primary DSM-IV diagnosis of OCD participated in the study; 28 were taking serotonin reuptake inhibitors (SRIs), and 24 were treatment-naïve (n=8) or had finished a washout period prior to their inclusion in other studies (n=16). The groups were well matched with regard to demographic and clinical variables, including symptom severity. Each group was administered a comprehensive neuropsychological battery to assess general intelligence, attention, verbal and non-verbal working memory, declarative and procedural learning, visuo-constructive skills, and executive functions. SRI-medicated did not differ from SRI-free patients on any neuropsychological measure. Benzodiazepines seemed to improve the patients' functioning on a semantic verbal fluency test. In addition, there were significant interactions between SRIs and benzodiazepines on the perseverative errors of the Wisconsin Card Sorting Test and on reaction times. SRI-medicated patients with OCD are able to perform on cognitive functioning tests at a comparable level with that of SRI-free patients, and these results have positive implications for OCD patients who respond to SRIs. The interactions between SRIs and benzodiazepines and their effect on cognition in OCD are likely to be complex and deserve further study.
11958970	Episodic and semantic memory are two forms of declarative memory which appear to function in distinct yet interdependent ways. Here we provide direct evidence for a functional relationship between these two memory systems by showing that left lateral temporal lobe regions involved in semantic memory play an important role in accurate episodic memory retrieval.
11949774	Previous studies have found adverse effects of both acute and chronic elevations of corticosteroids on cognitive function in humans and that cortisol levels may predict cognitive decline in elderly subjects. However, no previous studies have directly investigated the effects of hydrocortisone on cognitive functioning in the healthy elderly. Sixteen healthy elderly subjects took part in a placebo-controlled, double-blind, cross-over trial. Hydrocortisone 20 mg or placebo was administered twice, 12 h and 1 h before cognitive testing. On each occasion, a battery of neuropsychological tests was performed which included tests of attention, working memory, declarative memory and executive function. Salivary cortisol levels at the time of testing were elevated approximately 10-fold following hydrocortisone compared with placebo. No significant effects were found on memory or a range of other cognitive functions. The lack of effect of this regime of hydrocortisone is in contrast to studies in younger subjects. The elderly may be less sensitive to cognitive effects of short-term increases in cortisol levels, possibly due to an age-related downregulation of hippocampal glucocorticoid receptors.
11949711	Memory encoding and retrieval strategies were assessed in patients with behavior-executive variant frontotemporal dementia (FTD), language variant FTD, and Alzheimer's disease (AD) using verbal and visuospatial supraspan learning tests. FTD patients obtained higher free recall, cued recall, and recognition scores than AD patients. Comparison of free recall scores with cued recall and recognition scores was similar in the 3 dementia groups. Groups did not differ in semantic clustering strategies during learning, but serial-order recall was more common in FTD patients. These data do not support the idea that FTD patients' poor memory is due to a selective retrieval disorder, though FTD patients may fail to implement sophisticated organizational strategies during learning. FTD patients' retained capacity for encoding new information into long-term declarative memory is likely due to relatively spared medial temporal lobe involvement.
11933895	Functional magnetic resonance imaging (fMRI) was used to compare frontal-lobe activation in younger and older adults during encoding of words into memory. Participants made semantic or nonsemantic judgments about words. Younger adults exhibited greater activation for semantic relative to nonsemantic judgments in several regions, with the largest activation in the left inferior frontal gyrus. Older adults exhibited greater activation for semantic judgments in the same regions. but the extent of activation was reduced in left prefrontal regions. In older adults, there was a significant association between behavioral tests of declarative and working memory and extent of frontal activation. These results suggest that age-associated decreases in memory ability may be due to decreased frontal-lobe contributions to the initial encoding of experience.
11931922	Classical conditioning of the fear response is a basic form of nondeclarative (nonconscious) memory that mediates both normal and pathological responses to aversive stimuli. Because fear conditioning critically depends on the amygdala, a medial temporal lobe structure that frequently undergoes significant pathological changes early in the course of Alzheimer's disease (AD), we hypothesized that fear conditioning would be impaired in patients with mild to moderate AD. We examined simple classical fear conditioning in a group of 10 patients with probable AD and 14 demographically matched, neurologically intact elderly controls. During conditioning, one stimulus (e.g. a green rectangle, the conditioned stimulus (CS+)), was paired with an aversive stimulus (a loud noise, the unconditioned stimulus (US)) using a partial reinforcement conditioning schedule. The opponent color (e.g. red rectangle), the CS-, was never paired with the US. The elderly controls acquired robust fear responses as demonstrated by their differential skin-conductance responses to the CS+ and CS-. In contrast, the AD group showed a marked impairment in conditioning, failing to exhibit significant conditioned fear responses. This failure to acquire conditioned responses could not be attributed to diminished responding by patients, relative to controls, to the aversive US. The results indicate that fear conditioning, an amygdala-dependent form of memory, is impaired in AD. These findings complement previous reports of impairments in declarative emotional memory in AD by demonstrating that a basic form of nondeclarative emotional memory is also impaired in AD.
11931920	Evidence from experiments on perceptual learning, accumulated during the last few years, increasingly indicates that the relative 'front end' parts of the visual system are more plastic even in adults than was previously expected. Hence, it might be possible that perceptual learning is similar in several respects to procedural learning and may be achieved even without (declarative) memory traces present. Results on six patients suffering from global amnesia due to damage to hippocampal-diencephalic systems demonstrate, for the first time, that at least some amnesic patients are able to significantly improve performance in a visual hyperacuity task as a result of training, showing improvement as good as the observers in the control group. This result corroborates the notion of a relatively 'front end' location of at least some forms of perceptual learning.
11907688	Old age impairs the ability to form new associations for declarative memory, but the ability to acquire and retain procedural memories remains relatively intact. Thus, it is unclear whether old age affects the ability to learn the visuomotor associations needed to set efficient fingertip forces for handling familiar objects. We studied the ability for human subjects to use visual cues (color) about the mechanical properties (texture or weight) of a grasped object to control fingertip forces during prehension. Old and young adults (mean age 77 years and 22 years, respectively) grasped and lifted an object that varied in texture at the gripped surfaces (experiment 1: sandpaper versus acetate surface materials) or weight (experiment 2: 200 g versus 400 g). The object was color-coded according to the mechanical property in the "visual cue" condition, and the mechanical property varied unpredictably across lifts in the "no visual cue" condition. In experiment 1 (texture), the young adults' grip force (force normal to the gripped surface) when the object lifted from the support surface was 24% smaller when the surfaces were color-coded. The old adults' grip force did not vary between the visual conditions despite their accurate reports of the grip surface colors prior to each lift. Comparable findings were obtained in experiment 2, when object weight was varied and peak grip force rate prior to object lift-off was measured. Furthermore old and young subjects alike used about 2 N of grip force when lifting the 200 g object in experiment 2. Therefore, the old adults' failure to adjust grip force when the color cue was present cannot be attributed to a general inability or unwillingness to use low grip force when handling objects. We conclude that old age affects the associative learning that links visual identification of an object with the fingertip forces for efficiently handling the object. In contrast, old and young subjects' grip force was influenced by the preceding lift, regardless of visual cues, which supports existing theories that multiple internal representations govern predictive control of fingertip forces during prehension.
11903857	The ability to process recently acquired knowledge is clearly maintained during sleep. Here we assess whether and how far the sleeper controls this processing (in a non-volitional and non-conscious manner). We posit that during sleep, the cognitive concerns of previous waking may guide access to, and processing of, items of declarative knowledge with which those concerns are associated. In a delayed recall task, before each of three sleep onsets in the same night, 12 subjects heard a different nonsense sentence. When awakened in rapid eye movement (REM) sleep, they were asked to report their dream experience and to recall the last sentence heard. Occurrences of incorporation into dream content were more frequent for this sentence than for the sentences heard before previous sleep onsets, and also more frequent than occurrences of similar contents in reports from a control night. However, the modalities of elaboration of dream contents did not vary. These findings indicate that cognitive concern can affect the accessing of recently acquired declarative knowledge during sleep, but not the modalities by which this is inserted into dream content. They also suggest that cognitive concern may help consolidate knowledge by increasing the likelihood of it being processed during sleep.
11877495	Much data indicate that the perirhinal (PRH) cortex plays a critical role in declarative memory and that the amygdala facilitates this process under emotionally arousing conditions. However, assuming that the amygdala does so by promoting Hebbian interactions in the PRH cortex is hard to reconcile with the fact that variable distances separate amygdala neurons from their PRH projection sites. Indeed, to achieve a synchronized activation of distributed PRH sites, amygdala axons should display a uniform range of conduction times, irrespective of distance to target. To determine if amygdala axons meet this condition, we measured the antidromic response latencies of lateral amygdala (LA) neurons to electrical stimuli delivered at various rostrocaudal levels of the PRH cortex in cats anesthetized with isoflurane. Although large variations in antidromic response latencies were observed, they were unrelated to the distance between the PRH stimulation sites and LA neurons. To determine whether this result was an artifact due to current spread, two control experiments were performed. First, we examined the antidromic response latency of intrinsic PRH neurons. Although we used the same methods as in the first experiment, the antidromic response latency of PRH neurons to electrical stimuli applied in the PRH cortex increased linearly with the distance between the stimulating and recording sites. Second, we measured the antidromic response latency of PRH neurons projecting to the LA. In this pathway, we also found a statistically significant correlation between conduction times and distance to target. Thus these results support the intriguing possibility that the conduction velocity and/or trajectory of LA axons are adjusted to compensate for variations in distance between the LA and distinct rostrocaudal PRH sites. We hypothesize that because of their uniform range of conduction times to the PRH cortex, LA neurons can generate short time windows of depolarization facilitating Hebbian associations between coincident, but spatially distributed, activity patterns in the PRH cortex. In this context, the temporal scatter of conduction times in the LA to PRH pathway is conceived as a mechanism used to lengthen the period of depolarization to compensate for conduction delays within intrinsic PRH pathways. In part, this mechanism might explain how the amygdala promotes memory storage in emotionally arousing conditions.
11853359	Neuropsychological deficits, most notable in executive, visuospatial, and functions of gait and balance, are detectable in alcoholic men even after a month of sobriety. Less well established are the severity and profile of persisting deficits in alcoholic women. The authors used an extensive test battery to examine cognitive and motor functions in 43 alcoholic women who were sober, on average, for 3.6 months. Functions most severely affected in alcoholic women involved visuospatial and verbal and nonverbal working memory processes as well as gait and balance. Areas of relative sparing were executive functions, declarative memory, and upper-limb strength and speed. The authors found that lifetime alcohol consumption was related to impairment severity on Block Design (Wechsler Adult Intelligence Scale-Revised, D. Wechsler, 1981) and verbal and nonverbal working memory, suggesting a dose effect of alcohol abuse. The alcohol-related deficits in working memory, visuospatial, and balance implicate disruption of prefrontal, superior parietal, and cerebellar brain systems.
11849301	We have developed a simple connectionist model based on the idea that perirhinal cortex has properties similar to other regions in the ventral visual stream, or 'what' pathway. The model is based on the assumption that representations in the ventral visual stream are organized hierarchically, such that representations of simple features of objects are stored in caudal regions of the ventral visual stream, and representations of the conjunctions of these features are stored in more rostral regions. We propose that a function of these feature conjunction representations is to help to resolve 'feature ambiguity', a property of visual discrimination problems that can emerge when features of an object predict a given outcome (e.g. reward) when part of one object, but predict a different outcome when part of another object. Several recently reported effects of lesions of perirhinal cortex in monkeys have provided key insights into the functions of this region. In the present study these effects were simulated by comparing the performance of connectionist networks before and after removal of a layer of units corresponding to perirhinal cortex. The results of these simulations suggest that effects of lesions in perirhinal cortex on visual discrimination may be due not to the impairment of a specific type of learning or memory, such as declarative or procedural, but to compromising the representations of visual stimuli. Furthermore, we propose that attempting to classify perirhinal cortex function as either 'perceptual' or 'mnemonic' may be misguided, as it seems unlikely that these broad constructs will map neatly onto anatomically defined regions of the brain.
11836010	Many animal studies show an enhancing effect of vasopressin (VP) on memory, but not all human studies could confirm this finding. This study examined the influence of post-learning administration of VP (40 IU, intranasally) on the consolidation of declarative memories in healthy humans during different intervals of sleep and waking. We could not find any effect of VP on memory consolidation, but EEG activity indicated a significant arousing influence of VP. Results suggest that if VP affects memory function it might do so primarily at the stage of encoding of the materials to be learned but it leaves unaffected processes of consolidation.
11829323	The effect of Cavalheiro's pilocarpine model of epileptogenesis upon conditioned taste aversion (CTA), an important example of nondeclarative memory, was studied in adult Long Evans rats. Deterioration of CTA was studied during the silent period between pilocarpine-induced status epilepticus (SE) and delayed spontaneous recurrent seizures. SE was elicited by i.p. injection of pilocarpine (320 mg/kg ) and interrupted after 2 hours by clonazepame (1 mg/kg i.p.). Peripheral cholinergic symptoms were suppressed by methylscopolamine (1 mg/kg i.p.), administered together with pilocarpine. CTA was formed against the salty taste of isotonic LiCl. In the experiment of CTA acquisition, the CTA was formed and tested during the silent period after SE. In the experiment of CTA retrieval, the CTA was acquired before SE and the retrieval itself was tested during the silent period. Retrieval of CTA acquired before SE was impaired more than the retrieval of CTA formed during the silent period. Our findings indicate that epileptic seizures can disrupt even non-declarative memory but that CTA formed by the damaged brain can use its better preserved parts for memory trace formation. Ketamine (50 mg/kg i.p.) applied 2 min after the onset of pilocarpine-induced status epilepticus protected memory deterioration.
11811672	Declarative memory depends on the hippocampus and related medial temporal lobe and diencephalic structures. Declarative memory has usually been found to be available to conscious recollection. A recent study (Chun and Phelps, Nat Neurosci 1999;2:844-847) found that damage to the medial temporal lobe (including the hippocampus) impaired performance on a perceptual learning task, yet the learning was accomplished in the absence of memory for the stimuli. This finding raised the possibility that some hippocampus-dependent tasks may be inaccessible to awareness and may be performed without evoking conscious memory processes. Using the same task, we show that when damage is confined largely to the hippocampal formation, perceptual learning is intact. Thus, the available data suggest that damage limited to the hippocampal formation does not impair nonconscious (nondeclarative) memory. Further, the data do not contradict the idea that hippocampus dependent memory is accessible to conscious recollection. Finally, perceptual learning was impaired in patients, with extensive damage to the medial temporal lobe and with additional variable damage to lateral temporal cortex.
11780150	The present paper exposes the arguments against considering memory as a monolytic entity and how is it to be divided into several systems in order to understand its operation. Historically this division was acknowledge by different authors but in the last few decades it received the confirmation from the scientific research. The most accepted taxonomy establishes the existence of two major memory systems: declarative and non declarative memory. The article also presents the arguments for and against this kind of division, as well as an alternative classification in five major systems: procedural, perceptual representation, semantic, primary and episodic.
11778635	This study tested the question of whether executive failure associated with frontal lobe deficit is associated with, and therefore, may influence declarative memory dysfunction in Parkinson's disease (PD). A variety of memory and 'frontal sensitive' tasks were used. The 'frontal lobe dysfunction' hypothesis was tested in part, by examining the serial position effects (SPE) of word list learning across five successive trials. The relationship between memory and 'frontal sensitive' task scores was tested also. A total of 39 PD patients early in the course of the disease and 31 matched controls were included in the study. The PD subjects showed mild memory deficits in comparison to the healthy control group. In the face of any hypothesized selective 'dysexecutive' syndrome in PD group, the latter groups learning strategy across five trials did not differ from that of the control group. Also, the expected interrelation between memory and 'frontal sensitive' scores was not obtained. Therefore, the hypothesis that frontal dysfunction alone may account for memory impairments in PD is not fully supported.
11770919	The authors performed this study to assess brain activation during encoding and successful recall with a declarative memory paradigm that has previously been demonstrated to be effective for teaching students about the cranial nerves.Twenty-four students underwent functional magnetic resonance (MR) imaging during encoding and recall of the name, number, and function of the 12 cranial nerves. The students viewed mnemonic graphic and text slides related to individual nerves, as well as their respective control slides. For the recall paradigm, students were prompted with the numbers 1-12 (test condition) intermixed with the number 14 (control condition). Subjects were tested about their knowledge of cranial nerves outside the MR unit before and after functional MR imaging.	Students learned about the cranial nerves while undergoing functional MR imaging (mean post- vs preparadigm score, 8.1 +/- 3.4 [of a possible 12] vs 0.75 +/- 0.94, bilateral prefrontal cortex, left greater than right; P < 2.0 x 10(-12)) and maintained this knowledge at I week. The encoding and recall paradigms elicited distributed networks of brain activation. Encoding revealed statistically significant activation in the bilateral prefrontal cortex, left greater than right [corrected]; bilateral occipital and parietal associative cortices, parahippocampus region, fusiform gyri, and cerebellum. Successful recall activated the left much more than the right prefrontal, parietal associative, and anterior cingulate cortices; bilateral precuneus and cerebellum; and right more than the left posterior cingulate.	A predictable pattern of brain activation at functional MR imaging accompanies the encoding and successful recall of the cranial nerves with this declarative memory paradigm.	
11770918	The authors performed this study to compare a declarative memory paradigm developed to help teach medical students about the cranial nerves with a traditional text-based approach.The authors designed a clock-based paradigm to help medical students learn about the cranial nerves. To enhance memorization and related brain activation, the paradigm uses visual, spatial, and word associations in the context of an analog clock face. Twenty-one undergraduate students were randomly divided into two groups. Group T viewed traditional text slides, and group C viewed text slides followed by the corresponding cranial clock slides. Subjects were tested before and after these sessions.	Group C performed significantly better than group T in learning the names of the cranial nerves and their correct order (P < .011). Recall of name, number, and function was better for 11 of 12 cranial nerves, with statistical significance reached for nerves III (P = .005), V (P = .04), and X (P = .03).	Alternative teaching strategies may help improve declarative memory.	
11761491	Cognitive psychology research challenges traditional psychoanalytic understanding of memory. The memory of facts and events is now referred to as declarative memory. Nondeclarative memory systems, in contrast, process patterns of perception, emotion, and action without representing the past in terms of any consciously accessible content. The author examines the contributions of declarative and nondeclarative memory processes to resilience. Declarative memories can promote resilience through their capacity to evoke soothing emotional responses. Nondeclarative memory processes can foster resilience through underlying the capacity to elicit and maintain supportive relationships. The concept of nondeclarative memory has potential to inform the understanding of essential psychoanalytic phenomena, including transference, countertransference, and enactment.
11744779	This paper reports the case of a young patient with extensive pre-frontal damage in whom we tested the hypothesis that intensive training improves executive performance as assessed by the Wisconsin Card Sorting Test (WCST). As long as her declarative memory, complex perceptual abilities and global cognitive status were spared, we surmised that any deficit in executive learning would have occurred in relative isolation. We showed that her abnormal performance on the WCST, both on the standard as well as on the post-instruction condition, was due to an impairment of shifting attention across perceptual dimensions (extra-dimensional). In contrast, her ability to shift attention within perceptual categories (intra-dimensional) was spared, as were her declarative memory, object and visuospatial perception, oral language comprehension and praxis (ideomotor, tool use and constructional). This case supports the hypothesis that executive amnesia is a type of amnesic disorder distinct from the classic amnesic syndrome due to mamillo-temporomedial damage. As such, it is probably closely related to procedural learning and may depend on the same fronto-subcortical loops that mediate the actual execution of behaviour.
11742260	The hypothesis that sleep participates in the consolidation of recent memory traces has been investigated using four main paradigms: (1) effects of post-training sleep deprivation on memory consolidation, (2) effects of learning on post-training sleep, (3) effects of within sleep stimulation on the sleep pattern and on overnight memories, and (4) re-expression of behavior-specific neural patterns during post-training sleep. These studies convincingly support the idea that sleep is deeply involved in memory functions in humans and animals. However, the available data still remain too scarce to confirm or reject unequivocally the recently upheld hypothesis that consolidations of non-declarative and declarative memories are respectively dependent upon REM and NREM sleep processes.
11739825	Lesions of the thalamus interfere with cognitive functions mainly in the area of declarative learning and memory. Little is known about the role the thalamus plays in implicit learning.To study explicit and implicit learning and memory in subjects with thalamic lesions and to analyze the influence of lesion characteristics on cognitive performance.	The authors studied the performance of 15 subjects with focal thalamic infarction or hemorrhage on a comprehensive neuropsychological test battery focusing on tests of explicit memory and learning of a nondeclarative motor skill. Subjects with thalamic lesions were compared to 15 healthy matched control subjects and to a clinical control group of 22 subjects who had sustained basal ganglia lesions.	Subjects with thalamic lesions showed well-preserved intellectual and executive functions but demonstrated deficits on measures of attention and psychomotor speed, explicit memory, and implicit visuomotor sequence learning. Lesion size in the thalamus was clearly related to subjects' long-term explicit memory performance. However, few of the neuropsychological deficits found seemed specific to the long-term neuropsychological outcome of focal thalamic infarctions. Subjects with lesions in the basal ganglia demonstrated similar deficits.	Focal subcortical lesions in the thalamus and the basal ganglia lead to a similar profile of neuropsychological deficits. Lesions in the thalamus not only affect declarative memory but also interfere with nondeclarative motor skill learning.	
11738547	In a case of Fahr's disease with frontal lobe type dementia and hyperkinetic-hypotone syndrome, functional changes were investigated using positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) as a tracer. Computed tomography showed bilateral calcifications in the putamen and globus pallidus consistent with the diagnosis of Fahr's disease and a frontally pronounced brain atrophy. In contrast, reduced glucose uptake in PET was not only confined to the areas mentioned above, but extended to the temporal and parietal cortices, bilaterally. These functional changes corresponded to the neuropsychological deficits observed, i.e. disturbed selective attention and cognitive flexibility, verbal perseverations, and declarative memory deficits. It is suggested that functional changes may precede cerebral atrophy in Fahr's disease and may reflect deficits in functional circuits, which involve both the basal ganglia and the frontal, parietal, and temporal lobes.
11734855	Learning and memory in humans rely upon several memory systems, which appear to have dissociable brain substrates. A fundamental question concerns whether, and how, these memory systems interact. Here we show using functional magnetic resonance imaging (FMRI) that these memory systems may compete with each other during classification learning in humans. The medial temporal lobe and basal ganglia were differently engaged across subjects during classification learning depending upon whether the task emphasized declarative or nondeclarative memory, even when the to-be-learned material and the level of performance did not differ. Consistent with competition between memory systems suggested by animal studies and neuroimaging, activity in these regions was negatively correlated across individuals. Further examination of classification learning using event-related FMRI showed rapid modulation of activity in these regions at the beginning of learning, suggesting that subjects relied upon the medial temporal lobe early in learning. However, this dependence rapidly declined with training, as predicted by previous computational models of associative learning.
11728836	Evidence for neuropsychological deficits in schizophrenia is substantial whereas evidence for the specificity of dysfunction is relatively sparse. To assess specificity, we compared neuropsychological function in patients with chronic schizophrenia, patients with chronic psychotic bipolar disorder and normal controls. Groups were comparable on age, ethnicity and expected intellectual ability (based on single word reading). Patients with schizophrenia and bipolar psychoses were also relatively similar on age at onset and number of hospitalizations. Using multivariate analyses of variance with sex and parental SES as covariates (our primary analyses), patients with schizophrenia were significantly more impaired than controls on seven of eight neuropsychological functions (all but verbal ability), and were significantly more impaired than bipolar patients on abstraction, perceptual-motor speed and vigilance. Bipolar patients were significantly impaired compared to controls on declarative verbal memory, and showed moderate-to-large effect size decrements on abstraction, perceptual-motor speed and vigilance. Results were not attenuated when IQ was controlled, which was significantly lower in patients with schizophrenia. Analyses indicated that the two psychiatric groups had similar profile patterns, but that patients with schizophrenia had a more severe impairment than patients with bipolar psychoses. Further research is required to determine whether similar mechanisms underly the neurocognitive deficits in these disorders.
11723264	The assessment of mesial temporal lobe (MTL) function is important for the diagnosis and treatment of temporal lobe epilepsy (TLE) and other brain diseases. Declarative memory depends on the integrity of the MTL region.To investigate hemispheric asymmetries of MTL activity in patients with symptomatic TLE.	With use of blood oxygenation level-dependent fMRI, hemispheric asymmetries in MTL activation of 30 individual patients with refractory symptomatic TLE and 17 healthy control subjects were studied. Activation was induced by a task employing mental navigation and recall of landmarks based on the retrieval of individually familiar visuospatial knowledge.	The study demonstrated that the memory task used reliably activated MTL structures in individual control subjects and patients with refractory TLE including children, older subjects, and patients with low formal IQ. Interhemispheric differences in MTL activation lateralized the side of seizure onset in 90% of patients with symptomatic unilateral TLE. In contrast, healthy control subjects did not show a systematic asymmetry of MTL activation. Correlations between MTL activation and neuropsychological measures suggest that the fMRI-detectable MTL changes were specifically related to memory rather than to memory-independent visuospatial abilities.	fMRI of memory-induced MTL activation lateralizes the side of seizure onset in patients with refractory symptomatic TLE and may provide complementary information for presurgical evaluation.	
11718892	It is widely accepted that the hippocampus and related brain areas mediate declarative (or explicit) memory in humans. However, little is known about the fundamental cognitive mechanisms of hippocampal dependent memory or about the nature of hippocampal neural representations that underlie properties of declarative memory. Here, it is proposed that the hippocampus plays a critical role, when distinct personal experiences must be encoded in relation to one another and linked within an organization that supports flexible, inferential memory expression. This set of fundamental cognitive mechanisms is consistent with key properties of declarative memory as observed in humans. Furthermore, emerging evidence from recordings of hippocampal neural activity shows that hippocampal networks encode episodic memories as sequences of events and the places, where they occur. In addition, hippocampal neuronal networks encode events and places that are common across related episodes. This combination of coding properties suggests that the hippocampus contributes to declarative memory by mediating the construction of a "memory space" composed of a network of linked episodic representations.
11718887	The long held view that the hippocampal formation is not only essential, but also solely responsible for declarative memory in humans (and by analogy non-human primates) has come into question. Based on extensive reciprocal connection patterns between the hippocampal formation and the orbitoventromedial prefrontal cortex in primates and rats, a central role for the hippocampal formation in the attentional control of behavior is emerging. In this paper, evidence is reviewed showing that the hippocampal-orbitomedial prefrontal cortex circuit may be involved in attentional monitoring of the internal sensorium. This attentional monitoring system, in a sense, is the working memory of viscero-emotional processing. The hippocampal formation can thus be viewed as a discrepancy detector with respect to the relative activational status of cognitive/emotional set in the orbitomedial prefrontal cortex. Discrepancies between the current representation of the internal milieu and the "just-prior" representation held "on-line" in orbitomedial prefrontal cortex associative working memory, are signaled from the hippocampus to the prefrontal cortex prospective attentional systems to activate, process, and reconcile internal (past) with external (present) environments, and finally to effectively alter active working emotional "sets" to exert cognitive-emotional control of behavior.
11712845	The present article deals with theoretical and experimental aspects of language representation in the multilingual brain. Two general approaches were adopted in the study of the bilingual brain. The study of bilingual aphasics allows us to describe dissociations and double dissociations between the different subcomponents of the various languages. Furthermore, symptoms peculiar to bilingual aphasia were reported (pathological mixing and switching and translations disorders) which allowed the correlation of some abilities specific to bilinguals with particular neurofunctional systems. Another approach to the study of the bilingual brain is of the experimental type, such as electrophysiological investigations (electrocorticostimulation during brain surgery and event-related potentials) and functional neuroanatomy studies (positron emission tomography and functional magnetic resonance imaging). Functional neuroanatomy studies investigated the brain representation of languages when processing lexical and syntactic stimuli and short stories. Neurophysiologic and neuroimaging studies evidenced a similar cerebral representation of L1 and L2 lexicons both in early and late bilinguals. The representation of grammatical aspects of languages seems to be different between the two languages if L2 is acquired after the age of 7, with automatic processes and correctness being lower than those of the native language. These results are in line with a greater representation of the two lexicons in the declarative memory systems, whereas morphosyntactic aspects may be organized in different systems according to the acquisition vs learning modality.
11697943	Neuroanatomic substrates of specific cognitive functions have been inferred from anatomic distributions of activated pixels during fMRI studies. With declarative memory tasks, interest has focused on the extent to which various medial temporal lobe anatomic structures are activated while subjects encode new information. The aim of this project was to examine how commonly used variations in fMRI data processing methods affect the distribution of activation in anatomically defined medial temporal lobe regions of interest (ROIs) during a complex scene-encoding task. ROIs were drawn on an MRI anatomic template formed from 3D SPGR scans of eight subjects combined in Talairach space. Separate ROIs were drawn for the posterior and anterior hippocampal formation, parahippocampal gyrus, and entorhinal cortex. Twelve different activation maps were created for each subject by using four correlation coefficients and three cluster volumes. Friedman's two-way ANOVA by ranks was used to test the hypothesis that the distribution of activated pixels among defined anatomic ROIs varied as a function of the data processing method. By simply varying the combination of correlation coefficient and cluster volume, significantly different distributions of activation within named medial temporal lobe structures were obtained from the same fMRI datasets (P < 0.015; P < 0.001). The number of subjects studied (n = 8) is in a range commonly found in the literature yet this clearly resulted in spurious associations between processing parameter variations and activation distribution. Using data processing methods that are independent of the arbitrary selection of cutoff values for thresholding activation maps may reduce the likelihood of obtaining spurious results.
11697519	Cognitive syndromes are common clinical manifestations of hyperacute stroke and may be the single or dominant presenting features. They are related to acute dysfunction of complex integrated distributed functional networks serving different cognitive domains. The most common cortical syndromes include nonfluent or fluent aphasia, neglect, collor agnosia, pure alexia and Balint's syndrome. Disturbances of declarative memory are common following posterior cerebral artery and thalamic strokes. Abulia can follow thalamic, caudate and capsular lesions. Intraventricular and subarachnoid haemorrhages can cause preeminent neuropsychological changes. Disorientation is present in about 40% of acute stroke patients and delirium complicates the course of 25% of acute strokes. Some hyperacute cognitive stroke syndromes are useful indicators of later disability. Cognitive syndromes may pose special difficulties to neurology residents, unless formal teaching in neuropsychology and psychiatry is included in their training programs.
11694886	In humans, distinct processes within the hippocampus and rhinal cortex support declarative memory formation. But do these medial temporal lobe (MTL) substructures directly cooperate in encoding new memories? Phase synchronization of gamma-band electroencephalogram (EEG) oscillations (around 40 Hz) is a general mechanism of transiently connecting neural assemblies. We recorded depth-EEG from within the MTL of epilepsy patients performing a memorization task. Successful as opposed to unsuccessful memory formation was accompanied by an initial elevation of rhinal-hippocampal gamma synchronization followed by a later desynchronization, suggesting that effective declarative memory formation is accompanied by a direct and temporarily limited cooperation between both MTL substructures.
11666044	Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer's disease (AD) profoundly disrupts the hippocampaL cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.
11584932	A fundamental capacity of the human brain is to learn relations (contingencies) between environmental stimuli and the consequences of their occurrence. Some contingencies are probabilistic; that is, they predict an event in some situations but not in all. Animal studies suggest that damage to limbic structures or the prefrontal cortex may disturb probabilistic learning. The authors studied the learning of probabilistic contingencies in amnesic patients with limbic lesions, patients with prefrontal cortex damage, and healthy controls. Across 120 trials, participants learned contingent relations between spatial sequences and a button press. Amnesic patients had learning comparable to that of control subjects but failed to indicate what they had learned. Across the last 60 trials, amnesic patients and control subjects learned to avoid a noncontingent choice better than frontal patients. These results indicate that probabilistic learning does not depend on the brain structures supporting declarative memory.
11584931	In humans, the emotional nature of stimuli appears to have a complex influence on long-term declarative memory for those stimuli: Whereas emotion enhances memory for gist, it may suppress memory for detail. On the basis of prior studies, the authors hypothesized that the amygdala helps mediate the above 2 effects. Long-term memory for gist and for visual detail of aversive and neutral scenes was assessed in 20 subjects with unilateral amygdala damage and 1 rare subject with bilateral amygdala damage. Comparisons with 2 control groups (15 brain-damaged and 47 healthy) provided evidence that bilateral, but not unilateral, damage to the amygdala results in poorer memory for gist but superior memory for visual details. The pattern of findings provides preliminary support for the idea that the amygdala may help filter the encoding of relevant information from stimuli that signal threat or danger.
11584309	What are the psychological, computational and neural underpinnings of language? Are these neurocognitive correlates dedicated to language? Do different parts of language depend on distinct neurocognitive systems? Here I address these and other issues that are crucial for our understanding of two fundamental language capacities: the memorization of words in the mental lexicon, and the rule-governed combination of words by the mental grammar. According to the declarative/procedural model, the mental lexicon depends on declarative memory and is rooted in the temporal lobe, whereas the mental grammar involves procedural memory and is rooted in the frontal cortex and basal ganglia. I argue that the declarative/procedural model provides a new framework for the study of lexicon and grammar.
11580003	The purpose of this study was to examine the relationship between dissociative symptomatology and declarative and procedural memory. Subjects were 41 consecutively admitted adolescent psychiatric patients, 13 to 19 years old. Each subject completed the Adolescent Dissociative Experiences Scale (A-DES). Declarative memory was assessed by the California Verbal Learning Test and procedural memory by the Tower of Toronto puzzle. All subjects were controlled for IQ and severity of psychiatric illness. Data analysis was done by multiple regression. Multiple regression analysis revealed a model in which 71% variance of the A-DES scores was explained by psychiatric illness and specific memory variables. This study confirms a strong interrelationship between clinical dissociation and severity of psychiatric illness. Moreover, clinical dissociation seems to be associated with specific memory dysfunctions, indicating that dissociation exerts an impact on basic information processing.
11575598	Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary brain disease with a variety of neurologic and psychiatric manifestations. We studied 3 members of a family who each had leukoencephalopathy on neuroimaging studies and a characteristic mutation for CADASIL in the notch 3 region of chromosome 19q12. In all 3 cases, neurobehavioral impairment dominated the clinical picture, and a pattern of psychiatric dysfunction heralding cognitive decline emerged. Neuropsychological evaluation revealed diverse deficits, but a profile of frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, and relatively preserved language was evident. These cases provide a cross-sectional study of the evolution of CADASIL, and suggest that, as in other diseases characterized by white matter dementia, psychiatric dysfunction may occur initially, followed by pervasive cognitive dysfunction later in the course of the disease. CADASIL should be considered in young adults with unexplained leukoencephalopathy on neuroimaging studies, and in those with neurobehavioral dysfunction and a suggestive family history.
11574902	The syndrome of dementia is most commonly caused by Alzheimer's disease (AD), an age-related neurodegenerative process that primarily affects the cortex. Approximately 4 million Americans carry the diagnosis, and the number is expected to rise to 14 million by the year 2040. Affected individuals suffer multiple cognitive deficits that progressively affect the ability to communicate. Typically the earliest symptom is impairment of episodic memory, but other forms of declarative memory are ultimately impaired. To understand the communication problems of individuals with Alzheimer's, clinicians need to understand disease effects on knowledge stores and cognitive and memory processes. Using spared memory systems and less effortful cognitive processes to compensate for impaired stores and processes is the primary means by which optimal care can be provided. Recent advances in our understanding of disease effects on semantic memory suggest a greater potential for habilitation than previously thought. In this article, the neuropathology of AD is reviewed, effects on cognitive and communicative functions are specified, and principles for providing optimal patient care are discussed.
11562858	The hippocampus and the striatum have been proposed as respectively cerebral substrates of declarative and procedural memory. Both structures are vulnerable to traumatic brain injury. Although declarative and procedural memory have been reported to be impaired in traumatic brain injury (TBI), volumetric measures have so far failed to associate this impairment with atrophy of hippocampal and striatal structures. In our study, we investigated the profile of declarative and procedural memory in children who suffered from moderate to severe traumatic brain injury during childhood (injury test interval: 9.42+/-1.98 years).Nineteen patients and matched controls were evaluated on tests of declarative memory and motor learning. Results showed that TBI subjects exhibit poorer performance in both tasks. Moreover, structural magnetic resonance images were obtained from TBI subjects. In order to relate neuropsychological performance with hippocampal and neostriatal volumetric data, correlation analyses were performed.	Significant positive correlations were obtained between hippocampal volume and memory for objects. Striatal volume correlated positively with motor learning and with verbal memory.	It thus seems that plasticity does not completely compensate for the memory deficits resultant from neural loss in the immature brain.	
11548599	The electrophysiological responses of neurons were compared in hippocampal slices from rats acquired and not acquired the passive avoidance reaction after the same conditioning procedure. Associative conditioning was accompanied by a gradual increase in the amplitude of the population spike evoked in CA1 area by stimulation of Schaffer collaterals. However, after reaching the learning criterion, the population spike significantly decreased. These phenomena were observed only at low (not maximal) intensities of test stimuli. After reaching the learning criterion, the paired-pulse facilitation was significantly higher in the slices prepared from the well-learned animals as compared with other groups (those having not reached the learning criterion, passive and active control). The obtained evidence validates the hypothesis that the observed intergroup differences stem from modifications of synaptic efficacy and suggests that after behavioral acquisition, plasticity induced by associative learning was substituted by other mechanisms probably related with declarative memory formation.
11533222	Although it is well established that the hippocampal region is involved in the formation of declarative memory, the exact nature of its involvement is unclear. One view is that the hippocampal region is involved only in tasks that require the formation or use of associations. According to this view, the hippocampal region is not involved in traditional tests of recognition memory. An alternative view is that the hippocampal region combines and extends the processing carried out by structures in the parahippocampal gyrus and that it is involved in all forms of declarative memory, including recognition memory. Using event-related functional magnetic resonance imaging (fMRI), we observed hippocampal activity during both traditional and associative recognition memory tasks. Critically, the hippocampal region was no more active in the associative recognition task than in the traditional recognition task.
22034198	The aging process is associated with a progressive cognitive decline, but both the extent of this decline and the profile of age-related cognitive changes remain to be clearly established. Currently, cognitive deficits associated with aging may be diagnosed under the categories of age-associated memory impairment, age-associated cognitive impairment, or the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) category of age-related cognitive decline. Age-related decline has been reported for several cognitive domains, such as language (eg, verb naming, verbal fluency), visuospatial abilities (eg, facial discrimination), executive functions (eg, set shifting, problem solving), and memory functions (eg, declarative learning, source memory). There is an age-related decline in brain cortical volume, which primarily involves association cortices and limbic regions. Studies of brain metabolic activity demonstrate an age-related decline in neocortical areas. Activation studies using cognitive tasks demonstrate that older healthy individuals have a different pattern of activation from younger subjects, suggesting thai older subjects may recruit additional brain areas in order to maintain performance.
11527373	The effects of age and time on nondeclarative and declarative memory in young and elderly were examined in a 10-year longitudinal study using tests of word-stem priming, incidental recall, free recall, and recognition. The elderly were significantly impaired on all tests, but no reliable longitudinal decrement by the elderly was detected for priming, incidental recall,or recognition. The elderly demonstrated a significant longitudinal decline in declarative memory as assessed by a test of free recall. While nondeclarative memory declines with age, the longitudinal findings are consistent with the view that declarative memory is more susceptible to the effects of aging.
11527372	Normal performance on the Tower of Hanoi puzzle by amnesic patients has been taken as support for viewing this problem solving task as having a nondeclarative memory component. Individuals in each decade of life between the 20s and 80s were asked to solve this puzzle four times in four sessions with intersession intervals from 1 to 7 days (Davis & Keller, 1998). Participants in their 70s and 80s were significantly impaired compared to participants in their 20s and 30s. The elderly were also significantly impaired on five immediate trials of a 15 words verbal recall test. Participants were readministered these tests an average of 6.6 years later for the elderly (n = 12) and 7.7 years later for the young (n = 11). For the Tower of Hanoi, the performance of the elderly, but not the young individuals, was significantly poorer than their original performance. For the verbal recall test, no significant change over time was detected for the young or elderly participants. These findings support the view that some nondeclarative and/or problem solving tasks demonstrate as great or greater decline with age than some declarative tasks.
11525339	Chronic alcoholism is associated with impairment in sustained attention and visual working memory. Thus, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks, assumed to be subserved by regions of prefrontal cortex. To identify neural substrates associated with this impairment, we used functional MRI (fMRI) to determine whether alcoholics invoke the same or different brain systems as controls when engaged in working memory tasks that the two groups were able to perform at equivalent levels. The fMRI spatial working memory paradigm instructed subjects to respond with a button press when a target position was either in the center of the field (match to center) or matched the spatial position of one presented two items previously (match 2-back) or to rest. Using whole-brain fMRI, alcoholics showed diminished activation frontal cortical systems compared to controls (bilateral dorsolateral prefrontal cortex) when responding 2-back vs rest. In the center vs rest contrast, the control group compared with the alcoholic group activated a large expanse of prefrontal cortex (including Brodmann areas 9, 10, and 45), whereas there was significantly greater activation by the alcoholic group relative to the control group localized more posteriorly and inferiorly in the frontal cortex (area 47). Examination of within group activation patterns revealed two different patterns of activation: the control group exhibited activation of the dorsal ("Where?") stream for visual spatial working memory processing, whereas the alcoholic group exhibited activation of the ventral ("What?") stream and declarative memory systems to accomplish the spatial working memory task. The differences in the pattern of brain activations exhibited by the alcoholic and control groups, despite equivalence in behavioral performance, is consistent with a functional reorganization of the brain systems invoked by alcoholic individuals or invocation of an inappropriate brain system when engaged in a visual spatial task requiring working memory.
11506662	A key claim of current theoretical analyses of the memory impairments associated with amnesia is that certain distinct forms of learning and memory are spared. Supporting this claim, B. J. Knowlton and L. R. Squire found that amnesic patients and controls were indistinguishable in their ability to learn about and classify strings of letters generated from a finite-state grammar, but that the amnesics were impaired at recognizing the training strings. We show, first, that this pattern of results is predicted by a single-system connectionist model of artificial grammar learning (AGL) in which amnesia is simulated by a reduced learning rate. We then show in two experiments that a counterintuitive assumption of this model, that classification and recognition are functionally identical in AGL, is correct. In three further simulation studies, we demonstrate that the model also reproduces another type of dissociation, namely between recognition memory and repetition priming. We conclude that the performance of amnesic patients in memory tasks is better understood in terms of a nonselective, rather than a selective, memory deficit.
11502925	The authors report the longitudinal study of a 53-year-old man with severe lobar atrophy confined to the left frontal and temporal lobes, including the left hippocampus, but sparing other cortical regions. He experienced profound cognitive deterioration, sparing only visuospatial memory. Despite these deficits, he could play golf at a high level of competence, following rules and etiquette as well as monitoring the ongoing game. The patient's golf performance may have been supported by residual visuospatial declarative memory and complex flexible implicit memory programs.
11501738	The past three decades have seen tremendous growth in our understanding of the cerebral underpinnings of schizophrenia. including the neural correlates of the cognitive impairment seen in this syndrome. In this article we review the role that structural and functional neuroimaging has played in elucidating the cerebral basis for the declarative memory deficits associated with schizophrenia. Memory impairment in schizophrenia appears to involve abnormal connectivity between the prefrontal cortex and three regions important in normal learning and memory: the hippocampus, thalamus, and cerebellum.
11487283	The link between automatic and effortful processing and nonanalytic and analytic category learning was evaluated in a sample of 29 college undergraduates using declarative memory, semantic category search, and pseudoword categorization tasks. Automatic and effortful processing measures were hypothesized to be associated with nonanalytic and analytic categorization, respectively. Results suggested that contrary to prediction strong criterion-attribute (analytic) responding on the pseudoword categorization task was associated with strong automatic, implicit memory encoding of frequency-of-occurrence information. Data are discussed in terms of the possibility that criterion-attribute category knowledge, once established, may be expressed with few attentional resources. The data indicate that attention resource requirements, even for the same stimuli and task, vary depending on the category rule system utilized. Also, the automaticity emerging from familiarity with analytic category exemplars is very different from the automaticity arising from extensive practice on a semantic category search task. The data do not support any simple mapping of analytic and nonanalytic forms of category learning onto the automatic and effortful processing dichotomy and challenge simple models of brain asymmetries for such procedures.
11477427	Long-term memory formation consists of multiple phases. A new memory is initially labile and sensitive to disruption by a variety of interfering events or agents. To become stable, this new memory undergoes a process known as consolidation, which, in the case of declarative memories, occurs within the medial temporal lobes and requires gene expression. When recalled, memories re-enter a new phase of vulnerability and seem to require a reconsolidation process in order to be maintained. Here we show that consolidation but not reconsolidation of inhibitory avoidance memory requires the expression of the transcription factor CCAAT enhancer binding protein beta (C/EBPbeta) in the hippocampus. Furthermore, in the same region, de novo protein synthesis is not essential for memory reconsolidation. C/EBPbeta is an evolutionarily conserved genetic marker that has a selective role in the consolidation of new but not reactivated memories in the hippocampus.
11476097	We tested the proposal that trace and delay eyeblink conditioning aref fundamentally different kinds of learning. Strings of one, two, three, or four trials with the conditioned stimulus (CS) alone and strings of one, two, three, or four trials with paired presentations of both the CS and the unconditioned stimulus (US) occurred in such a way that the probability of a US was independent of string length. Before each trial, participants predicted the likelihood of the US on the next trial. During both delay (n = 20) and trace (n = 18) conditioning, participants exhibited high expectation of the US following strings of CS-alone trials and low expectation of the US following strings of CS-US trials--a phenomenon known as the gambler's fallacy. During delay conditioning, conditioned responses (CRs) were not influenced by expectancy but by the associative strength of the CS and US. Thus, CR probability was high following a string of CS-US trials and low following a string of CS-alone trials. The results for trace conditioning were opposite. CR probability was high when expectancy of the US was high and low when expectancy of the US was low: The results show that trace and delay eyeblink conditioning are fundamentally different phenomena. We consider how the findings can be understood in terms of the declarative and nondeclarative memory systems that support eyeblink classical conditioning.
11469166	Declarative memory impairment is a frequent complaint of patients suffering from posttraumatic stress disorder (PTSD). We assessed memory, attention, visual spatial skills, and executive function in Vietnam combat veterans with (n = 19) and without (n = 13) PTSD. Although PTSD subjects demonstrated a "generalized impairment" relative to non-PTSD subjects on a majority of tasks, only attention and memory provided unique and independent prediction of PTSD versus non-PTSD status. Our findings suggest that memory functioning represents a neurocognitive domain of specific relevance to the development of PTSD in trauma-exposed individuals, which can be distinguished from generalized attentional impairment as well as the effects of trauma exposure severity, IQ, comorbid depression, history of alcohol use, and history of developmental learning problems.
11440756	Pervasive retrograde amnesia without anterograde memory impairment has rarely been described as a consequence of circumscribed brain damage. We report this phenomenon in a 33 yr-old, right-handed man (JG) in association with the extension in the right thalamus of a previously small, bilateral thalamic lesion. JG presented with a dense amnesia for autobiographical material more than a few years old, with some sparing of recent memories. Furthermore, he was completely unable to recognise famous people or world events. Many other aspects of semantic knowledge were intact and there was no evidence of general intellectual impairment, executive dysfunction or loss of visual imagery. Magnetic resonance imaging revealed an acute lesion in the right thalamus and two small, symmetrical, bilateral non-acute thalamic lesions. Follow-up neuropsychological assessment indicated a stable pattern of impaired retrograde and spared anterograde memory over 18 months and psychiatric assessments yielded no evidence of confabulation, malingering or other symptoms to suggest psychogenic amnesia. JG's profile indicates that the division of declarative memory into just two categories - episodic and semantic - is inadequate. Rather, his case adds to the growing body evidence to suggest that world knowledge pertaining to people and events is stored or accessed similarly to autobiographical information and differently from other types of more general factual knowledge. We hypothesize that the right mediodorsal thalamic nucleus and immediately surrounding regions comprise the central processing mechanism referred to by McClelland (Revue Neurologique, 150 (1994) 570) and Markowitsch (Brain Research Review, 21 (1995) 117) as responsible for inducing and co-ordinating the recall of these sorts of cortically stored memory engrams.
11439241	Verbal memory impairment has been well explored in schizophrenia, but it is unclear whether findings relate to the type of material to be learned or the component process required by the memory task. Also, sparse data on non-verbal memory also open the question of how well schizophrenia patients encode this material. We tested whether episodic memory performance in schizophrenia varies as a function of stimulus material (verbal/non-verbal) and determined the integrity of various component memory processes. Memory tests that differ in stimulus material (words, California Verbal Learning Test, CVLT; designs, Biber Figure Learning Test-Extended, BFLT-E) yet produce similar memory component measures were used. Subjects were 28 neuroleptic-medicated inpatients with a diagnosis of chronic schizophrenia. Results showed that both verbal and non-verbal memory performance was impaired relative to age-matched controls. Learning and recall measures were most severely impaired, with memory storage problems and impairment in recognition memory evident. On the verbal task, the relative sparing of recognition memory suggested retrieval processes, in addition to encoding processes, were disrupted. On the non-verbal task, the deficits appeared more limited to encoding. Therefore, while the operational integrity of components such as encoding were compromised regardless of material, retrieval processes showed material-specific effects. To the degree verbal and non-verbal memory functions can be lateralized in the brain, these data support the possibility of deficits in both right and left hemisphere declarative memory systems in schizophrenia.
11436246	The author reviews a contemporary cognitive psychology perspective on memory that views memory as being composed of multiple separate systems. Most researchers draw a fundamental distinction between declarative/explicit and non-declarative/implicit forms of memory. Declarative memory is responsible for the conscious recollection of facts and events--what is typically meant by the everyday and the common psychoanalytic use of the word 'memory'. Non-declarative forms of memory, in contrast, are specialised processes that influence experience and behaviour without representing the past in terms of any consciously accessible content. They operate outside of an individual's awareness, but are not repressed or otherwise dynamically unconscious. Using this theoretical framework, the question of how childhood relationship experiences are carried forward from the past to influence the present is examined. It is argued that incorporating a conceptualisation of non-declarative memory processing into psychoanalytic theory is essential. Non-declarative memory processes are capable of forming complex and sophisticated representations of the interpersonal world. These non-declarative memory processes exert a major impact on interpersonal experience and behaviour that needs to be analysed on its own terms and not mistakenly viewed as a form of resistance.
11431236	This study sought to determine the relationship of estrogen levels with psychiatric symptoms and neuropsychological function in female patients with schizophrenia.Psychiatric symptoms were assessed and average estrogen and progesterone levels from four consecutive weekly blood samples were measured in 22 female inpatients with schizophrenia who were also administered a neuropsychological battery.	There were strong positive correlations between average estrogen level and cognitive function, especially measures of global cognitive function, verbal and spatial declarative memory, and perceptual-motor speed. Correlations of hormone levels with psychiatric symptoms were nonsignificant.	Higher estrogen levels in female patients with schizophrenia are associated with better cognitive ability. These results may have implications for potential treatment of cognitive dysfunction with adjunctive estrogen in female patients with schizophrenia.	
11427332	After an era in which lesion studies have identified the declarative memory system and its essential anatomical structures, functional imaging and event-related potential studies have begun to delineate the neural underpinnings of declarative memory formation at the system level. By memory formation, we refer to those mnemonic processes present during encoding that transform perceptual representations into enduring memories. Recent studies have revealed that distinct regions in medial temporal and prefrontal areas exhibit more neural activity during successful than unsuccessful memory formation. We attempt to identify the nature of the processes underlying these subsequent memory effects. Reviewed data suggest specific mnemonic operations in the medial temporal lobe that may be integrated with semantic/perceptual operations and subserving operations in the prefrontal cortex. The formation of relational and non-relational memories may be supported by distinct subregions within these two brain regions. While the medial temporal lobe may have a serial organizational structure, with a processing hierarchy, interactions between medial temporal and prefrontal areas seem to occur in a parallel and bi-directional fashion. Interacting with this system, emotionally arousing events enhance neural activity in the amygdala, which in turn may modulate processing in other brain regions responsible for declarative memory formation.
11417924	Electroconvulsive therapy (ECT) is an effective treatment for a variety of psychiatric syndromes. However, one of its adverse secondary effects is neurocognitive dysfunction. The aim of this paper is to review different subtypes of memory dysfunction associated with ECT from a neuropsychological perspective. Declarative memory is clearly impaired after ECT. Immediate memory, however, is broadly preserved. Few studies have addressed procedural and incidental memory. Selective memory is impaired, probably due to the disruption of specific brain regions. Some of the possible neurobiological bases of ECT memory dysfunction are discussed in this paper. Synaptic plasticity, the cerebral neurotransmission system, and cerebral metabolism are examined in relation to the dysfunction and subsequent recovery of each memory subtype.
11401885	Sleep-disordered breathing (SDB) has been associated with neuropsychological (NP) deficits. The extent to which such effects are attributable to unmeasured confounders or selection biases, or are manifest across a range of SDB is unclear. The relationship of SDB with a broad range of NP functions was examined in 100 volunteers with a spectrum of SDB and without underlying comorbidity. Factor analysis suggested that the NP tests could be summarized as four constructs: declarative memory, signal discrimination, working memory, and set shifting. These factors plus vigilance were dependent variables. Independent variables were age, the respiratory disturbance index (RDI), a sleepiness score, the arousal index, and sleep-associated hypoxemia. Factors "declarative memory" (measuring 25% of the common variance, alpha = 0.95), "signal discrimination" (10% variance, alpha = 0.70), and "working memory" (9% variance, alpha = 0.52) were each significantly, linearly predicted by hypoxemia and/or the RDI, with no evidence for significant threshold effects. SDB measures accounted for 4-6% of the variance in NP constructs. In contrast, sleepiness best predicted vigilance. Thus, adverse exposures (hypoxemia or RDI) during sleep may negatively influence NP functions in a dose-response relationship, and, other than vigilance, these effects may not be directly attributable to sleepiness.
11373680	Surgical, pharmacological and genetic lesion studies have revealed distinct anatomical sites involved with different forms of learning. Studies of patients with localized brain damage and work in rodent model systems, for example, have shown that the hippocampal formation participates in acquisition of declarative tasks but is not the site of their long-term storage. Such lesions are usually irreversible, however, which has limited their use for dissecting the temporal processes of acquisition, storage and retrieval of memories. Studies in bees and flies have similarly revealed a distinct anatomical region of the insect brain, the mushroom body, that is involved specifically in olfactory associative learning. We have used a temperature-sensitive dynamin transgene, which disrupts synaptic transmission reversibly and on the time-scale of minutes, to investigate the temporal requirements for ongoing neural activity during memory formation. Here we show that synaptic transmission from mushroom body neurons is required during memory retrieval but not during acquisition or storage. We propose that the hebbian processes underlying olfactory associative learning reside in mushroom body dendrites or upstream of the mushroom body and that the resulting alterations in synaptic strength modulate mushroom body output during memory retrieval.
11373065	Neuropsychological studies of amnesic patients, cognitive studies of normal individuals, and functional neuroimaging studies have shaped our understanding of the cognitive and neural bases of various forms of human memory. This article reviews the functional and neural characteristics of working memory, declarative memory, and nondeclarative memory. In so doing, it highlights the pattern of impaired and preserved memory abilities that characterize different neurologic populations. This knowledge provides a framework for analyzing patients' neuropsychological deficits in terms of underlying cognitive processes.
11345956	From Day 2 to Day 4 of life, chicks were fed daily in a large enclosure with 2 identical food caches, each filled with a different type of seed. On Day 5, binocular and monocular chicks were fed in their home cages 1 type of seed exclusively for 30 min. At test, soon after this devaluation phase, both binocular and right-eyed chicks chose the food caches containing the seeds that had not been devalued; in contrast, left-eyed chicks did not show a clear choice. Experiments revealed that the asymmetry was not due to lack of motivation, worse spatial memory, or inability to remember the consequences of devaluation by left-eyed chicks. Results suggest that young chicks can form declarative-like memories of the content of food caches. However, chicks using their left eye (which provides a supply mainly to the right hemisphere) failed to integrate memory of the content of food caches with memory of the consequences of devaluation.
11345124	Rats with ibotenic acid lesions of the hippocampus (H-IBO) were trained on the trial-unique delayed nonmatching-to-sample task (DNMS) using a short delay of 4 s. The H-IBO group learned the nonmatching rule as quickly as control animals. However, performance was impaired on the DNMS task when the delay between the sample and choice phase was increased to 1 or 2 min. The use of 4-s delay (probe) trials indicated that the H-IBO animals retained the nonmatching-to-sample rule throughout testing. In a second experiment, using the same groups of rats, extended training at the 1-min delay did not ameliorate the deficit produced by H-IBO lesions. The finding of impaired recognition memory in rats after hippocampal lesions is consistent with findings from humans and monkeys. Several methodological issues are considered that have complicated the interpretation of earlier studies of recognition memory in rats following hippocampal lesions. The capacity for recognition memory in humans, monkeys, and rodents is discussed as a straightforward example of hippocampus-dependent (declarative) memory.
11335704	Previous work has identified the prefrontal cortex (PFC) and striatum as participating in the planning and selection of movements. We compared the brain activation patterns during planning in Parkinson's disease patients and age-matched controls using H(2)(15)O-PET and the Tower of London (TOL) task. In this study, our mildly affected Parkinson's disease group performed as well as the control group but showed a different pattern of neuronal activation. In the two groups, overlapping areas of the PFC were activated but, whereas the right caudate nucleus was activated in the control group, this was not evident in the Parkinson's disease patients. This suggests that normal normal frontal lobe activation can occur in Parkinson's disease despite abnormal processing within the basal ganglia. Moreover, right hippocampus activity was suppressed in the controls and enhanced in the Parkinson's disease patients. This could represent a shift to the declarative memory system in Parkinson's disease during performance of the TOL task, possibly resulting from insufficient working memory capacity within the frontostriatal system.
11330203	A role for sleep in memory processes and neural plasticity has been suggested many times and in many different forms. However, we are far from a consensus on what this role might be and why it would be fulfilled preferentially by sleep. In this review, we distinguish between memory acquisition, consolidation, and maintenance, and we consider how sleep may specifically contribute to each of these phases. We also distinguish between declarative and nondeclarative memories and their relationships to different stages of sleep. Finally, we discuss whether different molecular and cellular aspects of neural plasticity may be associated preferentially with different behavioral states. A consideration of such molecular aspects could lead to more conclusive experiments concerning the relationship between sleep and plasticity.
11320217	Fibroblast growth factor-2 (FGF-2) promotes proliferation of neuroprogenitor cells in culture and is up-regulated within brain after injury. Using mice genetically deficient in FGF-2 (FGF-2(-/-) mice), we addressed the importance of endogenously generated FGF-2 on neurogenesis within the hippocampus, a structure involved in spatial, declarative, and contextual memory, after seizures or ischemic injury. BrdUrd incorporation was used to mark dividing neuroprogenitor cells and NeuN expression to monitor their differentiation into neurons. In the wild-type strain, hippocampal FGF-2 increased after either kainic acid injection or middle cerebral artery occlusion, and the numbers of BrdUrd/NeuN-positive cells significantly increased on days 9 and 16 as compared with the controls. In FGF-2(-/-) mice, BrdUrd labeling was attenuated after kainic acid or middle cerebral artery occlusion, as was the number of neural cells colabeled with both BrdUrd and NeuN. After FGF-2(-/-) mice were injected intraventricularly with a herpes simplex virus-1 amplicon vector carrying FGF-2 gene, the number of BrdUrd-labeled cells increased significantly to values equivalent to wild-type littermates after kainate seizures. These results indicate that endogenously synthesized FGF-2 is necessary and sufficient to stimulate proliferation and differentiation of neuroprogenitor cells in the adult hippocampus after brain insult.
11309674	Patients who sustained closed-head injury (CHI) have been shown to have impaired memory for temporal order when measured under intentional, but not incidental, retrieval conditions. A group of 26 patients who sustained CHI and a matched control group of 26 individuals were tested on a declarative sequence learning task--"Chain Making" (CM), and a nondeclarative sequence learning task--Tower of Hanoi puzzle (TOHP). The TOHP is a problem solving task that requires planning and a strategic approach. The latter are cognitive processes known to be impaired following frontal lobe damage, as has been frequently documented in CHI patients. The goal of the present study was to test whether CHI patients' nondeclarative learning as measured by the TOHP task is preserved, as seen in amnesic patients, or impaired, as would be predicted following frontal lobe damage. Half of the participants in each group underwent active training, and the other half went through passive training of the tasks. The results demonstrate that the control group outperformed the CHI group (in most measures) in both declarative and nondeclarative sequence learning tasks. The effect of type of training differed for the two tasks: while performance of the control group on the TOHP was better under passive training (CHI patients did not improve on either one of the training modes), performance on the CM task was better under active training for both groups. The results are discussed in light of the role of the frontal lobes in memory generally, and in sequence learning particularly.
11302360	Novice (Experiment 1) and experienced (Experiment 2) young, middle-aged, and older adults learned a new word-processing application in keystrokes, menus, or menus-plus-icons interface conditions. Novices showed strong age differences in the time to complete the 3-day tutorial and in declarative and procedural tests of word-processing knowledge. Menus and menus-plus-icons were superior to keystrokes condition. though interface did not interact with age. Experienced users showed age-related slowing in learning rate but minimal age differences in test performance when retrained on a new word-processing program. Age and computer experience accounted for much of the variance in both learning time and word-processing performance; interface type, speed of processing, and spatial generation ability made additional contributions. Experience interacted with age to predict performance. Implications for training and retraining older workers are discussed.
11301570	The implicit-explicit distinction is applied to knowledge representations. Knowledge is taken to be an attitude towards a proposition which is true. The proposition itself predicates a property to some entity. A number of ways in which knowledge can be implicit or explicit emerge. If a higher aspect is known explicitly then each lower one must also be known explicitly. This partial hierarchy reduces the number of ways in which knowledge can be explicit. In the most important type of implicit knowledge, representations merely reflect the property of objects or events without predicating them of any particular entity. The clearest cases of explicit knowledge of a fact are representations of one's own attitude of knowing that fact. These distinctions are discussed in their relationship to similar distinctions such as procedural-declarative, conscious-unconscious, verbalizable-nonverbalizable, direct-indirect tests, and automatic-voluntary control. This is followed by an outline of how these distinctions can be used to integrate and relate the often divergent uses of the implicit-explicit distinction in different research areas. We illustrate this for visual perception, memory, cognitive development, and artificial grammar learning.
11291183	Our use of language depends upon two capacities: a mental lexicon of memorized words and a mental grammar of rules that underlie the sequential and hierarchical composition of lexical forms into predictably structured larger words, phrases, and sentences. The declarative/procedural model posits that the lexicon/grammar distinction in language is tied to the distinction between two well-studied brain memory systems. On this view, the memorization and use of at least simple words (those with noncompositional, that is, arbitrary form-meaning pairings) depends upon an associative memory of distributed representations that is subserved by temporal-lobe circuits previously implicated in the learning and use of fact and event knowledge. This "declarative memory" system appears to be specialized for learning arbitrarily related information (i.e., for associative binding). In contrast, the acquisition and use of grammatical rules that underlie symbol manipulation is subserved by frontal/basal-ganglia circuits previously implicated in the implicit (nonconscious) learning and expression of motor and cognitive "skills" and "habits" (e.g., from simple motor acts to skilled game playing). This "procedural" system may be specialized for computing sequences. This novel view of lexicon and grammar offers an alternative to the two main competing theoretical frameworks. It shares the perspective of traditional dual-mechanism theories in positing that the mental lexicon and a symbol-manipulating mental grammar are subserved by distinct computational components that may be linked to distinct brain structures. However, it diverges from these theories where they assume components dedicated to each of the two language capacities (that is, domain-specific) and in their common assumption that lexical memory is a rote list of items. Conversely, while it shares with single-mechanism theories the perspective that the two capacities are subserved by domain-independent computational mechanisms, it diverges from them where they link both capacities to a single associative memory system with broad anatomic distribution. The declarative/procedural model, but neither traditional dual- nor single-mechanism models, predicts double dissociations between lexicon and grammar, with associations among associative memory properties, memorized words and facts, and temporal-lobe structures, and among symbol-manipulation properties, grammatical rule products, motor skills, and frontal/basal-ganglia structures. In order to contrast lexicon and grammar while holding other factors constant, we have focused our investigations of the declarative/procedural model on morphologically complex word forms. Morphological transformations that are (largely) unproductive (e.g., in go-went, solemn-solemnity) are hypothesized to depend upon declarative memory. These have been contrasted with morphological transformations that are fully productive (e.g., in walk-walked, happy-happiness), whose computation is posited to be solely dependent upon grammatical rules subserved by the procedural system. Here evidence is presented from studies that use a range of psycholinguistic and neurolinguistic approaches with children and adults. It is argued that converging evidence from these studies supports the declarative/procedural model of lexicon and grammar.
11279851	Ovarian steroids have numerous effects on the brain throughout the life span, beginning during gestation and continuing into senescence. Ovarian steroids have widespread effects on catecholaminergic neurons and serotonergic pathways and on the basal forebrain cholinergic system. Another important action of ovarian hormones is the regulation of synapse turnover in the hippocampus as exhibited during the fourth or fifth day of a female rat's estrus cycle. In the human brain, estrogen replacement therapy is associated with improvements in episodic and declarative memory, which depend on the hippocampus, and is involved in the processing of emotional information. Because of their widespread influences on neuronal systems, ovarian steroids are important factors to consider in the treatment of depressive illness.
11274654	Declarative memory changes are the hallmark of Alzheimer's disease, although their functional neuroanatomy is not restricted to a single structure. Factor analysis provides statistical methods for evaluating patterns of cerebral changes in regional glucose uptake.Thirty-three Alzheimer's patients and 33 age- and gender-matched control subjects were studied with magnetic resonance imaging and positron emission tomography with [(18)F] deoxyglucose. During the tracer-uptake period, subjects performed a serial verbal learning task. Cortical activity was measured in 32 regions of interest, four in each lobe on both hemispheres.	Factor analysis with varimax rotation identified seven factors explaining 80% of the variance ("parietal cortex," "occipital cortex," "right temporo-prefrontal areas," "frontal cortex," "motor strip," "left temporal cortex," and "posterior temporal cortex"). Relative to control subjects, Alzheimer's patients showed significantly reduced values on the factors occipital cortex, right temporo-prefrontal areas, frontal cortex, and left temporal cortex. The factor temporo-prefrontal areas showed large differences between patients with good and poor performance, but little difference when control subjects were similarly divided.	Findings suggest that Alzheimer's disease is characterized by altered patterns of cortical activity, rather than deficits in a single location, and emphasize the importance of right temporo-prefrontal circuitry for understanding memory deficits.	
11268212	Freud proposed that unwanted memories can be forgotten by pushing them into the unconscious, a process called repression. The existence of repression has remained controversial for more than a century, in part because of its strong coupling with trauma, and the ethical and practical difficulties of studying such processes in controlled experiments. However, behavioural and neurobiological research on memory and attention shows that people have executive control processes directed at minimizing perceptual distraction, overcoming interference during short and long-term memory tasks and stopping strong habitual responses to stimuli. Here we show that these mechanisms can be recruited to prevent unwanted declarative memories from entering awareness, and that this cognitive act has enduring consequences for the rejected memories. When people encounter cues that remind them of an unwanted memory and they consistently try to prevent awareness of it, the later recall of the rejected memory becomes more difficult. The forgetting increases with the number of times the memory is avoided, resists incentives for accurate recall and is caused by processes that suppress the memory itself. These results show that executive control processes not uniquely tied to trauma may provide a viable model for repression.
11262738	Memory processing in humans is essential for consciousness, cognitive-behavioral development and individual biography. In epilepsy, declarative memory functions show characteristic patterns of impairment when mesiotemporal and associated neocortical structures are affected by lesions, ongoing epileptic activity, or the undesired effects of conservative or operative treatment. Major issues are thus the etiology, onset and course of memory impairment, as well as the prevention of further memory decline during treatment. New input in the field has resulted from improved imaging techniques, sophisticated experimental study designs, more selective surgical approaches, and new antiepileptic drugs.
11252767	Recent neurobiological studies have begun to reveal the cognitive and neural coding mechanisms that underlie declarative memory--our ability to recollect everyday events and factual knowledge. These studies indicate that the critical circuitry involves bidirectional connections between the neocortex, the parahippocampal region and the hippocampus. Each of these areas makes a unique contribution to memory processing. Widespread high-order neocortical areas provide dedicated processors for perceptual, motor or cognitive information that is influenced by other components of the system. The parahippocampal region mediates convergence of this information and extends the persistence of neocortical memory representations. The hippocampus encodes the sequences of places and events that compose episodic memories, and links them together through their common elements. Here I describe how these mechanisms work together to create and re-create fully networked representations of previous experiences and knowledge about the world.
11243040	27 patients aged 47-64 years with left hemispheric ischemic stroke with similar cognitive and educational levels were examined. Pharmacotherapy of the stroke directed to improvement of both memory and thinking was taken into consideration. To evaluate both different kinds of memory and a degree of the cognitive functions' impairments in the patients with a local ischemic stroke in anterior, posterior and middle parts of the left hemisphere the following tests were used: evaluation of both the immediate memory of the digits and the short-term audio-verbal memory; short-term trials of the pathological action of interference; Benton test, Meily test; evaluation of the declarative, procedure, semantic, strategic, mediated, long-term kinds of memory. It is shown that remembering of the new information concerning verbal names, digits, was worse in mediobasal, frontal and temporal location of the stroke in the left hemisphere and depended on clinical manifestations of the disorders. The working semantic and strategic kinds of the memory were also damaged, while long-term memory (autobiographic, professional) was impaired in less degree.
11220740	Layer II of the entorhinal cortex contains the cells of origin for the perforant path, plays a critical role in memory processing, and consistently degenerates in end-stage Alzheimer's disease. The extent to which neuron loss in layer II of entorhinal cortex is related to mild cognitive impairment without dementia has not been extensively investigated. We analyzed 29 participants who came to autopsy from our ongoing longitudinal study of aging and dementia composed of religious clergy (Religious Orders Study). All individuals underwent detailed clinical evaluation within 12 months of death and were categorized as having no cognitive impairment (n = 8), mild cognitive impairment (n = 10), or mild or moderate Alzheimer's disease (n = 11). Sections through the entorhinal cortex were immunoreacted with an antibody directed against a neuron-specific nuclear protein (NeuN). Stereological counts of NeuN-immunoreactive stellate cells, their volume, and the volume of layer II entorhinal cortex were estimated. Cases exhibiting no cognitive impairment averaged 639,625 +/- 184,600 layer II stellate neurons in the right entorhinal cortex. Individuals with mild cognitive impairment (63.5%; p < 0.0003) and mild or moderate Alzheimer's disease (46.06%; p < 0.0017) displayed significant losses of layer II entorhinal cortex neurons relative to those with no cognitive impairment but not relative to each other (p > 0.33). There was also significant atrophy of layer II entorhinal cortex neurons in individuals with mild cognitive impairment (24.1%) and Alzheimer's disease (25.1%). The volume of layer II was also reduced in individuals with mild cognitive impairment (26.5%), with a further reduction in those with Alzheimer's disease (46.4%). The loss and atrophy of layer II entorhinal cortex neurons significantly correlated with performance on clinical tests of declarative memory. Atrophy of layer II entorhinal cortex and the neurons within this layer significantly correlated with performance on the Mini Mental Status Examination. These data indicate that atrophy and loss of layer II entorhinal cortex neurons occur in elderly subjects with mild cognitive impairment prior to the onset of dementia and suggests that these changes are not exacerbated in early Alzheimer's disease.
11216891	To address the controversy of whether an intact procedural memory system alone can support the learning of the recursive strategy for solving the Tower of Hanoi Puzzle, the authors tested 2 amnesic patients, H.M. and P.N. Contrary to the report of N. J. Cohen, H. Eichenbaum, B. S. Deacedo, and S. Corkin (1985), both patients failed to master the recursive strategy under the active-interaction condition. In contrast, normal control participants were able to master the strategy under identical testing conditions. The failure of H.M. and P.N. could not be attributed to the differences between the original and current testing conditions. In addition, neither patient showed frontal lobe dysfunction or impairment in procedural memory. Together with evidence provided by theoretical analyses of this puzzle as well as studies on normal participants, the authors conclude that declarative memory plays a vital role in the acquisition of the recursive strategy for solving the Tower of Hanoi Puzzle.
11202489	Eye movements were monitored to assess memory for scenes indirectly (implicitly). Two eye movement-based memory phenomena were observed: (a) the repetition effect, a decrease in sampling of previously viewed scenes compared with new scenes, reflecting memory for those scenes, and (b) the relational manipulation effect, an increase in viewing of the regions where manipulations of relations among scene elements had occurred. In normal control subjects, the relational manipulation effect was expressed only in the absence of explicit awareness of the scene manipulations. Thus, memory representations of scenes contain information about relations among elements of the scenes, at least some of which is not accessible to verbal report. But amnesic patients with severe memory impairment failed to show the relational manipulation effect. Their failure to show any demonstrable memory for relations among the constituent elements of scenes suggests that amnesia involves a fundamental deficit in relational (declarative) memory processing.
11198125	Recent findings have significantly advanced our understanding the mechanisms of memory formation. Most of these advances stemmed from behavioural pharmacology research involving, particularly, the localized infusion of drugs with specific molecular actions into specific brain regions. This approach has revealed brain structures involved in different memory types and the main neurotransmitter systems and sequence of metabolic cascades that participate in memory consolidation. Biochemical studies and, in several cases, studies of genetically manipulated animals, in which receptors or enzymes affected by the various drugs were absent or overexpressed, have complemented the pharmacological research. Although most studies have concentrated on the involvement of the hippocampus, many have also investigated the entorhinal cortex, other regions of the cortex, and the amygdala. Behavioural pharmacology has been of crucial importance in establishing the major neurohumoral and hormonal systems involved in the modulation of memory formation. These systems act on specific steps of memory formation in the hippocampus and in the entorhinal, parietal, and cingulate cortex. A specialized system mediated by the basolateral amygdaloid nucleus, and involving several neuromodulatory systems, is activated by emotional arousal and serves to regulate memory formation in other brain regions. The core mechanisms involved in the formation of explicit (declarative) memory are in many respects similar to those of long-term potentiation (LTP), particularly in the hippocampus. However, there are also important differences between memory formation and LTP. Memory formation involves numerous modulatory influences, the co-participation of various brain regions other than the hippocampus, and some properties that are specific to memory and absent in LTP (i.e. flexibility of response). We discuss the implications of these similarities and differences for understanding the neural bases of memory.
11169616	The durability of declarative memory suggests that it has either a chemical or a structural basis. Current models of long-term memory are based on the general assumption that traces of memory are stored by structural modifications of synaptic connections, resulting in alterations in the patterns of neural activity. Changes in gene expression, regulated at both the transcriptional and the translational levels, are considered essential for structural synaptic modifications. Here we present an alternative hypothesis stating that permanent memory has a chemical rather than a structural basis. We suggest that the mechanism of memory coding in the brain is similar to that in the immune system so that the permanence of memories in the nervous system is ensured at the genomic level by a somatic recombination mechanism. Thus, we hypothesize that traces of permanent declarative memory might present within cerebral neurons in the form of novel proteins coded by the modified genes. This discussion is intended to provide evidence in support of a DNA recombination mechanism for memory storage in the brain and to stimulate further research working toward the evaluation of this hypothesis.
11142642	Rats with hippocampus, medial caudoputamen (CPU), lateral CPU, or control lesions were trained on declarative and procedural knowledge variants of a novel rodent sequential learning task. Medial CPU lesions impaired rats' ability to learn the procedure of running through a sequence of open maze arms but did not disrupt their capacity to explicitly generate (i.e.. "declare") maze arm sequences. Hippocampus lesions produced the opposite set of results. Rats with lateral CPU lesions were not impaired on either version of the task. Transfer tests indicated that control rats predominantly used egocentric cues to solve the procedural task and allocentric spatial cues to solve the declarative task. These findings suggest a double dissociation between the medial CPU and hippocampus in processing egocentric-procedural and allocentric-declarative sequential information, respectively.
11127081	Various factors may contribute to cognitive deterioration in temporal lobe epilepsy, and there is controversy as to which has the greatest effect.In this study, we establish a comparison between patients with temporal lobe epilepsy controlled by drugs and drug-resistant patients, with the object of discovering the effect of different factors in causing cognitive damage.	The persons whose disorder was controlled by pharmacological means had better results in memory and intelligence tests than those with drug-resistance. The latter had alterations of declarative memory for verbal material (left) and for visio-spatial material (right) in delayed free recall tests. Also, the greater proportion of symptomatic epilepsies in the drug-resistant group affected their greater cognitive deterioration.	Our results show that having long-standing epilepsy with great frequency of seizures and symptomatic epilepsy is correlated with cognitive alterations in memory function in temporal lobe epilepsy. Most deterioration is seen in patients with long-standing drug resistant symptomatic left mesial temporal epilepsy.	
11127048	In this study neuronal correlates of encoding and retrieval in paired association learning were compared using two different neuroimaging methods: positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).6 right-handed normal male volunteers took part in the study. Each subject underwent six 0-15-butanol PET scans and on fMRI study comprising four single epochs on a different day. The subjects had to learn and retrieve 12 word pairs which were visually presented (highly imaginable words, not semantically related).	Mean recall accuracy was 93% in the PET as well as in the fMRI experiment. During encoding and retrieval we found anterior cingulate cortex activation, and bilateral prefrontal cortex activation in both imaging modalities. Furthermore, we demonstrate the importance of the precuneus in episodic memory. With PET the results demonstrate frontopolar activations whereas fMRI fails to show activations in this area probably due to susceptibility artifacts. In fMRI we found additionally parahippocampal activation and due to the whole-brain coverage cerebellar activation during encoding. The distance between the center-of-mass activations in both modalities was 7.2 +/- 6.5 mm.	There is a preponderance of commonalities in the activation patterns yielded with fMRI and PET. However, there are also important differences. The decision to choose one or the other neuroimaging modality should among other aspects depend on the study design (single subject vs. group study) and the task of interest.	
11120428	Declarative memory refers to the recall and recognition of factual information. In contrast, non-declarative memory entails a facilitation of memory based on prior exposure and is typically assessed with priming and perceptual-motor sequencing tasks. In this study, schizophrenia patients were compared to normal comparison subjects on two computerized memory tasks: the Word-stem Priming Test (n=30) and the Pattern Sequence Learning Test (n=20). Word-stem Priming includes recall, recognition (declarative) and priming (non-declarative) components of memory. The schizophrenia patients demonstrated an impaired performance on recall of words with relative improvement during the recognition portion of the test. Furthermore, they performed normally on the priming portion of the test. Thus, on tests of declarative memory, the patients had retrieval deficits with intact performance on the non-declarative memory component. The Pattern Sequence Learning Test utilizes a serial reaction time paradigm to assess non-declarative memory. The schizophrenia patients' serial reaction time was significantly slower than that of comparison subjects. However, the patients' rate of acquisition was not different from the normal comparison group. The data suggest that patients with schizophrenia process more slowly than normal, but have an intact non-declarative memory. The schizophrenia patients' dissociation on declarative vs. non-declarative memory tests is discussed in terms of possible underlying structural impairment.
11116776	In an earlier study we showed that a powerful emotional experience (the Kobe earthquake) reinforced memory retention in patients with Alzheimer's disease, but we could not control factors other than the emotional impact of the earthquake.To test our previous findings in a controlled experimental study.	Recall tests consisting of two short stories were administered to 34 patients with Alzheimer's disease and 10 normal subjects. The two stories were identical except for one passage in each story: one was emotionally charged (arousing story) and the other (neutral story) was not.	In both groups, the emotionally charged passage in the arousing story was remembered better than the counterpart in the neutral story. In addition, the extent of the memory improvement was similar in the subjects and in the controls.	The results provide further evidence that emotional arousal enhances declarative memory in patients with Alzheimer's disease, and give a clue to the management of people with dementia.	
11105102	Several studies have documented that emotional arousal may enhance long-term memory. This is an adaptation of a paradigm previously used in North American and European samples in investigations of the influence of emotion on long-term retention. A sample of 46 healthy adults of high and low educational levels watched a slide presentation of stories. A randomly assigned group watched a story with an arousing content and another group watched a neutral story. The stories were matched for structure and comprehensibility and the set and order of the 11 slides were the same in both conditions. Immediately after viewing the slide presentation, the participants were asked to rate the emotionality of the narrative. The arousing narrative was rated as being more emotional than the neutral narrative (t(44) = -3.6, P<0.001). Ten days later subjects were asked to remember the story and answer a multiple-choice questionnaire about it. The subjects who watched the arousing story had higher scores in the free recall measure (t(44) = -2.59, P<0. 01). There were no differences between groups in the multiple-choice test of recognition memory (t(44) = 0.26). These findings confirm that an emotional arousing content enhances long-term declarative memory and indicate the possibility of applying this instrument to clinical samples of various cultural backgrounds.
11104191	This study tested the role of basal ganglia in visuomotor skill learning. Thirty-nine patients early in the course of Parkinson's disease (PD) and 30 patients after operation for an aneurysm of the anterior communicating artery (ACoA) were compared with 31 matched control subjects on a Serial Reaction Time test (SRTt). The patients with PD showed impaired visuomotor skill learning across the repeating blocks, in the presence of preserved declarative knowledge of embedded sequences, in contrast to the ACoA group in whom the reverse pattern was observed. The significant correlation in patients with PD between the standard neuropsychological and motor measures and the performance observed in the skill acquisition test, in the ACoA group and control subjects was not observed. The suggestion that this learning impairment could not be attributed to a motor deficit per se was also confirmed more directly for patients with PD. Accuracy of performance after the initial learning phase on the SRTt in patients with PD was associated predominantly with visual span capacity measures. Declarative knowledge of the embedded sequence of the SRTt was correlated to general cognitive and verbal span abilities in the PD group. The impairment observed in the PD group was not the result of a general decline in cognitive functioning, mood disturbances, or the severity of the motor symptoms.
11103682	The development of symptoms of posttraumatic stress disorder (PTSD) in patients with neurogenic amnesia for the traumatic event is recorded in 2 own patients and in 19 cases from the clinical literature. With a single exception, all patients were accident victims with closed head injuries. Only about three quarters of the patients completely fulfilled DSM-III-R criteria of PTSD. Nineteen patients displayed involuntary conscious memories of aspects of the traumatic event (presenting as recurrent intrusive thoughts, images or dreams) co-existent with a complete or partial lack of voluntary conscious memories of the trauma, suggesting that different memory systems and distinct brain mechanisms subserve these phenomena. The said clinical observations are discussed against the background of current neuropsychological models of multiple memory systems. The recorded cases demonstrate that declarative episodic memory is not necessary for symptoms of PTSD to emerge, whereas preserved functions of non-declarative memory systems represent a sufficient condition for the development of PTSD symptoms.
11098724	The present work was aimed at determining, both at the psychological and at the neurobiological levels, aspects of rodent memory that fall into line with human declarative memory which is known to be selectively impaired in amnesic subjects and during the course of ageing. The ability to compare and to contrast items in memory, and to support inferential use of memories in novel situations (flexibility), were considered to be the two key psychological features of human declarative memory that were altered by both hippocampal lesions and hippocampal dysfunction. Adult and aged mice were trained on learning tasks using two-stage paradigms, the aim of which was to assess memory performance through these two psychological aspects in the same subjects. Results suggest that ageing specifically impairs the ability to both compare and contrast items in memory (declarative/relational memory based on complex associations), without altering memory based on simple S-R associations (procedural memory). Hippocampal lesions in adult mice produced the same dissociation between relational memory (impaired) and procedural memory (spared). Pharmacological experiments showed that, depending on the drug used, the relational memory deficit of aged mice may be selectively reversed (i.e. without changes in procedural memory) and that the behavioural efficacy of certain treatments was shown to parallel their potency in re-establishing normal (i.e. adult) levels of hippocampal plasticity-related mechanisms. Together with previous findings, these results suggest that the storage and use of relational representations would critically depend on the plasticity of hippocampal synapses, which via their connections with cortical areas, would support the storage of associations between perceptual, behavioral and cognitive events.
11085604	Amnesic patients and controls listened to verbal descriptions of imaginary animals and then classified novel descriptions according to whether they belonged to the studied category. Controls performed well, but the amnesic patients did not acquire categorical knowledge. These findings contrast with previous demonstrations of intact category learning by amnesic patients for dot patterns, artificial grammars, and cartoon animals. It appears that category knowledge can be acquired implicitly when training exemplars are presented visually and when the similarities among items can be readily perceived. Verbal category learning requires the extraction and retention of meaning from training exemplars that are separated in time and may make demands on declarative memory that are beyond the capacity of amnesic patients.
11063969	Studies of the hippocampus as a target of stress and stress hormones have revealed a considerable degree of structural plasticity in the adult brain. Repeated stress causes shortening and debranching of dendrites in the CA3 region of the hippocampus and suppresses neurogenesis of dentate gyrus granule neurons. Both forms of structural remodeling of the hippocampus appear to be reversible and are mediated by glucocorticoid hormones working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors, along with transmitters such as serotonin and the GABA-benzodiazepine system. Glucocorticoids, EAA, and NMDA receptors are also involved in neuronal damage and death that is caused in pyramidal neurons by seizures and by ischemia. A similar mechanism may be involved in hippocampal damage caused by severe and prolonged psychosocial stress. Studies using magnetic resonance imaging have shown that there is a selective atrophy of the human hippocampus in a number of psychiatric disorders, as well as during aging in some individuals, accompanied by deficits in declarative, spatial, and contextual memory performance. It is therefore important to appreciate how hippocampal dysfunction may play a role in the symptoms of the psychiatric illness and, from a therapeutic standpoint, to distinguish between a permanent loss of cells and a reversible remodeling to develop treatment strategies to prevent or reverse deficits. Remodeling of the hippocampus may be only the tip of the iceberg; other brain regions may also be affected.
11040258	While the role of the perirhinal cortex in declarative memory has been well established, it has been unclear whether the perirhinal cortex might serve an additional nonmnemonic role in visual perception. Evidence that the perirhinal cortex might be important for visual perception comes from a recent report that monkeys with perirhinal cortical lesions are impaired on difficult (but not on simple) visual discrimination tasks. We administered these same tasks to nine amnesic patients, including three severely impaired patients with complete damage to perirhinal cortex bilaterally (E.P., G.P., and G.T.). The patients performed all tasks as well as controls. We suggest that the function of perirhinal cortex as well as antero-lateral temporal cortex may differ between humans and monkeys.
11036271	In primates, visual long-term memory of objects is presumably stored in the inferior temporal (IT) cortex. Because brain-derived neurotrophic factor (BDNF) is involved in activity-dependent neural reorganization, we tested the hypothesis that BDNF would be upregulated in IT cortex during formation of visual pair-association memory. To eliminate genetic and cognitive variations between individual animals, we used split-brain monkeys for intra-animal comparison in PCR-based mRNA quantitation. The monkeys learned a pair-association (PA) task using one hemisphere and a control visual task using the other, to balance the amount of visual input. We found that BDNF was upregulated selectively in area 36 of IT cortex during PA learning, but not in areas involved in earlier stages of visual processing. In situ hybridization showed that BDNF-expressing cells were localized in a patchlike cluster. The results suggest that BDNF contributes to reorganization of neural circuits for visual long-term memory formation in the primate.
11030656	Participants playing the computer game Tetris reported intrusive, stereotypical, visual images of the game at sleep onset. Three amnesic patients with extensive bilateral medial temporal lobe damage produced similar hypnagogic reports despite being unable to recall playing the game, suggesting that such imagery may arise without important contribution from the declarative memory system. In addition, control participants reported images from previously played versions of the game, demonstrating that remote memories can influence the images from recent waking experience.
11027310	Performance on the visual paired-comparison task depends on the integrity of the hippocampal formation in humans, monkeys, and, for an analogous task, in rats. The present study sought additional evidence in healthy volunteers concerning the nature of this task. We found that performance on the visual paired-comparison task was predictive of subsequent recognition memory performance whereas perceptual priming was unrelated to subsequent recognition memory performance. The results are consistent with the data from lesions and suggest that performance on the visual paired-comparison task measures a form of declarative memory.
11026396	Elevated glucose levels are associated with increased recall on declarative memory tasks. No previous studies have examined such a relationship using a common features-derived prototype memory abstraction task. 20 participants volunteered, 10 each in an experimental group who were given 40 g of glucose to drink and a control group given an artificially sweetened beverage after fasting. Analysis indicated that common features-derived prototype memory abstractions seem resistant to glucose fluctuations.

11000199	The role of the amygdala in enhancing declarative memory for emotional experiences has been investigated in a number of animal, patient, and brain imaging studies. Brain imaging studies, in particular, have found a correlation between amygdala activation during encoding and subsequent memory. Because of the design of these studies, it is unknown whether this correlation is based on individual differences between participants or within-subject variations in moment-to-moment amygdala activation related to individual stimuli. In this study, participants saw neutral and negative scenes and indicated how emotionally intense they found each scene. Separate functional magnetic resonance imaging responses in the amygdala for each scene were related to the participants' report of their experience at study and to performance in an unexpected memory test 3 weeks after scanning. The amygdala had the greatest response to scenes rated as most emotionally intense. The degree of activity in the left amygdala during encoding was predictive of subsequent memory only for scenes rated as most emotionally intense. These findings support the view that amygdala activation reflects moment-to-moment subjective emotional experience and that this activation enhances memory in relation to the emotional intensity of an experience.
10995855	Activity-dependent plasticity is a fundamental feature of most CNS synapses and is thought to be a synaptic correlate of memory in rodents. In humans, NMDA receptors have been linked to verbal memory processes, but it is unclear whether NMDA receptor-dependent synaptic plasticity can be recruited for information storage in the human CNS. Here we have for the first time analyzed different forms of synaptic plasticity in human hippocampus. In human subjects who show a morphologically intact hippocampus that is not the primary seizure focus, NMDA receptor-dependent long-term potentiation (LTP) and forskolin-induced long-lasting potentiation are readily induced at the perforant path-dentate gyrus synapse. In this group, long-term potentiation could be partially depotentiated by low-frequency stimulation. Because patients with a hippocampal seizure focus showed a marked reduction in verbal memory performance in previous studies, we asked whether synaptic plasticity is similarly affected by the presence of a hippocampal primary seizure focus. We found that the amount of potentiation induced by high-frequency stimulation or perfusion of forskolin is dramatically reduced in this patient group. In addition, low-frequency stimulation is not effective in inducing synaptic depression. In summary, we show that activity-dependent synaptic plasticity with properties similar to the rodent is available for information storage in the human hippocampus. Because both verbal memory processes and synaptic plasticity are impaired by a hippocampal seizure focus, we suggest that impaired synaptic plasticity may contribute to deficient declarative memory in human temporal lobe epilepsy.
10985281	The structures forming the medial temporal lobe appear to be necessary for the establishment of long-term declarative memory. In particular, they may be involved in the "consolidation" of information in higher-order associational cortices, perhaps through feedback projections. This review highlights the fact that the medial temporal lobe is organized as a hierarchy of associational networks. Indeed, associational connections within the perirhinal, parahippocampal, and entorhinal cortices enables a significant amount of integration of unimodal and polymodal inputs, so that only highly integrated information reaches the remainder of the hippocampal formation. The feedback efferent projections from the perirhinal and parahippocampal cortices to the neocortex largely reciprocate the afferent projections from the neocortex to these areas. There are, however, noticeable differences in the degree of reciprocity of connections between the perirhinal and parahippocampal cortices and certain areas of the neocortex, in particular in the frontal and temporal lobes. These observations are particularly important for models of hippocampal-neocortical interaction and long-term storage of information in the neocortex. Furthermore, recent functional studies suggest that the perirhinal and parahippocampal cortices are more than interfaces for communication between the neocortex and the hippocampal formation. These structures participate actively in memory processes, but the precise role they play in the service of memory or other cognitive functions is currently unclear.
10973129	This article is a transcription of an electronic symposium in which some active researchers were invited by the Brazilian Society for Neuroscience and Behavior (SBNeC) to discuss the last decade's advances in neurobiology of learning and memory. The way different parts of the brain are recruited during the storage of different kinds of memory (e.g., short-term vs long-term memory, declarative vs procedural memory) and even the property of these divisions were discussed. It was pointed out that the brain does not really store memories, but stores traces of information that are later used to create memories, not always expressing a completely veridical picture of the past experienced reality. To perform this process different parts of the brain act as important nodes of the neural network that encode, store and retrieve the information that will be used to create memories. Some of the brain regions are recognizably active during the activation of short-term working memory (e.g., prefrontal cortex), or the storage of information retrieved as long-term explicit memories (e.g., hippocampus and related cortical areas) or the modulation of the storage of memories related to emotional events (e.g., amygdala). This does not mean that there is a separate neural structure completely supporting the storage of each kind of memory but means that these memories critically depend on the functioning of these neural structures. The current view is that there is no sense in talking about hippocampus-based or amygdala-based memory since this implies that there is a one-to-one correspondence. The present question to be solved is how systems interact in memory. The pertinence of attributing a critical role to cellular processes like synaptic tagging and protein kinase A activation to explain the memory storage processes at the cellular level was also discussed.
10966906	A glucose drink has been shown to improve memory in persons with poor glucose regulation and poor cognition.The objective of this study was to determine 1) whether an association between cognition and glucose regulation is apparent in healthy seniors and 2) the effects of dietary carbohydrates on cognition.	After an overnight fast, 10 men and 10 women (aged 60-82 y) consumed 50 g carbohydrate as glucose, potatoes, or barley or a placebo on 4 separate mornings. Cognitive tests were administered 15, 60, and 105 min after ingestion of the carbohydrate. Plasma glucose and serum insulin were measured.	In a multiple regression analysis, poor baseline (placebo) verbal declarative memory (immediate and 20-min delayed paragraph recall and word list recall) and visuomotor task performance were predicted by poor beta cell function, high incremental area under the glucose curve, low insulin resistance, and low body mass index. The difference in plasma glucose after food consumption [glucose > potatoes > barley > placebo (P: < 0.03)] did not predict performance. Although overall performance did not differ with consumption of the different test foods, baseline score and beta cell function correlated with improvements in immediate and delayed paragraph recall for all 3 carbohydrates (compared with placebo); the poorer the baseline memory or beta cell function, the greater the improvement (correlation between beta cell function and improvement in delayed paragraph recall: r > -0.50, P: < 0.03). Poor beta cell function correlated with improvement for all carbohydrates in visuomotor task performance but not on an attention task.	Glucose regulation was associated with cognitive performance in elderly subjects with normal glucose tolerance. Dietary carbohydrates (potatoes and barley) enhanced cognition in subjects with poor memories or beta cell function independently of plasma glucose.	
10962214	The correlation between clinical measures of memory and subjectively reported memory is often poor. Regarding this we investigated in patients with temporal lobe epilepsy (TLE) whether there is evidence that persons mistake other cognitive performances for memory due to subjective memory theories.a neuropsychological test battery comprising measures of attention, verbal/figural memory and other visual or language related functions was applied in patients with left (L-TLE, n=24) or right temporal lobe epilepsy (R-TLE, n=21) and healthy volunteers (n=20). In addition, subjective self- and other-reported memories were assessed by the subjective memory questionnaire (SMQ).	subjective measures as well as objective measures indicate significant cognitive impairment in TLE and in L-TLE in particular. Self-reports and other-reports are interrelated but only self-reported memory correlates significantly with objective memory performance. Regression analysis indicates that self-reported memory is best predicted by word fluency followed by verbal memory and vocabulary, and other-reported memory is best predicted by word fluency, vocabulary, confrontation naming, and verbal recognition memory.	The results suggest that attribution of memory refers to a subjective view of memory which is wider than its neuropsychological definition. It furthermore differs dependent on the observer's point of view. Memory is preferentially concluded from verbal behaviors. These reflect language skills and access to vocabulary rather than declarative memory. Consideration of subjective memory theories and associated attribution processes can significantly contribute to our understanding of the often-poor relationship between objective test results and subjective impairment in TLE.	
10935246	In this review we describe the main studies in which transcranial magnetic stimulation (TMS) has been used in the study of superior cognitive function.The various studies published in the literature show that TMS can modulate neuropsychological processes such as attention, different types of memory such as working memory, declarative memory, memory of procedures and language. In most cases TMS acts on the different cognitive abilities blocking or making them difficult. Thus TMS may be used as a method of causing transient lesions bringing the relationship brain-conduct to a dimension of cause and avoiding certain limitations of the classical method for creating lesions. The positive effects of TMS in certain tasks involving language and memory has also been shown. The latter offer new possibilities of future application in cognitive rehabilitation.	TMS has an obvious effect on neuropsychological functions. Over the past ten years studies in this field have increased progressively. At the present time the results obtained by using TMS in cognitive neuroscience are of a basic type, limited to experimental laboratory work. It has mainly been used on normal persons. However, it cannot be long before it is used clinically in neuropsychological patients.	
10923671	Substantial evidence indicates that the hippocampus plays a critical role in long-term declarative memory. In contrast, the role of the human hippocampus in working memory, particularly when information needs to be maintained only for a few seconds, remains controversial. Using PET, we show robust activation of the right anterior hippocampus proper during the performance of both object and spatial alternation tasks. Hippocampal activation emerged even though subjects only had to remember a single, simple stimulus over a minimum delay of 1 s. No hippocampal activation occurred when the delay was increased to 5 s. This suggests that the role of the hippocampus in working memory is not to maintain information across a delay interval. Instead, its activity reflects a more transient function during encoding and/or retrieval. These data are among the first observations to demonstrate human hippocampal involvement in working memory.
10873917	At least three studies have indicated that patients with psychotic major depression studied under non-drug-free conditions differ from patients with nonpsychotic major depression and healthy comparison subjects on several measures of neuropsychological performance. The current study explored specific impairments in cognitive function in subjects with psychotic major depression, subjects with nonpsychotic major depression, and healthy comparison subjects studied under drug-free conditions.A battery of neuropsychological tests was administered to 11 patients with psychotic major depression, 32 patients with nonpsychotic major depression, and 23 normal comparison subjects under drug-free conditions. The three groups did not differ statistically in age, sex, or level of education. To ensure that participants had minimal levels of severity and endogenicity, all patients were required to have a score of at least 20 on the 21-item Hamilton Depression Rating Scale and a score of at least 7 on the Core Endogenomorphic Scale, which uses eight items from the Hamilton depression scale.	Patients with psychotic major depression demonstrated significantly greater impairment than patients with nonpsychotic major depression and/or comparison subjects in attention and response inhibition (as measured by the Stroop color-word subscale score) as well as in verbal declarative memory (as measured by the Paragraph Recall Test).	These data indicate that patients with psychotic major depression demonstrate impairment in functions thought to be mediated by the frontal cortex and mediotemporal lobes.	
10867659	The connections between the medial temporal cortical areas and CA1 of the hippocampus were examined in the Japanese monkey (Macaca fuscata) by means of retrograde and anterograde tract-tracing methods with wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) and fluorescent dyes (Fast Blue and Diamidino Yellow). The posterior parahippocampal (areas TF1, TF2, and TH), perirhinal (areas 35 and 36), and ventral inferotemporal areas (areas TEav and TEpv) were reciprocally connected with CA1. Projection fibers from CA1 to the medial temporal cortical areas originated in the pyramidal cell layer, whereas those from the medial temporal cortical areas to CA1 terminated in the molecular layer. Each of these cortical areas was reciprocally connected with the entire rostrocaudal extent of CA1. However, the intensity of the connections varied along the rostrocaudal axis of CA1: areas TH and TF2 were connected most markedly with the anterior and middle parts of CA1, respectively. Areas TF, 35, 36, TEav, and TEpv were connected predominantly with the posterior part of CA1. In the coronal plane of CA1, labeled cells were located in proximal CA1 (i. e., near the prosubiculum), but not in distal CA1 (i.e., near CA2). The medial temporal cortical areas in direct reciprocal connection with CA1 were presumed to be involved in the memory system, especially in the system for declarative memory.
10837507	Case studies of patients with bilateral amygdala damage and functional imaging studies of normal individuals have demonstrated that the amygdala plays a critical role in encoding emotionally arousing stimuli into long-term declarative memory. However, several issues remain poorly understood: the separate roles of left and right amygdala, the time course over which the amygdala participates in memory consolidation, and the type of knowledge structures it helps consolidate. We investigated these questions in eight subjects with unilateral amygdala damage, using several different measures. For comparison, our main task used stimuli identical to those used previously to investigate emotional declarative memory in patients with bilateral amygdala damage. Contrasts with both brain-damaged and normal control groups showed that subjects with left amygdala damage were impaired in their memory for emotional stimuli, despite entirely normal memory for neutral stimuli (because of a number of caveats, the findings from subjects with right amygdala damage were less clear). Follow-up experiments suggested that the normal facilitation of memory for emotional stimuli may develop over an extended time course (>30 min), consistent with prior findings, and that the specific impairment we report may depend in part on the lexical nature of the task used (written questionnaire). We stress the complex and temporally extended nature of memory consolidation and suggest that the amygdala may influence specific components of this process.
10832902	Chronic excessive consumption of alcohol produces marked deficits in cognitive and motor abilities, although not all functions are affected to the same extent. Furthermore, although the occurrence of neuropsychological deficits in recently detoxified alcoholics is firmly established, the relative severity of these deficits, the specific neural systems that underlie the deficits, and their relationship to age and alcohol consumption variables either are less established or have proven elusive altogether.We administered an extensive battery of neuropsychological tests, chosen for their known sensitivity to brain lesions in specific locations, to 71 recently (1 month) detoxified alcoholic men and 74 healthy controls who spanned the adult age range. Test scores were standardized to the controls for age and grouped a priori into composites that reflected performance in six functional domains: executive functions, short-term memory, upper limb motor ability, declarative memory, visuospatial abilities, and gait and balance. Analogous verbal and nonverbal materials and left- and right-hand upper limb motor tasks were used to test whether alcohol-related deficits were greater for left or right hemisphere.	Compared with controls, the alcoholics were impaired on executive functions, visuospatial abilities, and gait and balance even after we accounted for group differences in estimated premorbid IQ and education. Within the alcoholic group, the most salient deficits were in gait and balance and visuospatial abilities. No consistent lateralized deficit was observed across the four domains tested. Unlike the cognitive composites, the upper limb motor ability and gait and balance composites both showed increasing vulnerability to age, with an independent contribution to the gait and balance dysfunction from the amount of alcohol consumed over a lifetime.	The pattern of functional deficits implicates at least two principal neural systems: the cerebellar-frontal system and the corticocortical system between the prefrontal and parietal cortices. In addition, age and amount of alcohol consumption were better predictors of motor than cognitive impairments.	
10804225	Eighteen monkeys with lesions of the hippocampal region (the hippocampus proper, the dentate gyrus, and the subiculum) made by an ischemic procedure, radio frequency, or ibotenic acid were tested on a simple, two-choice object discrimination learning task that has been shown to be sensitive to large lesions of the medial temporal lobe. The monkeys were also tested on two other discrimination tasks (pattern discrimination and eight-pair concurrent discrimination) that can be learned normally by monkeys with large medial temporal lobe lesions. All of the lesion groups were impaired at learning the simple object discrimination task. Seven of the monkeys who had sustained damage to the hippocampal region also sustained damage to the tail of the caudate nucleus. These seven monkeys, but not the other 11 monkeys with hippocampal lesions, were impaired on pattern discrimination and concurrent discrimination learning. The results suggest that the hippocampal region is important for learning easy, two-choice discriminations, whereas the caudate nucleus is necessary for the normal learning of more difficult, gradually acquired discrimination tasks. The findings support the distinction between declarative memory, which depends on the hippocampus and related medial temporal lobe structures, and habit learning, which depends on the caudate nucleus.
10791835	Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects.
10789884	It is known that glucose administration is capable of improving performance on tests of declarative verbal memory and non-mnemonic tasks requiring high "mental effort". At the same time, cognitively demanding tasks are associated with elevated heart rate, a response that could feasibly be part of a physiological mechanism serving to increase the delivery of glucose to active brain substrates.The present placebo-controlled, double-blind, balanced, crossover study examined the interaction between glucose administration, cognitive performance and heart rate during three tasks of differing mental demand and somatically-matched control tasks.	The effects of a glucose drink on participants' performance on two serial subtraction tasks (Serial Threes and Serial Sevens) and a Word Retrieval (Verbal Fluency) task were assessed. Heart rates were monitored throughout the experiment, and participants rated each task in terms of its perceived mental demand.	Serial Sevens was rated as the most mentally demanding task, followed by Word Retrieval, then Serial Threes. Glucose consumption significantly improved performance on Serial Sevens, with a trend for improved performance on Word Retrieval. Both Serial Sevens and Serial Threes were associated with significant heart rate elevation above that seen in somatically matched control tasks (ruling out the possibility that accelerated heart rate was due to peripheral mechanisms alone). Unexpectedly, participants in the glucose condition had higher heart rates during cognitive processing. Additionally, individuals whose baseline heart rates were below the median performed better on Serial Threes and Serial Sevens.	We suggest that supplemental glucose preferentially targets tasks with a relatively high cognitive load, which itself (through unknown mechanisms) mobilises physiological reserves as part of a natural response to such tasks. Furthermore, baseline heart rate and responses to cognitive demand and glucose administration may represent important physiological individual differences.	

10718263	In 2 experiments, deferred imitation procedures were used to trace age-related changes in declarative memory by human infants over the first 2 years of life. An adult modeled 3 actions with an object, and infants' ability to reproduce those actions was assessed 24 hr later. Some infants were tested with a new object or in a new context relative to the original demonstration. Changes in the context disrupted the performance of 6-month-olds but had no effect on the performance of 12- and 18-month-olds. Changes in the object disrupted the performance of 6- and 12-month-olds but had no effect on the performance of 18-month-olds. This age-related increase in representational flexibility may account for the decline of childhood amnesia during the 3rd year of life.
10677648	Color perception is dependent on the generation of an excitation vector which, acting on a pool of color detectors (color detector map), produces a corresponding sensation. The generation of the color excitation vector starts at the retinal level, proceeds in the lateral geniculate body, and reaches color detectors at the cortical level. Following processing at the level of declarative memory and semantic maps, results in a verbal categorization of colors. Parallel to the excitation vector pathway, a network computing color differences is operating. The computation of color differences at the retinal level possibly takes place in phasic bipolar cells and progresses in the lateral geniculate body and at the cortical level. Detectors of color differences are assumed to be a basis of respective numerical estimations in humans. Data from frogs, fish, monkeys and humans are compared.
10689557	In a variation of Deese's (1959, Journal of Experimental Psychology, 58, 17-22) list-learning paradigm, 32 first-graders, 32 younger adults, and 24 older adults self-generated words that were semantically related to study items prior to recall. This manipulation increased false recollection for children and older adults, but not for younger adults. These data suggest that source-monitoring deficits underlie children's and older adults' illusory memories within the list-learning format. The differential roles played by source monitoring versus declarative memory in the production of false memories are discussed from a life span developmental perspective.
10668353	Extensive evidence has been amassed that the cerebellum, hippocampus, and associated circuitry are activated during classical conditioning of the nictitating membrane/eyeblink response. In this article, the authors argue that the cerebellum is essential to all eyeblink classical conditioning paradigms. In addition, the septohippocampal system plays a critical role when the classical conditioning paradigm requires the formation of associations in addition to the simple association between the conditioned and unconditioned stimuli. When only a simple conditioned stimulus--unconditioned stimulus association is needed, the septohippocampal system has a more limited, modulatory role. The neutral stimulus association versus simple association-response distinction is one of the ways in which declarative or relational memory can be separated from nondeclarative or nonrelational memory in classical conditioning paradigms.
10666558	Declarative and procedural memory functions are related to dissociable neuroanatomic substrates. In the present study differential effects of pharmacologically induced changes in dopaminergic, GABAergic, and cholinergic activity in the brain on declarative (object and face recognition, immediate and delayed word recall) and procedural memory processes (compensatory tracking) were investigated. In a double-blind design, either 3 mg of haloperidol, 11 mg of midazolam, 1 mg of scopolamine, or placebo were administered to 80 healthy volunteers randomly assigned to one of the four drug conditions. Although all three drugs produced a detrimental effect on immediate and delayed word recall, recall performance was substantially more impaired by the benzodiazepine midazolam than by either haloperidol or scopolamine. While recognition of faces was affected by neither of the drugs, performance on object recognition was significantly decreased by midazolam as compared to placebo. Procedural learning was markedly impaired by all drugs but, again, the observed effect was most pronounced with midazolam. Additional analyses of measures of subjective activation, cortical arousal, and psychomotor performance argued against the assumption that the observed memory-impairing effects were secondary to drug-induced sedation. The overall pattern of results revealed that memory processes are much more susceptible to changes in GABAergic than in dopaminergic or cholinergic neurotransmitter activity. Furthermore, the present findings point to the conclusion that the modulating effects of dopaminergic, GABAergic, and cholinergic neurotransmitter systems on declarative and procedural memory functions are less specific than suggested by neuropsychological studies in patients.
10653284	The preclinical stage of Alzheimer's disease is inconspicuous and there are - almost by definition - no reliable and valid symptoms and signs which would allow a very early diagnosis before the manifestation of irreversible deficits. For a clinical diagnosis of dementia, cognitive impairment has to be severe enough to compromise the activities of daily living. In the mild dementia stage, difficulties with declarative memory are usually prominent; depressive symptoms are not infrequent, but the patient usually manages to live alone. Supervision is needed in the moderate dementia stage, when other cognitive domains are affected in a more obvious manner and non-cognitive disturbances of thought, perception, affect, and behavior put increasing stress on the caregivers. Complete dependence of the patients, who frequently develop neurological disturbances, is typical of the late stage of illness. The life expectancy of patients with a clinical diagnosis of Alzheimer's disease is significantly reduced, but to date there is hope that the period of relative well-being and not of suffering can be prolonged with modern symptomatic treatment interventions.
10645377	Research suggests that 9-month-old infants are able to recall single object-specific actions over delays of 24 hours. In the present research we investigated whether 9-month-olds are able to recall over more extended delays, and to recall the temporal order of events, as well as the individual actions in them. In addition, we investigated whether recall can be enhanced by pre- and/or re-exposure to target events. Using elicited imitation of novel, multi-step event sequences, we demonstrated that, as a group, 9-month-olds are able to recall target actions after delays of five weeks. However, after this long delay, only 45% of the infants recalled the temporal order of the events. Re-exposure to events during the delay interval proved necessary for boys, but not for girls; pre-exposure to events did not affect later recall. The implications of individual differences in infants' recall ability for the understanding of the development of the neural correlates of declarative memory are discussed.
10634350	The functional anatomy of anxiety involves amygdala-based neurocircuits with critical reciprocal connections to the medial prefrontal cortex. Traumatic experiences leave emotional imprints involving the amygdala, with facilitated fear-conditioned associations involving declarative memory traces. Avoidance conditioning is an additional component. An understanding of the functional anatomy of anxiety allows for a new perspective on the various anxiety disorders. The neurotransmitters involved in these circuits are reviewed for their relevance to the pharmacologic choices in the treatment of anxiety. Potent serotonin reuptake inhibitors appear to have superior efficacy in many of the anxiety disorders, with indications that norepinephrine reuptake inhibitors have an advantage in severe forms of major depression. Medications with dual effects--blocking reuptake of both serotonin and norepinephrine (e.g., clomipramine and venlafaxine XR)--have superior benefits in achieving remission in major depression and GAD. These medications may also offer a faster onset of action and theoretically superior benefits in patients with comorbid anxiety disorder and major depression.
10627621	Monkeys with lesions limited to the hippocampal region (the hippocampus proper, the dentate gyrus, and the subiculum) were impaired on two tasks of recognition memory: delayed nonmatching to sample and the visual paired-comparison task. Recognition memory was impaired in five different groups of monkeys, whether the lesions were made by an ischemic procedure, by radio frequency, or by ibotenic acid. The finding that the hippocampal region is essential for normal recognition memory performance is considered in the context of current ideas about the role of the hippocampus in declarative memory.
10617287	In order to address the question of whether the basal ganglia are involved exclusively in regulation of motor sequence learning, or if they are involved in non-motor sequence learning as well, two versions of the serial reaction time (SRT) task were administered: First is the standard version of the SRT task in which the sequence is executed motorically, and the second is a non-motor version of the task which requires response only to a particular position of the sequence. Sixteen patients with damage restricted to the region of the basal ganglia and 16 matched control subjects participated in this study. In addition to the motor and non-motor SRT tasks, two declarative memory tests (Visual Paired Associates and Rey Auditory-Verbal Learning Test) were administered to the participants. Results indicate that the two groups did not differ either on learning rate of the two declarative tasks, or on the declarative component of the SRT tasks (i.e., 'generate'). However, the control group was significantly superior to the basal ganglia (BG) group in learning a specific sequence in the motor and non-motor SRT tasks. Results suggest that the basal ganglia are involved in the regulation of non- motor as well as motor sequence learning.
10591291	Increasing plasma glucose levels improves memory in patients with Alzheimer disease (AD). Increasing plasma glucose levels also increases endogenous insulin levels, raising the question of whether memory improvement is due to changes in insulin, independent of hyperglycemia. We address this question by examining memory and counterregulatory hormone response during hyperglycemia when endogenous insulin was suppressed by concomitant infusion of the somatostatin analogue octreotide (Sandostatin).Twenty-three patients with AD and 14 similarly aged healthy adults participated in 4 metabolic conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57 pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h); (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting insulin and glucose); and (4) an active control condition in which somatostatin alone was infused (150 mg/h). Declarative memory (story recall) and selective attention (Stroop interference test) were measured during steady metabolic states.	Patients with AD showed improved memory during hyperinsulinemia relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory for patients with AD (P<.05). Hyperinsulinemia increased cortisol levels in subjects with AD, whereas somatostatin alone lowered cortisol concentrations.	These results confirm that elevated insulin without hyperglycemia enhances memory in adults with AD, and indicate that insulin is essential for hyperglycemic memory facilitation. These results also suggest a potential therapeutic role for somatostatin in AD.	
10588579	At test times 18 months apart (Time 1 and Time 2), men (n Time 1 = 31, Time 2 = 23), women estrogen-users (n Time 1 = 14, Time 2 = 10), and women estrogen non-users (n Time 1 = 41, Time 2 = 27), whose average age was 72.1 and 73.4 years at Time 1 and Time 2, respectively, were tested with a battery of neuropsychological tests measuring verbal memory, visual memory, concentration/attention, language fluency and semantic memory. Plasma levels of CRT and DHEAS were assayed by radioimmunoassay at both test times. The men had higher DHEAS levels than both groups of women at both test times (p < 0.001) and also had a higher DHEAS/CRT ratio compared to the estrogen non-users (p < 0.05). Although there were no group differences in CRT levels at either time, CRT levels increased in the estrogen non-using women from Time 1 to Time 2 (p < 0.001). Subjects with lower CRT levels performed better than those with higher levels on several tests of declarative memory (p < 0.05). Men and estrogen-users had higher Digit Span scores compared to female estrogen non-users at both test times (p < 0.01), and women estrogen-users also had higher Backward Digit Span scores than non-users (p < 0.05). Both groups of women performed better than men on Category Retrieval (p < 0.01). These findings suggest that higher CRT levels in elderly men and women are associated with poorer explicit memory functioning; however, these results failed to provide any evidence that DHEAS is protective against declarative memory decline with aging.
10560021	There is extensive evidence indicating that the noradrenergic system of the amygdala, particularly the basolateral nucleus of the amygdala (BLA), is involved in memory consolidation. Infusions of norepinephrine or beta-adrenoceptor agonists into the BLA enhance memory for inhibitory avoidance as well as water maze training. Other findings show that alpha 1-adrenoceptor activation also enhances memory for inhibitory avoidance training through an interaction with beta-adrenergic mechanisms. The central hypothesis guiding the research reviewed in this chapter is that stress hormones released during emotionally arousing experiences activate noradrenergic mechanisms in the BLA, resulting in enhanced memory for those events. Findings from experiments using rats have shown that the memory-modulatory effects of the adrenocortical stress hormones epinephrine and glucocorticoids are mediated by influences involving activation of beta-adrenoceptors in the BLA. In addition, both behavioral and microdialysis studies have shown that the noradrenergic system of the BLA also mediates the influences of other neuromodulatory systems such as opioid peptidergic and GABAergic systems on memory storage. Other findings indicate that this stress hormone-induced activation of noradrenergic mechanisms in the BLA regulates explicit/declarative memory storage in other brain regions.
10549995	Neuropathological studies use the presence of mammillary body (MB) pathology as a cardinal, diagnostic feature of Wernicke's encephalopathy (WE) in neuropsychiatric diseases, most notably alcoholism. Although Korsakoffs Syndrome (KS), which is marked behaviorally by dense global amnesia, is a typical sequela of WE, it remains controversial whether these two conditions necessarily co-occur and whether MB pathology is therefore a diagnostic requisite for KS.We investigated these issues by examining, in vivo, 24 nonamnesic alcoholics (ALC), 5 amnesic alcoholics (KS), and 51 normal controls with three-dimensional MRI and memory testing. MB volume was determined from successive, 1 mm thick slices.	The ALC group had significantly smaller MB volumes bilaterally (mean = 54.5 +/- 22.0 mm3) than controls (mean = 66.3 +/- 17.1 mm3), and the KS group had even smaller MB volumes than the ALC group (mean = 20.7 +/- 14.8 mm3). Only 2 ALC patients met historical clinical criteria for past WE, and their MB volumes were well within range of the remaining 22 ALC patients. Although all five KS patients met historical clinical criteria for WE, three KS did not have accompanying dementia and had the same degree of MB volume loss as the ALC; the remaining two KS had accompanying dementia and MB volumes half the volume of the ALC group and of KS patients without dementia.	These findings provide volumetric in vivo evidence that: (1) MB volume deficits do occur in alcoholics without amnesia, although these deficits are not present in ail such alcoholics; (2) greater MB volume deficits are present in alcoholics with clinically detectable amnesia or dementia; (3) MB shrinkage is related to severity of cognitive and memory dysfunction, which suggests a continuum of MB pathology in chronic alcoholism to KS; and (4) the presence of WE in all of the KS patients and in the two ALC patients with the greatest long-term declarative memory deficit supports the possibility of an additional and unique pathology distinguishing nonamnesic and amnesic alcoholism.	
10549798	Age-associated memory impairment (AAMI) is a clinical entity which was originally described to define memory problems linked to normal aging. Apolipoprotein E and ACE genes have both been associated with cognitive impairment in aging and dementia. The purpose of this study was to investigate memory and executive functions in AAMI according to the genetic background. We found that subjects carrying the Apo E epsilon4 allele exhibit lower memory performance on tests of both declarative and procedural memory. We did not find differences on frontal lobe tests. These findings give further support to the hypothesis concerning a genetic susceptibility for cognitive impairment in aging.
10527065	The striatum is thought to play an essential role in the acquisition of a wide range of motor, perceptual, and cognitive skills, but neuroimaging has not yet demonstrated striatal activation during nonmotor skill learning. Functional magnetic resonance imaging was performed while participants learned probabilistic classification, a cognitive task known to rely on procedural memory early in learning and declarative memory later in learning. Multiple brain regions were active during probabilistic classification compared with a perceptual-motor control task, including bilateral frontal cortices, occipital cortex, and the right caudate nucleus in the striatum. The left hippocampus was less active bilaterally during probabilistic classification than during the control task, and the time course of this hippocampal deactivation paralleled the expected involvement of medial temporal structures based on behavioral studies of amnesic patients. Findings provide initial evidence for the role of frontostriatal systems in normal cognitive skill learning.
10513581	The hippocampus is critical to declarative memory in humans and spatial memory in rodents. This review attempts to bridge between these two characterizations of hippocampal dependent memory, and in doing so reveal fundamental cognitive and neural coding mechanisms that are common to both. Evidence is presented that the hippocampus and its connections are critical to the establishment of a systematic organization of memories and to flexible expression of memory outside repetition of the training experience. In addition, evidence is presented that hippocampal neurons encode a broad range of experience and that these codings may be organized as representations of episodes in memory. It is suggested that these episodic codings are linked by common elements to construct an organized representation of acquired knowledge.
10511433	Early sleep dominated by slow-wave sleep has been found to be particularly relevant for declarative memory formation via hippocampo-neocortical networks. Concurrently, early nocturnal sleep is characterized by an inhibition of glucocorticoid release from the adrenals. Here, we show in healthy humans that this inhibition serves to support declarative memory consolidation during sleep. Elevating plasma glucocorticoid concentration during early sleep by administration of cortisol impaired consolidation of paired associate words, but not of non-declarative memory of visuomotor skills. Since glucocorticoid concentration was enhanced only during retention sleep, but not during acquisition or retrieval, a specific effect on the consolidation process is indicated. Blocking mineralocorticoid receptors by canrenoate did not affect memory, suggesting inactivation of glucocorticoid receptors to be the essential prerequisite for memory consolidation during early sleep.
10510196	The present study was built on the original report of Eichenbaum et al. [Eichenbaum, H., Fagan, A., Mathews, P. & Cohen, N.J. (1988), Behav. Neurosci., 102, 3531-3542] on the contrasting effects of fornix lesion in different versions of an odour-guided discrimination task in rats, and attempted to extend this into a mouse model for the preferential loss of declarative memory seen in human senescence. Each of the two experiments reported here consisted of a two-stage paradigm, with an initial learning phase followed by a test phase. The information acquired in the first stage was identical in both experiments, i.e. the valence or reward contingency associated with six (three positive and three negative) arms of a radial maze. The only parameter which was varied between Experiment A and B, and also between the two successive stages within each experiment, was the way of presenting the arms to the mice, i.e. either in pairs (simultaneous discriminations) or one at a time (successive go : no-go discrimination). Performance in the first stage demonstrated that our aged mice were impaired in learning concurrent simultaneous discriminations but not successive go/no-go discrimination, thereby resembling that reported in rats with hippocampal damage. Most importantly, our present set of data supports the conclusion that two forms of memory expression for the same piece of acquired experience can be assessed in the same subjects by manipulating the way of presenting two arms that were previously experienced separately. These two forms of memory expressions are differentially affected in aged mice, thereby demonstrating the highly selective and specific deleterious effect of ageing.
10510193	The involvement of distributed brain regions in declarative memory has been hypothesized based on studies with verbal memory tasks. To characterize episodic declarative memory function further, 14 right-handed volunteers performed a visual verbal learning task using paired word associates. The volunteers underwent positron emission tomography. 15O-butanol was used as a tracer of regional cerebral blood flow (rCBF). Inter-regional functional interactions were assessed based on within-task, across-subject inter-regional rCBF correlations. Anatomical connections between brain areas were based on known anatomy. Structural equation modelling was used to calculate the path coefficients representing the magnitudes of the functional influences of each area on the ones to which it is connected by anatomical pathways. The encoding and the retrieval network elicit similarities in a general manner but also differences. Strong functional linkages involving visual integration areas, parahippocampal regions, left precuneus and cingulate gyrus were found in both encoding and retrieval; the functional linkages between posterior regions and prefrontal regions were more closely linked during encoding, whereas functional linkages between the left parahippocampal region and posterior cingulate as well as extrastriate areas and posterior cingulate gyrus were stronger during retrieval. In conclusion, these findings support the idea of a global bihemispheric, asymmetric encoding/retrieval network subserving episodic declarative memory. Our results further underline the role of the precuneus in episodic memory, not only during retrieval but also during encoding.
10491611	Studies of patients and animals with brain lesions have implicated the hippocampal formation in spatial, declarative/relational and episodic types of memory. These and other types of memory consist of a series of interdependent but potentially dissociable memory processes-encoding, storage, consolidation and retrieval. To identify whether hippocampal activity contributes to these processes independently, we used a novel method of inactivating synaptic transmission using a water-soluble antagonist of AMPA/kainate glutamate receptors. Once calibrated using electrophysiological and two-deoxyglucose techniques in vivo, drug or vehicle was infused chronically or acutely into the dorsal hippocampus of rats at appropriate times during or after training in a water maze. Our findings indicate that hippocampal neural activity is necessary for both encoding and retrieval of spatial memory and for either trace consolidation or long-term storage.
10489259	We collected functional neuroimaging data while volunteers performed similar categorization and recognition memory tasks. In the categorization task, volunteers first studied a series of 40 dot patterns that were distortions of a nonstudied prototype dot pattern. After a delay, while fMRI data were collected, they categorized 72 novel dot patterns according to whether or not they belonged to the previously studied category. In the recognition task, volunteers first studied five dot patterns eight times each. After a delay, while fMRI data were collected, they judged whether each of 72 dot patterns had been studied earlier. We found strikingly different patterns of brain activity in visual processing areas for the two tasks. During the categorization task, the familiar stimuli were associated with decreased activity in posterior occipital cortex, whereas during the recognition task, the familiar stimuli were associated with increased activity in this area. The findings indicate that these two types of memory have contrasting effects on early visual processing and reinforce the view that declarative and nondeclarative memory operate independently.
10485922	The effects of normal aging on the primate brain are incompletely understood. Although both human and nonhuman primates demonstrate clear functional declines in selective attention, "executive" functions, and some components of declarative memory with aging, most studies have failed to demonstrate extensive neuronal atrophy or loss as a substrate for these degenerative changes in primates. In particular, extensive age-related neuronal loss in memory-related brain regions such as the hippocampus and entorhinal cortex has not been found. However, it is possible that neuronal loss or atrophy might occur in subcortical nuclei that modulate the activity of neocortical regions, thereby accounting for altered cognitive function with aging. In the present study, we describe, to our knowledge for the first time, a significant and extensive decline in the number and size of immunolabeled neurons in subcortical cholinergic basal forebrain regions of aged rhesus monkeys, the best animal model of human aging, by using stereological methods. Notably, the loss of subcortical cholinergic neuronal markers in aged monkeys was nearly completely reversed by human nerve growth factor gene delivery. These findings (i) identify reversible cellular atrophy as a potential mechanism contributing to age-related cognitive decline in primates, (ii) suggest, when considered with other studies, that subcortical brain regions exhibit greater vulnerability to the effects of aging than cortical regions, and (iii) indicate that neurotrophin gene transfer may be an effective means of preventing neuronal atrophy or degeneration in age-related neurodegenerative disorders.
10481830	Mood disorders are common, recurrent and disabling illnesses which are frequently associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and memory loss. The hippocampus provides negative feedback to the HPA axis and has an important role in key aspects of spatial and declarative memory. Thus, hippocampal dysfunction could account for both the memory impairment and neuroendocrine abnormalities found in mood disorders. The critical role of the hippocampus in declarative memory, emotional processing, and vulnerability to stress has been demonstrated in both animal and human studies. Cellular processes in the hippocampus including long-term potentiation, neurogenesis, and dendritic remodeling are currently areas of intense study. Human studies report cognitive impairment consistent with hippocampal dysfunction in depression, bipolar disorder, Cushing's disease, and in those individuals receiving exogenous corticosteroids. This review examines data on the role of corticosteroids in hippocampal remodeling and atrophy in patients with mood disorders. Interventions to prevent or reverse the damaging effects of corticosteroids on the hippocampus are discussed.
10480777	Severe hypoglycemia may impair medial temporal-mediated cognitive skills, such as the ability to recall past events explicitly (delayed declarative memory). The objective of this study was to determine whether delayed declarative memory deficits are present in a group of diabetic children with an increased risk of severe hypoglycemia.Nondiabetic children (n = 16) and children with type 1 diabetes who had been randomly assigned to either intensive (IT) (n = 13) or conventional (CT) (n = 12) diabetes therapy at the time of diagnosis participated in the study. All episodes of severe hypoglycemia were prospectively ascertained. All children were tested on memory tasks that have been closely linked to medial temporal functioning and on reaction time measures.	Our results demonstrated that the IT group had a threefold higher rate of severe hypoglycemia, performed less accurately on a spatial declarative memory task, and performed more slowly, but not less accurately, on a pattern recognition task than did the CT group or control subjects. In addition, both groups of type 1 diabetic children were significantly impaired on a motor speed task compared with their nondiabetic peers.	These results indicate a selective relative memory impairment associated with IT that is consistent with the effects of severe hypoglycemia and medial temporal damage or dysfunction. If larger prospective studies determine that severe hypoglycemia is the mediating factor for this memory impairment, extreme caution in imposing overly strict standards for glucose control in young patients with type 1 diabetes would be indicated because of the increased risk of hypoglycemia associated with IT regimens.	
10477525	A fundamental question about human memory is which brain structures are involved, and when, in transforming experiences into memories. This experiment sought to identify neural correlates of memory formation with the use of intracerebral electrodes implanted in the brains of patients with temporal lobe epilepsy. Event-related potentials (ERPs) were recorded directly from the medial temporal lobe (MTL) as the patients studied single words. ERPs elicited by words subsequently recalled in a memory test were contrasted with ERPs elicited by unrecalled words. Memory formation was associated with distinct but interrelated ERP differences within the rhinal cortex and the hippocampus, which arose after about 300 and 500 milliseconds, respectively. These findings suggest that declarative memory formation is dissociable into subprocesses and sequentially organized within the MTL.
10474005	A number of constructs developed to account for bilingual aphasia phenomena have been advantageously extended to increase our understanding of language representation, processing, breakdown and rehabilitation in unilinguals as well. In particular, focus on the right-hemisphere-based pragmatic component of verbal communicative competence, the activation threshold, the control of resources, the role of emotion in second language acquisition and that of procedural vs. declarative memory, has led to the suggestion that unilinguals are in fact at one end of a continuum, with multilinguals who speak genetically unrelated languages at the other end. No function is available to the bilingual speaker that is not already available to the unilingual, unidialectal speaker. The only difference seems to be the degree of use the speaker makes of each of the relevant cerebral systems.
10461210	Declarative memory, the conscious recollection of past experiences, is known to involve the hippocampus. Now a study of amnesic patients shows that hippocampus-dependent learning can occur in the absence of conscious awareness.
10461122	Deferred imitation has recently surfaced as a hallmark measure of nonverbal declarative memory. In two experiments, we examined the developmental origins of deferred imitation during early infancy. Six- and 9-month-old human infants observed an experimenter perform specific actions with multiple objects. The infants' ability to reproduce those actions was assessed following a 24-hr delay. With a single demonstration session, infants of both ages reproduced significantly more actions that had been demonstrated than control actions that had not. These findings challenge the view that memory development is characterized by the emergence of a fundamentally different, declarative memory system later in development. We conclude that the rudiments of declarative memory are present by at least 6 months of age.
10459403	Memory function is an important but under researched area for neuropsychological investigation in persons with bipolar disorder. Previous studies have reported cognitive deficits on tasks of declarative memory in bipolar patients in the euthymic state.This study extended these findings by investigating declarative as well as procedural learning and memory in bipolar patients (with and without alcohol abuse) who were examined in the euthymic state. The California Verbal Learning Test, Star Mirror Tracing Task, Pursuit Rotor Task, American National Adult Reading Test, and the Vocabulary Subtest of the WAIS-R, were administered to bipolar patients and control subjects by researchers who were blind to the subject's group.	Bipolar patients performed worse than control subjects on a measure of declarative memory (California Verbal Learning Test) but did not differ from the performance of control subjects on either of the two procedural learning tasks (Pursuit Rotor Task and Star Mirror Task).	These results suggest disturbed function of temporal lobe, but not basal ganglia, structures in persons with bipolar disorder.	
10458163	The hippocampus is part of a system of structures in the medial temporal lobe that are essential for memory. One influential view of hippocampal function emphasizes its role in the acquisition and retrieval of spatial knowledge. By this view, the hippocampus constructs and stores spatial maps and is therefore essential for learning and remembering places, including those learned about long ago. We tested a profoundly amnesic patient (E.P.), who has virtually complete bilateral damage to the hippocampus and extensive damage to adjacent structures in the medial temporal lobe. We asked him to recall the spatial layout of the region where he grew up, from which he moved away more than 50 years ago. E.P. performed as well as or better than age-matched control subjects who grew up in the same region and also moved away. In contrast, E.P. has no knowledge of his current neighbourhood, to which he moved after he became amnesic. Our results show that the medial temporal lobe is not the permanent repository of spatial maps, and support the view that the hippocampus and other structures in the medial temporal lobe are essential for the formation of long-term declarative memories, both spatial and non-spatial, but not for the retrieval of very remote memories, either spatial or non-spatial.
10456071	Emotional arousal has been demonstrated to enhance declarative memory (conscious recollection) in humans in both naturalistic and experimental studies. Here, we examined this effect in amnesia. Amnesic patients and controls viewed a slide presentation while listening to an accompanying emotionally arousing story. In both groups, recognition memory was enhanced for the emotionally arousing story elements. The magnitude of the enhancement was proportional for both amnesic patients and controls. Emotional reactions to the story were also equivalent. The results suggest that the enhancement of declarative memory associated with emotional arousal is intact in amnesia. Together with findings from patients with bilateral amygdala lesions, the results indicate that the amygdala is responsible for the enhancement effect.
10456070	Everyday experience suggests that highly emotional events are often the most memorable, an observation supported by psychological and pharmacological studies in humans. Although studies in animals have shown that nondeclarative emotional memory (behaviors associated with emotional situations) may be impaired by lesions of the amygdala, little is known about the neural underpinnings of emotional memory in humans, especially in regard to declarative memory (memory for facts that can be assessed verbally). We investigated the declarative memory of two rare patients with selective bilateral amygdala damage. Both subjects showed impairments in long-term declarative memory for emotionally arousing material. The data support the hypothesis that the human amygdala normally enhances acquisition of declarative knowledge regarding emotionally arousing stimuli.
10443770	The effects of various doses (40 microg/kg/hr, 300 microg/kg/hr, 600 microg/kg/hr or placebo) of hydrocortisone on tasks assessing working and declarative memory function were measured in 4 groups of 10 young men. During the infusion, participants were given an item-recognition working memory task, a paired-associate declarative memory task, and a continuous performance task used to control possible concomitant effects of corticosteroids on vigilance. The results revealed significant acute effects of the highest dose of hydrocortisone on working memory function, without any significant effect on declarative memory function or arousal-vigilance performance. These results suggest that working memory is more sensitive than declarative memory to the acute elevations of corticosteroids, which could explain the detrimental effects of corticosteroids on acquisition and consolidation of information, as reported in the literature.
10443769	Exposure to members of a category facilitates later categorization of similar but novel instances of the category. Past studies have suggested that category knowledge can be acquired implicitly and independently of declarative memory. However, these studies have relied on dot pattern stimuli that, unlike most real-world objects, are difficult to verbalize and cannot be broken into component features. It is therefore unclear how relevant such studies are to an understanding of everyday categorization. In the present studies, category learning in amnesic patients was tested with stimuli that both exhibit discrete features and are easy to describe (namely, cartoon animals). Amnesic patients were as competent as healthy volunteers in learning to categorize these animals, despite their impairment in recalling the animals' features. The results suggest that the implicit acquisition of category knowledge is a common process in everyday experience, and that it can occur whenever individuals encounter a large group of related items.
10442025	A wordstem priming task (nondeclarative memory), and a mental spatial rotation task (declarative memory) were presented to subjects of an experimental "sleep" group (n = 11) and of a "wake" control group (n = 10). Repetition priming effects and recall of spatial memory were tested after 3-hr retention intervals, which followed learning and were placed either in the early or in the late half of the night. Sleep group subjects slept during the retention intervals while subjects of the wake group stayed awake. As expected, early retention sleep was dominated by slow wave sleep (SWS), whereas rapid eye movement (REM) sleep prevailed during late retention sleep. After early retention sleep, recall of spatial memory was superior to that after late retention sleep (p < 0.01), and also to that after retention intervals of wakefulness (p < 0.05). In contrast, priming was more effective after late than early retention sleep (p < 0.05). It appears that early sleep dominated by SWS facilitates consolidation of declarative memory whereas late sleep dominated by REM sleep facilitates consolidation of nondeclarative memory.
10420098	In addition to the existence of complex memory (similar to the implicit nondeclarative memory of Squire), the existence of a phylogenetically old apparatus of a memory of situations (SMA) is supposed, which is to some extent comparable with the declarative memory of Squire. During actual sensory information the SMA generates a general frame and forms a general 'mark', indicating whether a given information has its origin inside or outside the body, and whether it is new or known. The procedure of this marking process can be explained as the time-depending arrest of a copy of the actual original information-transporting signal 'shower'; this copy must last until the feedback from thalamocortical centers indicates the termination of the processing of the original signal showers. The arrest of the shower copies is the performance of neuronal networks of the entorhinal cortex (EC) and the gyrus dentatus (GD). The psychopathological and biochemical analyses of experimental dibenamine psychosis show a different effect of dibenamine on the noradrenaline (NA) receptors of the EC and GD, respectively: these effects are responsible for the repeated perception cycles of a single situation. N,N-Dibencylamine blocks the postsynaptic alpha(1)-receptors of the EC without influencing the beta-receptors of the GD. Thus the interaction between EC and GD is changed: instead of new scenes, perceptions that have just been experienced get repeated presence and the quality of familiarity. The prolonged arrest of shower copies simultaneously blocks the entrance of new signal showers from the EC to the GD. No information-transporting signal showers can come in as long as the arrest lasts. In case of a disturbance in NA-dependent actions within the EC and the GD, the duration of arrest of information-transporting signal showers is shortened. Thus the formal frame of experience receives the quality of novelty instead of familiarity, and in addition the qualities of uncertainty, vagueness, and alienity. These very changes in perception and experience represent the basic disturbance of schizophrenia. All the symptoms of schizophrenia may be explained by this basic disturbance. The analysis of biochemical aspects turns attention to the energetic situation of NA and N-methyl-D-aspartate systems. These considerations suggest a genetic background of the basic disturbance of schizophrenia: transmitter effects on membranes of neurons and possibly also on glial cells, and energy supply of these effects may be predetermined genetically. It may be assumed that the compensation of such membrane-dependent disturbances will be possible within wide areas of the neural network, except for the 'bottleneck' of the overlapping region of the iso- and allocortex.
10404518	The memory phenomenon is described and characterized giving also definitions connected with it--engrams and learning. Several classifications of memory are reviewed discussing differences between instant and "processed" memory, and memory declarative and procedural. Theories are presented briefly of the nature of memory, the hypothesis of closed neuronal circuits, synaptic plasticity, neurochemical theory, and Fuster's new network theory, including arguments for and against them. Attention is called to the possibility of "watching" of the mechanisms of memory, provided by the introduction of neurovisual methods PET and MRI. Finally, observations are mentioned indicating that subconscious learning occurs more frequently than it is supposed, and the mechanisms of knowledge acquiring in this way are diverse.
10385988	Participants viewed digit strings and typed them on a computer keyboard. When they used the same key configuration across training and test, they typed test strings that adhered to the same sequence rule as training strings faster than test strings that adhered to the opposite rule (general-regularity [GR] learning), and they typed test strings that were processed repeatedly during training faster than test strings that were not (specific-sequence [SS] learning). However, when they used different key configurations at training and at test, GR learning, but not SS learning, was observed. Conversely, when they did not type but spoke the strings aloud during training, SS learning, but not GR learning, was observed. Results suggest that in addition to declarative memory for specific sequences, relatively independent subsystems underlie procedural learning of perceptual-motor sequence components (producing GR effects) and sequence wholes (producing SS effects).
10359467	Glucocorticoids (GCs) can regulate hippocampal metabolism, physiologic functions, and memory. Despite evidence of memory decreases during pharmacological GC treatment, and correlations between memory and cortisol levels in certain disease conditions, it remains unclear whether exposure to the endogenous GC cortisol at levels seen during physical and psychological stress in humans can inhibit memory performance in otherwise healthy individuals.Randomized, double-blind, placebo-controlled comparison of 2 fixed oral doses of cortisol (40 mg/d and 160 mg/d using split doses to approximate circadian rhythm) given for 4 days to matched groups of healthy subjects (n = 51). Lower-dose treatment approximated cortisol exposure during mild stress, whereas the higher dose approximated cortisol exposure during major stress. Cognitive testing and plasma sampling were done at baseline, after 1 and 4 days of treatment, and after a 6-day washout period, hypothesizing dose-dependent decreases in verbal declarative memory.	Cortisol treatment at the higher dose produced reversible decreases in verbal declarative memory without effects on nonverbal memory, sustained or selective attention, or executive function. A significant interaction between time and treatment condition for paragraph recall was explained by treatment-induced differences in performance after 4 treatment days, with lower immediate and delayed recall performance during higher-dose cortisol treatment compared with lower-dose treatment and placebo.	Several days of exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can-similar to pharmacological GC treatment-reversibly decrease specific elements of memory performance in otherwise healthy individuals.	
10356058	Acallosal and callosotomized subjects usually show impairments on tasks requiring bilateral interdependent motor control. However, few studies have assessed the ability of these subjects to learn a skill that requires the simultaneous contribution of each hemisphere in its acquisition. The present study examined whether acallosal and callosotomized subjects could learn a visuomotor skill that involved a motor control from either both or a single hemisphere. Eleven adult patients, six acallosal and five callosotomized, participated in this study. Seven of these patients had epileptic foci located in the frontal and/or temporal areas and one of the acallosal patients showed bilateral prefrontal atrophy following surgical removal of an orbitofrontal cyst. The performance of the experimental subjects was compared with that of 11 matched control subjects, on a modified version of a serial reaction time task developed by Nissen and Bullemer (Cogn Psychol 1987; 19: 1-32). This skill acquisition task involved bimanual or unimanual key-pressing responses to a sequence of 10 visual stimuli that was repeated 160 times. A declarative memory task was then performed to assess explicit knowledge of the sequence. None of the experimental subjects learned the task in the bimanual condition. Patients with frontal epileptic foci or orbitofrontal damage also failed to learn the task in the unimanual condition when they were using the hand contralateral to the damaged hemisphere. All other subjects, including the acallosal and callosotomized patients with temporal foci, learned the visuomotor skill as well as their controls in the unimanual condition. In spite of the absence of transfer and interhemispheric integration of procedural learning, some of the acallosal and callosotomized patients were able to learn the sequence explicitly. These findings indicate that the corpus callosum and the frontal cortical areas are important for procedural learning of a visuomotor skill. They also confirm the dissociation described by Squire (Science 1986; 232: 1612-9 and J Cogn Neurosci 1992; 4: 232-43) between the declarative and procedural memory systems and extend this dissociation to processes involving simultaneous bihemispheric co-operation.
10355239	An important question about the organization of memory is whether information available in non-declarative memory can contribute to performance on tasks of declarative memory. Dorfman, Kihlstrom, Cork, and Misiaszek (1995) described a circumstance in which the phenomenon of priming might benefit recognition memory performance. They reported that patients receiving electroconvulsive therapy improved their recognition performance when they were encouraged to relax their criteria for endorsing test items as familiar. It was suggested that priming improved recognition by making information available about the familiarity of test items. In three experiments, we sought unsuccessfully to reproduce this phenomenon in amnesic patients. In Experiment 3, we reproduced the methods and procedure used by Dorfman et al. but still found no evidence for improved recognition memory following the manipulation of decision criteria. Although negative findings have their own limitations, our findings suggest that the phenomenon reported by Dorfman et al. does not generalize well. Our results agree with several recent findings that suggest that priming is independent of recognition memory and does not contribute to recognition memory scores.
10322468	It is widely acknowledged that the perirhinal cortex, located in the ventromedial aspect of the temporal lobe, is essential for certain types of memory in macaque monkeys. For example, removal of the perirhinal cortex yields severe impairments on tests of stimulus recognition and stimulus-stimulus association. There is considerable disagreement, however, about the most accurate way to characterize the function of the perirhinal cortex; some views emphasize a role in perception whereas others posit a role exclusively in declarative memory. In this article, we review recent findings from anatomical, physiological and ablation studies in monkeys, and discuss related findings obtained in humans, in an attempt to identify not only the cognitive functions of the perirhinal cortex, but also the implications of these findings for theoretical views concerning the organization of memory.
10320870	CPE claim that procedural and declarative representations differ on two important dimensions: flexibility and compositionality. I have proposed that the apparent flexibility of a memory depends entirely on the transfer conditions. Any retest is, in some sense, a test of flexibility, because something has changed since the original encoding episodic. I have argued that if one changes something that does not provide support to memory performance, the memory will appear flexible, and resistant to changes in the environment. If one changes the very thing that the representation codes, the memory will appear inflexible and easily disrupted by changes in the environment. This principle is equally true for procedural and declarative memory. CPE contend that procedural representations lack compositionality. An ideal test of this claim would examine the representation of a task that is widely agreed to be procedural (e.g. that has been demonstrated to be learned normally by amnesic patients, and in the absence of awareness by neurologically intact subjects). Such experiments appear not to have been conducted, and the fact is that many tasks that are widely agreed to be procedural probably are not compositional. They appear to be, as CPE contend, biases in a processing system; it is hard to imagine how repetition priming could be compositional. Nevertheless, this is not true of all procedural memories. There is a good deal of evidence that motor behaviour is organised hierarchically and has compositionality. There is every reason to think that most if not all motor behaviour is procedural; motor behaviour might be driven by goals that are declarative, but the low-level operations that actually manipulate effectors are closed to consciousness, do not depend on the medial temporal lobe or diencephalon, and would therefore be classified as procedural. CPE framed their theory of differences between procedural and declarative memory systems as an account of the deficit in amnesic patients. They therefore predict that the learning of amnesic patients should not show flexibility or compositionality. There is already at least one study showing learning in amnesic patients that is as flexible as that of control participants (Knowlton & Squire, 1996). There are not, to my knowledge, data on whether the motor skill learning of amnesic patients shows compositionality, but one might expect that it would, given that it does in neurologically intact participants, and given that motor skill learning appears unimpaired in amnesic patients. Thus, the conception of declarative and procedural memory provided by CPE may not provide a complete account of amnesic performance. The anatomic distinction between procedural and declarative memory systems appears quite strong, and there is therefore reason to believe that there are accompanying computational differences. There does not, however, appear to be sufficient evidence to support those differences proposed by CPE.
10234230	The question of whether episodic memory, the ability to recall unique, personal experiences, is restricted to humans is a matter of current controversy. Recent work on food-storing jays suggests that several features of episodic memory may not be as exclusive to humans as previously thought. In this review we outline the critical features of episodic memory in humans, its relationship to declarative memory, and recent results revealing that jays can learn to perform a task that depends on certain features of episodic memory and can thus be considered 'episodic-like'. Finally, we compare this avian performance with a contemporary definition of human episodic memory and consider the implications for studies of hippocampal function and animal cognition.
10226772	Macaque monkeys can learn arbitrary mappings between stimuli and spatially directed actions (often termed conditional motor learning), and, after the development of a strong learning set, can do so in just a few trials. Ablation studies have shown that the hippocampus plus subjacent cortex is necessary for this rapid and highly flexible type of learning. We consider evidence that the arbitrary mapping function of the hippocampal system may be more general and fundamental than currently accepted and what limitations there may be, if any, on the information that it can map. Removal of the hippocampal system yields a pattern of deficits and preserved abilities that correlates remarkably closely with that found in human global amnesics, such as patient H.M., on a variety of declarative memory tasks. Thus, the rapid acquisition of arbitrary visuomotor mappings may represent an example of declarative memory in nonhuman primates.
10215093	As an explanation of the pattern of slow information processing after closed head injury (CHI), hypotheses of impaired access to declarative memory and intact application and acquisition of procedural memory after CHI are presented. These two hypotheses were tested by means of four cognitive reaction-time tasks, a semantic memory task, a memory comparison task, a mental rotation task and a mirror reading task. These tasks were administered on two different days to 12 survivors of a CHI tested more than 5 years after injury and a healthy control group of comparable age and education. In three tasks the difficulty of access to declarative knowledge was varied and it was expected that this would slow the CHI group more than the controls. In two tasks opportunities for procedural learning were provided by repeatedly presenting the same cognitive tasks and in one task, the difficulty of access to procedural memory was varied. It was expected that the CHI group would profit as much from this as would the control group. Both hypotheses were supported.
10210177	The hippocampus plays an important role in the declarative or explicit memory in humans and is necessary for allocentric spatial learning and olfactory memory in animals. In primates and rodents, the bilateral hemispheres of the brain (especially the forebrain) symmetrically and asymmetrically contribute to diverse cognitive manipulations. In this study, we investigated the role of the hippocampus in spatial memory and in odor-paired associate memory by unilaterally or bilaterally lesioning this region in rats. The bilateral removal, but not the unilateral removal, of the hippocampus impaired both the acquisition of spatial working memory in the radial maze task and the retrieval of maze performance tested 1 month after the acquisition trials. In contrast, neither bilateral nor unilateral removal impaired the odor-paired associate learning. These findings suggest that the hippocampus is critical to the spatial memory, and that a unilateral hippocampus is sufficient for executing a spatial task. The present results also indicate that the hippocampus plays a minor role in odor-dominated associate learning and that some kinds of memories in rats may be processed independently by the left or right hippocampus.
10202533	The hippocampus is a target of stress hormones, and it is an especially plastic and vulnerable region of the brain. It also responds to gonadal, thyroid, and adrenal hormones, which modulate changes in synapse formation and dendritic structure and regulate dentate gyrus volume during development and in adult life. Two forms of structural plasticity are affected by stress: Repeated stress causes atrophy of dendrites in the CA3 region, and both acute and chronic stress suppresses neurogenesis of dentate gyrus granule neurons. Besides glucocorticoids, excitatory amino acids and N-methyl-D-aspartate (NMDA) receptors are involved in these two forms of plasticity as well as in neuronal death that is caused in pyramidal neurons by seizures and by ischemia. The two forms of hippocampal structural plasticity are relevant to the human hippocampus, which undergoes a selective atrophy in a number of disorders, accompanied by deficits in declarative episodic, spatial, and contextual memory performance. It is important, from a therapeutic standpoint, to distinguish between a permanent loss of cells and a reversible atrophy.
10197901	Three amnesic patients with damage limited to the hippocampal formation, a severely amnesic patient with extensive medial temporal lobe damage, and 9 controls were tested on the transverse patterning problem (A + B-, B + C-, and C + A-) and also on 2 control problems. One of the control problems was matched to the transverse patterning problem with respect to the number of pairwise decisions that were required. The 2nd control problem was matched to the transverse patterning problem with respect to the number of trials needed by controls to learn the task. The amnesic patients were impaired at solving both the transverse patterning problem and the control problems. The findings suggest that impaired learning of the transverse patterning problem by amnesic patients derives from their general impairment in declarative memory, which affects performance on most 2-choice discrimination tasks.
10101736	To investigate the role of glucocorticoids for effects of early and late nocturnal sleep on declarative and procedural memory, 2 mg dexamethasone (versus placebo) were administered to healthy men 7 h prior to retention sleep. The retention sleep interval covered either the early or late half of nocturnal sleep. Following placebo, recall of a paired associate list (declarative memory) benefitted more from early than late sleep and recall of mirror tracing skills (procedural memory) benefitted more from late than early sleep. Dexamethasone did not affect slow wave sleep dominating early sleep, but blocked the beneficial effect of early sleep on recall of paired associates. Conversely, dexamethasone reduced rapid eye movement sleep dominating late sleep, but did not affect late sleeps beneficial effect on mirror tracing skills. The natural inhibition of endogenous glucocorticoid secretion during early sleep seems to be essential for a sleep-related facilitation of declarative memory.
10088903	In the last several years there have been impressive strides in the ability to explore the nature of hippocampal system functioning in humans by employing functional neuroimaging methods, permitting such methods to be used in conjunction with neuropsychological methods to better understand the role of the hippocampal system in memory. In this paper, we review the literature on functional imaging studies of the hippocampal system, summarizing the data and testing these data against a number of theories or explanatory accounts of hippocampal function. We consider five alternative explanatory accounts of, or ideas about, hippocampal function- some from already existing work, for which the functional imaging data can provide a new test, and others that have emerged directly from the functional imaging work, and that have yet to be tested for their fit of data from neuropsychological methods. We conclude that the relational (declarative) memory account, in which it is proposed that the hippocampal system plays a critical role in binding together multiple inputs to permit representations of the relations among the constituent elements of scenes or events, can better accommodate the full range of imaging (and other existing) data than any other explanatory account of hippocampal function.
10088902	This article discusses the potential usefulness of brain/ behavior correlational analyses in functional neuroimaging studies of memory, and how such analyses can illuminate the role of medial temporal lobes (MTL) and the hippocampus in episodic and declarative memory processes such as encoding and retrieval. Reanalysis of the results of four previously reported positron emission tomography (PET) studies yielded evidence of both positive and negative between-subjects correlations between recognition-memory accuracy and regional blood flow. The sites of these correlations were in MTL regions as well as in other cortical and subcortical areas, including frontal lobes (Brodmann areas 6, 9, 10, 11, and 47), temporal lobes (BAs 21, 22, and 38), insula, fusiform gyrus, and cuneus/precuneus. These findings were discussed with respect to issues such as localization of the correlation sites, the distinction between brain sites revealed by brain/cognition correlational analyses ("how" sites) and those yielded by cognitive subtraction methods ("what" sites), the tendency of the "how" sites in MTL to occur in the left hemisphere, the tendency of other "how" sites to occur in one or the other hemisphere, rather than bilaterally, and the meaning and "reality" of both brain/behavior correlations and task-related activations. Because of the known incidence of false-positives, all neuroimaging data, including those involving the localization of "what" and "how" memory sites in MTL and other brain regions, need to be interpreted cautiously, and findings of individual studies should not be overinterpreted.
10088901	In contrast to early failures, recent functional brain imaging studies have shown that medial temporal lobe (MTL) structures are active during performance of a variety of tasks. These studies have revealed three properties of the MTL that are consistent with its critical role in establishing new declarative memories. First, the MTL is automatically engaged whenever an event is experienced, with the side of activation (left, right) dependent on the nature of the material presented (verbal, nonverbal). Second, the strength or amount of activity depends on how well the material is encoded. Deep encoding will produce more MTL activity than shallow encoding. Depth of encoding-related increases in activity are more commonly seen on the left, because deep encoding is nearly always synonymous with encoding for meaning, and, therefore, depends on left-lateralized language mechanisms. Third, the amount of MTL activity depends on novelty. Unfamiliar events and contexts will produce more MTL activity than familiar events and contexts. Novelty-related increases are more commonly seen on the right, perhaps reflecting the greater role of the right hemisphere in maintaining tonic attention and arousal. These findings suggest a hemispheric division of labor involving encoding for meaning (left) and novelty detection (right), both of which lead to better remembering.
10088900	Functional neuroimaging is uniquely placed to examine the dynamic nature of normal human memory, the distributed brain networks that support it, and how they are modulated. Memory has traditionally been classified into context-specific memories personally experienced ("episodic memory") and impersonal non-context-specific memories ("semantic memory"). However, we suggest that another useful distinction is whether events are personally relevant or not. Typically the factors of personal relevance and temporal context are confounded, and it is as yet not clear the precise influence of either on how memories are stored or retrieved. Here we focus on the retrieval of real-world memories unconfounding personal relevance and temporal context during positron emission tomography (PET) scanning. Memories differed along two dimensions: They were personally relevant (or not) and had temporal specificity (or not). Recollection of each of the resultant four memory subtypes-autobiographical events, public events, autobiographical facts, and general knowledge-was associated with activation of a common network of brain regions. Within this system, however, enhanced activity was observed for retrieval of personally relevant, time-specific memories in left hippocampus, medial prefrontal cortex, and left temporal pole. Bilateral temporoparietal junctions were activated preferentially for personal memories, regardless of time specificity. Finally, left parahippocampal gyrus, left anterolateral temporal cortex, and posterior cingulate cortex were involved in memory retrieval irrespective of person or time. Our findings suggest that specializations in memory retrieval result from associations between subsets of regions within a common network. We believe that these findings throw new light on an old debate surrounding episodic and declarative theories of memory and the precise involvement of the hippocampus.
10088898	Functional magnetic resonance imaging (fMRI) with high acquisition rate was performed during the intentional memorizing of words to specify which medial temporal lobe structure is important in determining what words are subsequently remembered in a cued-recall test and to characterize the time course of activation in that structure. Functional images of six healthy young subjects were analyzed by two subject- and voxel-wise statistics: First, to identify brain areas transiently engaged in encoding of words, brain activity during memorizing visually presented words and watching a fixation cross was compared by a Kolmogorov-Smirnov statistic (KS-test). Second, to identify brain areas whose activity correlates with memory encoding success, a Kendall's correlation was calculated between signal intensity at study and performance in a subsequent cued-recall test. Averaged signal intensities were plotted as a function of time to depict the time course of brain activity detected by both statistical tests. The level of slowly modulated, sustained activity in Brodmann area 28 (entorhinal cortex) did not respond transiently as study words appeared, but did correlate positively with subsequent test performance. More left than right activity in Brodmann area 45 (dorso-lateral prefrontal cortex) and bilateral activity in Brodmann area 44 (premotor cortex) exhibited transient hemodynamic responses that did not show any relation to subsequent memory performance. Thus, the study identified a novel pattern of slowly modulated brain activity in human entorhinal cortex that may represent a declarative memory encoding state whose level predicts whether experiences will be remembered or forgotten.
10074814	Animal research indicated that vasopressin (VP) exerts its principle behavioral influence, the improvement of memory formation, through an action on septo-hippocampal and connected limbic structures. Here human research is reviewed with the notion of a comparable effect of VP in healthy humans. Although the human studies yielded less consistent results than those in rats, they indicate that VP is able to improve declarative memory formation which is the type of memory essentially relying on hippocampal function. The effect appears to center on the encoding process for memory. In examinations of event-related brain potentials (ERPs) VP was consistently found to increase the 'mismatch negativity' (MMN) and the P3 components which are ERP potentials closely linked to the hippocampal processing of novel, unexpected and salient events. Enhanced processing of these stimulus aspects is considered to precipitate memory encoding. The regulation of voluntary selective attention and arousal do not appear to be primary targets of VP effects in humans. A mediation of effects by peripheral changes can be excluded since the central nervous effects were observed in studies using intranasal VP administration providing a direct access to brain functions.
10071947	Memory, the ability to store and retrieve information, is essential for learning in children. Modern neurobiology research is revealing some of the fundamental steps that encode memories within networks of neuronal synaptic connections in the brain. Somewhat different networks store verbal declarative memories and habit or procedural memories. Several biochemical steps convert short-term memories into permanent memories. These changes include activation of neurotransmitter and growth factor receptors, intracellular protein kinases, and nuclear transcription factors that stimulate gene expression of memory proteins. The proteins strengthen synaptic connections and stabilize long-term memories. Genetic defects in those pathways appear to be responsible for several human retardation and learning disability syndromes, including Coffin-Lowry syndrome and neurofibromatosis.
10067780	To evaluate the effect of age at various conditioned stimulus (CS)-unconditioned stimulus (US) intervals, 144 young, middle-aged, and older adults were tested on eyeblink classical conditioning at CS-US intervals of 500, 1,000, or 1,500 ms. Reaction time, response timing, motor learning, declarative memory, and attention were assessed to identify correlates of conditioning at various CS-US intervals. Previously reported middle-aged and older adults were impaired at a 400-ms CS-US interval, but the addition of 100 ms to the CS-US interval in this study enabled equal conditioning in middle-aged and young adults. At a 1,000-ms CS-US interval, older adults remained significantly impaired. It was only at the 1,500-ms CS-US interval that conditioning was equal for the 3 age groups. Measures of reaction time, timing, and motor learning were not correlated systematically with conditioning. Whereas the results of age differences at various CS-US intervals were clear and striking, patterns of relationships among neuropsychological and conditioning variables were not consistent in indicating sources of age differences.
10050854	In humans the hippocampal region of the brain is crucial for declarative or episodic memory for a broad range of materials. In contrast, there has been controversy over whether the hippocampus mediates a similarly general memory function in other species, or whether it is dedicated to spatial memory processing. Evidence for the spatial view is derived principally from the observations of 'place cells'-hippocampal neurons that fire whenever the animal is in a particular location in its environment, or when it perceives a specific stimulus or performs a specific behaviour in a particular place. We trained rats to perform the same recognition memory task in several distinct locations in a rich spatial environment and found that the activity of many hippocampal neurons was related consistently to perceptual, behavioural or cognitive events, regardless of the location where these events occurred. These results indicate that nonspatial events are fundamental elements of hippocampal representation, and support the view that, across species, the hippocampus has a broad role in information processing associated with memory.
25147475	Long-term recall memory, as indexed by deferred imitation, was assessed in 12-month-old infants. Independent groups of infants were tested after retention intervals of 3 min, 1 week and 4 weeks. Deferred imitation was assessed using the 'observation-only' procedure in which infants were not allowed motor practice on the tasks before the delay was imposed. Thus, the memory could not have been based on re-accessing a motor habit, because none was formed in the first place. After the delay, memory was assessed either in the same or a different environmental context from the one in which the adult had originally demonstrated the acts. In Experiments 1 and 3, infants observed the target acts while in an unusual environment (an orange and white polka-dot tent), and recall memory was tested in an ordinary room. In Experiment 2, infants observed the target acts in their homes and were tested for memory in a university room. The results showed recall memory after all retention intervals, including the 4 week delay, with no effect of context change. Interestingly, the forgetting function showed that the bulk of the forgetting occurred during the first week. The findings of recall memory without motor practice support the view that infants as young as 12 months old use a declarative (nonprocedural) memory system to span delay intervals as long as 4 weeks.
9973665	Rendaku is a well-documented phenomenon in Japanese phonology in which a word-initial voiceless obstruent becomes voiced when it is the second member of a compound (e.g., ori + kami --> origami 'paper folding'). It was hypothesized that Japanese specifically language-impaired (SLI) children who appear to rely on explicit declarative memory as opposed to implicit procedural memory to learn language would have difficulty forming such compounds: word-initial voiceless obstruents would remain unvoiced in the second members of non-frequent and novel compounds. Six Japanese SLI children, ranging in age from 8;9 to 12;1, 6 age-matched non-SLI children and 4 younger non-SLI children were given a word formation task involving three different categories of compounds. A significant difference in performance between the groups was found. The data indicate that the SLI children did not in fact voice most of the initial obstruents of the second member in non-frequent and novel compounds, whereas the age-matched non-SLI children did voice the appropriate obstruents of all the compounds and the younger non-SLI children voiced some initial obstruents of all the compounds. Qualitative differences in the responses provide evidence that the SLI children did not have or were unable to construct a productive procedural rule of voicing.
9932440	Nitric oxide (NO) is widespread in the nervous system and is thought to play a role in a variety of different neuronal functions, including learning and memory (see other chapters, this volume). A number of behavioral studies have indicated that NO is involved in several types of learning such as motor learning (Yanagihara and Kondo, 1996), avoidance learning (Barati and Kopf, 1996; Myslivecek et al., 1996), olfactory learning (Okere et. al., 1996; Kendrick et al., 1997), and spatial learning (Holscher et al., 1995; Yamada et al., 1996) (for review of earlier papers see Hawkins, 1996). Moreover, NO is thought to be involved in neuronal plasticity contributing to these different types of learning in different brain areas including the cerebellum (chapter by R. Tsien, this volume) and hippocampus. In this chapter we review evidence on the role of NO in long-term potentiation (LTP), a type of synaptic plasticity in hippocampus that is believed to contribute to declarative forms of learning such as spatial learning.
9929668	In a series of studies we have been exploring the role of hippocampal function in memory using the model system of olfactory-hippocampal pathways and odor learning in rats. Our experiments show that hippocampus itself is not essential to memory for single odors, but is critical for forming the representations of relations among odor memories, and for the expression of odor memory representations in novel situations. These studies that exploit the exceptional qualities of olfactory learning are helping to clarify the nature of higher order memory processes in all mammals, and extending to declarative memory in humans.
9892260	We determined the nature and recovery of procedural and declarative memory functioning in a cocaine-abusing cohort in the 45-day period following use.Thirty-seven cocaine abusers and 27 control subjects were administered the following memory and mood measures: California Verbal Learning Test, recall of the Rey-Osterrieth Complex Figure Test, Pursuit Rotor Task, and Profile of Mood States at 4 visits (within 72 hours of admission and at 10, 21, and 45 days following abstinence).	Analysis of performance on the Rey-Osterrieth Complex Figure Test revealed that both groups improved in their recall over repeated administrations, though the control group recalled significantly more of the information than cocaine subjects during the 45-day interval. Results for the California Verbal Learning Test indicated improved learning for both subject groups over time, but no group x time interaction. On the Pursuit Rotor Task, cocaine abusers improved their performance at a faster rate than controls at visit 1. At day 45 (visit 4), cocaine abusers again showed improvement on the Pursuit Rotor Task, whereas controls demonstrated a relative plateau in rate of learning.	This study documented a lasting detrimental effect on a sensitive nonverbal declarative memory task in cocaine-dependent subjects following abstinence of 45 days. In contrast, abstinence from cocaine during this 45-day period was associated with sustained improvement on a motor learning test in the cocaine abusers relative to controls.	
9885791	N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are reported to induce schizophrenia-like symptoms in humans, including cognitive impairments. Shortcomings of most previous investigations include failure to maintain steady-state infusion conditions, test multiple doses and/or measure antagonist plasma concentrations. This double-blind, placebo-controlled, randomized, within-subjects comparison of three fixed subanesthetic, steady-state doses of intravenous ketamine in healthy males (n = 15) demonstrated dose-dependent increases in Brief Psychiatric Rating Scale positive (F[3,42] = 21.84; p < 0.0001) and negative symptoms (F[3,42] = 2.89; p = 0.047), and Scale for the Assessment of Negative Symptoms (SANS) total scores (F[3,42] = 10.55; p < 0.0001). Ketamine also produced a robust dose-dependent decrease in verbal declarative memory performance (F[3,41] = 5.11; p = 0.004), and preliminary evidence for a similar dose-dependent decrease in nonverbal declarative memory, occurring at or below plasma concentrations producing other symptoms. Increasing NMDA receptor hypofunction is associated with early occurring memory impairments followed by other schizophrenia-like symptoms.
9884144	Understanding the nature of cognitive deficits among adolescent patients with fetal alcohol syndrome (FAS) can direct future research on assessment and intervention. In an exploratory study, nine nonretarded teenagers with FAS were administered tests of IQ and adaptive behavior, and neuropsychological tests presumed sensitive to alcohol effects. Their performance was compared with psychometric norms and to data from a sample of 174 adolescents with minimal or no prenatal alcohol exposure. These nonretarded FAS patients commonly showed behavior problems, decreased social competence, and poor school performance. Neuropsychological testing revealed significant deficits, although no one neuropsychological profile characterized all patients and not all tests revealed problems. Relatively intact performance was observed in procedural memory, some measures of reaction time, and some reading measures. Deficits were seen on attentional and memory tasks tapping visual-spatial skills, short-term auditory attention and memory, declarative learning, and cognitive flexibility and planning. Difficulties in processing speed and accuracy were also seen. Comparison with a subgroup of 52 nonalcohol-exposed or minimally alcohol-exposed adolescents with a similar range of IQ scores demonstrated that deficits among these FAS patients were not fully explained by a general lowering of IQ.
9884125	Male tree shrews were exposed to alternating non-stressful and stressful conditions, and their memory performance was tested during three different stress periods and after rest periods of various lengths using a modified holeboard. This paradigm circumvents confounding factors, e.g. food or water deprivation, transport to a special testing arena, and excludes the development of automatic cognitive processes by complex memory tasks. In experimental tree shrews, psychosocial conflict caused elevated cortisol levels during the stress phases. While this resulted in an impairment of the stress-sensitive declarative memory during the second stress phase, no memory deficit was found during the first and third stress phase. Despite normalized cortisol levels, significant memory deficits in experimental animals were observed even 10 weeks after the last stressful experience. The alternating order of stressful events revealed that the negative correlation between the level of adrenal steroid hormones and memory performance does not account for the long-lasting effects of psychosocial stress in tree shrews.
9868706	In this study, neuroanatomical correlates of encoding and retrieval in paired associate learning were evaluated with positron emission tomography using auditorily presented highly imaginable words.Six right-handed normal male volunteers took part in the study. Each subject underwent six O-15-butanol PET scans. On each of the six trials the memory task began with the injection of a bolus of O-15-butanol. The subjects had to learn and retrieve twelve word pairs (highly imaginable words, not semantically related). The presentation of nonsense words served as reference condition.	Recall accuracy after 2-4 presentations was high during the PET measurement. In both encoding and retrieval we found anterior cingulate activation. We show bilateral dorsolateral prefrontal activation during the encoding of auditorily presented word pair associates, whereas retrieval led to left frontal activation. Furthermore, we demonstrate the importance of the precuneus in the retrieval of highly imaginable word-pair associates.	Our results support the hypothesis of the presence of distributed widespread brain structures subserving episodic declarative memory.	
9867232	We present neuroanatomical correlates of encoding and retrieval in an episodic memory task using visually presented highly imaginable word-pair associates. A total of 13 right-handed normal male volunteers took part in the study. Each subject underwent six (15)O-butanol PET scans. On each of the six trials the memory task began 30 s before the injection of a bolus of (15)O-butanol. The subjects had to learn and retrieve 12 word pairs (highly imaginable words, not semantically related, hard associations). The presentation of nonsense words served as a reference condition. Recall accuracy after 2-4 presentations was 66.1%+/-21.1 correct during the PET measurement so that scanning during the retrieval of word pair associates was appropriate to capture the brain activity associated with retrieval. The results obtained support the hypothesis of the presence of an asymmetric network consisting of distributed brain structures subserving associative memory. We show left dorsolateral prefrontal activation during the encoding of visually presented word pair associates, whereas retrieval led to bilateral frontal activation. Furthermore, the importance of the precuneus in the retrieval of highly imaginable word-pair associates using visual imagery as a mnemonic strategy is demonstrated.
9865857	Human participants were instructed to walk out along each of the arms of a 15-m in diameter, 8-arm radial maze once and only once. In order to approximate the circumstances under which laboratory rats remember visited sites, our human participants were asked to select arms in an unsystematic order. They scored an average of 7.6 to 7.8 correct choices, even if midway during a trial there was a 5-min interruption filled with a verbal-spatial interfering task (a scavenger hunt) or a 15-min interruption filled with a visuospatial task (a maze-running computer simulation). This finding extends our earlier research with humans in 13- or 17-arm radial mazes under nondelay conditions, in which we also found working memory (WM) capacity for about 7 to 9 places, the same as that of laboratory rats. We discuss earlier findings in other laboratories, showing that rats can successfully bridge long radial maze task interruptions of 5 or 8 h, and we compare our results also to those from studies in which human participants were not discouraged from reducing memory load by responding systematically in radial mazes. Because the radial maze task takes minutes to complete even under nondelay conditions its routine consideration as a working memory task in the animal literature alters the assumptions often made about the duration of WM in the human literature. Accumulating empirical findings about place-memory in humans, nonhuman mammals, and birds suggest it might be productive to reevaluate this theoretical issue with respect to present knowledge about the roles of the hippocampus and other brain structures in declarative memory and in procedural or implicit memory, while considering the hypothesis that some forms of information may exploit long-term memory in parallel with working memory.
9836525	To test the hypothesis that glycemic thresholds for cognitive dysfunction during hypoglycemia, like those for autonomic and symptomatic responses, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM), 15 patients were studied on two occasions. Cognitive functions were assessed during morning hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) after, in random sequence, nocturnal (2330-0300) hypoglycemia (48 +/- 2 mg/dl) on one occasion and nocturnal euglycemia (109 +/- 1 mg/dl) on the other. Compared with nondiabetic control subjects (n = 12), patients with T1DM had absent glucagon (P = 0.0009) and reduced epinephrine (P = 0.0010), norepinephrine (P = 0.0001), and neurogenic symptom (P = 0.0480) responses to hypoglycemia; the epinephrine (P = 0.0460) and neurogenic symptom (P = 0.0480) responses were reduced further after nocturnal hypoglycemia. After nocturnal hypoglycemia, in contrast to nocturnal euglycemia, there was less deterioration of cognitive function overall (P = 0.0065) during hypoglycemia based on analysis of the sum of standardized scores (z-scores). There was relative preservation of measures of pattern recognition and memory (the delayed non-match to sample task, P = 0.0371) and of attention (the Stroop arrow-word task, P = 0.0395), but not of measures of information processing (the paced serial addition task) or declarative memory (the delayed paragraph recall task), after nocturnal hypoglycemia. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, like those for autonomic and symptomatic responses to hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with T1DM.
9829453	The integrity of the hippocampal formation is necessary for the correct function of declarative memory for facts and events. Normal aging is associated with a widespread decrease in cortical volume, including the hippocampal formation and related cortical areas, although in many cases, memory is only minimally impaired. In the present study, we quantified the extent of the parahippocampal gyrus (entorhinal cortex, as well as the medial temporal lobe proisocortical areas related to memory function, such as temporopolar cortex, perirhinal cortex, and posterior parahippocampal cortex) in 42 control cases. After detailed cytoarchitectonic analysis (based on homology with the nonhuman primate medial temporal lobe), planimetric measurement (calculated area) of a two-dimensional reconstruction of the parahippocampal gyrus was performed, and cases older than 70 years were compared with cases younger than 70 years. All areas showed atrophy with aging (average, entorhinal cortex, 5%; perirhinal cortex, 4%; posterior parahippocampal cortex, 15%; temporal pole, not assessable). Both entorhinal and posterior parahippocampal cortices reached statistical significance. Our results suggest that cortical areas relevant in memory function, and anatomically linked to the hippocampus, present a small degree of atrophy with aging, thereby permitting the reciprocal flow of information between the hippocampus and the cerebral cortex necessary for memory encoding and retrieval.
9826730	Participation of two medial temporal lobe structures, the hippocampal region and the amygdala, in long-term declarative memory encoding was examined by using positron emission tomography of regional cerebral glucose. Positron emission tomography scanning was performed in eight healthy subjects listening passively to a repeated sequence of unrelated words. Memory for the words was assessed 24 hr later with an incidental free recall test. The percentage of words freely recalled then was correlated with glucose activity during encoding. The results revealed a striking correlation (r = 0.91, P < 0.001) between activity of the left hippocampal region (centered on the dorsal parahippocampal gyrus) and word recall. No correlation was found between activity of either the left or right amygdala and recall. The findings provide evidence for hippocampal involvement in long-term declarative memory encoding and for the view that the amygdala is not involved with declarative memory formation for nonemotional material.
9802132	Aging is accompanied by a continuous decline of the adrenal steroid hormone DHEA and its ester DHEAS. Results from studies in rodents have demonstrated that DHEA(S) administration can enhance memory in several test paradigms. However studies from this laboratory did not find positive effects of DHEA treatment on cognitive performance in young and elderly humans. With respect to a possible mechanism of DHEA activity, effects on several neurotransmitter receptors as well as a possible antiglucocorticoid action are discussed. For high levels of glucocorticoids, a disruptive effect on hippocampal mediated memory is documented in rodents and humans. Therefore it was speculated that, if an antiglucocorticoid action of DHEA would underlie the observed beneficial effects of DHEA on memory, these effects might only be detectable if subjects are stressed (and therefore have high cortisol levels). To test this hypothesis 75 elderly women and men participated in a placebo controlled experiment. Subjects took DHEA (50 mg/day) or placebo for 2 weeks (double blind). Thereafter they participated in a standardized psychosocial laboratory stressor (Trier Social Stress Test; TSST). Before and after stress exposure subjects completed two declarative memory tests (visual-verbal and spatial) as well as one attention test. In addition recall of visual material learned before stress was assessed after stress. Baseline DHEAS levels were significantly lower compared with young adults. DHEA replacement increased DHEAS levels into ranges found in young subjects. DHEA-substituted subjects showed a trend towards a larger cortisol stress response. In the visual memory test subjects under DHEA recalled less items after stress which they had learned before stress. In the attention test however subjects under DHEA performed better than subjects from the placebo group after stress. No interaction between stress and DHEA was found for the spatial memory task. The effects of DHEA substitution on memory and attention after stress exposure seem to be heterogenous. While recall of previously learned material seems to be impaired, attention is enhanced. These results do not support the idea of a direct antiglucocorticoid or anti-stress effect of DHEA on hippocampal mediated memory functions.
9800094	The distinction between procedural and declarative memory is widely accepted in the memory literature. Converging evidence makes a strong case that the medial aspects of the temporal lobes and the diencephalon subserve the declarative memory system. However, the neuroanatomy of procedural memory is much less clear. In animal studies, damage to the basal ganglia has been found to affect procedural memory, but studies of patients suffering from degenerative diseases of the basal ganglia (e.g., Parkinson's and Huntington's disease) are less conclusive. Two groups of Parkinson's disease subtypes, with tremor (PDt) and bradykinesia (PDb) as the predominant motor symptom, were compared to controls on declarative and procedural memory tasks. The two patient groups did not differ from each other on the declarative tasks. However, in the procedural learning tasks, the PDb but not the PDt group, was significantly impaired compared to the control group. The results are discussed in terms of the differential involvement of discrete neuroanatomic loops connecting the basal ganglia and the prefrontal cortex.
9774737	Previous research has shown that glucose can enhance memory in animals and humans. In humans, the facilitative effect of glucose is best observed with declarative memory tasks in older subjects. While the memory-enhancing action of glucose is well established, the underlying physiological mechanisms and the specific aspects of memory that are modulated by glucose in humans are not well understood. The present study sought to examine the effects of glucose on memory in young women using a memory paradigm sensitive to specific encoding and retrieval strategies. The glucose dose was adjusted for the weight of each participant in order to generate a dose response curve covering most doses used in previous studies. The results showed that 300 mg/kg glucose enhanced the primacy effect as defined by the recall of the first five items of the lists. However, none of the doses of glucose produced changes in the recall priority given to primacy items. The effect of glucose appears to be localized on the recall primacy effect, suggesting that glucose acts on precise memory operations. This improvement, however, is independent of the order in which subjects recalled the words. Cholinergic drugs have been shown to alter the recall of the primacy part of word lists and this observation is consistent with the hypothesis that glucose acts on memory through an interaction with brain cholinergic systems.
9759333	Two recent findings are summarized here that bear on the organization of memory and brain systems. First, the capacity for simple recognition of familiarity (a form of declarative memory) depends on the hippocampal region in both humans and nonhuman primates. Second, probabilistic classification learning (a form of nondeclarative memory akin to habit learning) depends on the caudate nucleus and putamen. These findings are related to the classification of long-term memory and current understanding of the participating brain systems.
9753602	Investigations of the neural basis of mammalian memory have focused more often on the medial temporal lobe (MTL) than on any other brain region. In humans, the amnesic syndrome revealed the essential importance of the multiple structures located in the MTL system for declarative memory (the remembrance of events and facts). Other neural systems mediate procedural forms of memory, including delay eyeblink conditioning, which depends on the cerebellum, and cognitive skill learning, which depends on the striatum. We review three functional imaging studies that reveal different patterns of MTL activation associated with declarative and procedural memory tasks. One study shows separate MTL activations during the encoding or retrieval of declarative memories. A second study shows MTL activation that occurs in parallel with cerebellum-dependent delay eyeblink conditioning, but does not appear to influence that form of procedural memory. A third study reveals suppression of the MTL during striatum-dependent cognitive skill learning. These studies provide images of MTL activations that are correlated with, independent from, or antagonistic to memory performance.
9753151	Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.
9744966	Functional properties of motor memory change with the passage of time. The time-dependent nature of memories in humans has also been demonstrated for certain "declarative" memories. When the declarative memory system is damaged, are the time-dependent properties associated with motor memories intact? To approach this question, we examined five subjects with global amnesia (AMN), including subject H.M., and a group of age-matched control subjects. The task was to make reaching movements to visually presented targets. We found that H.M. (but not the other subjects) was significantly impaired in the ability to perform the visuomotor kinematic transformations required in this task, to accurately move the hand in the direction specified by a target. With extensive practice, H.M.'s performance improved significantly. At this point, a force field was imposed on the hand. With practice in field A, H.M. and other AMN subjects developed aftereffects and maintained these aftereffects for 24 h. To quantify postpractice properties associated with motor memories, subjects learned field B on day 2 and at 5 min were retested in field A. In both subject groups, performance in field A was significantly worse than their own naive performance a day earlier. The aftereffects indicated persistence of the just-learned but now inappropriate motor memory. After 4 h of rest, subjects were retested in B. Performance was now at naive levels. The aftereffects at 4 h indicated a reduced influence of the memory of field A. The time-dependent patterns of motor memory perseveration, as measured at 5 min and 4 h, were not different in the AMN and normal control groups.
9742509	An effect size analysis of neurocognitive function in patients with major depressive disorder using meta-analytic principles was conducted. The results from 726 patients with depression and 795 healthy normal controls revealed that depression had the largest effect on measures of encoding and retrieval from episodic memory. Intermediate effect sizes were recorded on tests of psychomotor speed and tests that require sustained attention. Minimal effect sizes were found on tests of semantic memory, primary memory, and working memory. Moreover, major depressive disorder is accompanied by dysfunction of effortful encoding of information along with an accompanying inefficiency of retrieving poorly encoded information from declarative memory.
9723934	Recently, Doyon et al. [20] demonstrated that lesions to both the striatum and to the cerebellum in humans produce a similar deficit in the learning of a repeated visuomotor sequence, which occurs late in the acquisition process. We now report the results of two experiments that were designed to examine whether this impairment was due to a lack of automatization of the repeating sequence of finger movements by using a dual-task paradigm and by testing for long-term retention of this skill. In Experiment 1, the performance of groups of patients with Parkinson's disease, or with damage to the cerebellum or to the frontal lobes, was compared to that of matched control subjects on the Repeated Sequence Test (primary task) and the Brooks' Matrices Test (secondary task). These two tests were administered concomitantly in both early and late learning phases of the visuomotor sequence. Overall, the groups did not differ in their ability to execute the primary task. By contrast, in accordance with the predictions, patients in Stages 2-3 of Parkinson's disease or with a cerebellar lesion failed to reveal the expected increase in performance on the secondary task seen with learning, suggesting that the latter groups of patients did not have access to the same level of residual cognitive resources to complete the matrices compared to controls. In Experiment 2, the same groups of patients and control subjects were retested again 10-18 months later. They were given four blocks of 100 trials each of the repeating sequence task, followed by a questionnaire and a self-generation task that measured their declarative knowledge of that sequence. The results revealed a long-term retention impairment only in patients who changed from Stage I to Stage II of the disease (suggesting further striatal degeneration) during the one-year interval, or who had a cerebellar lesion. By contrast, performance of the three clinical groups did not differ from controls on declarative memory tests. These findings suggest that both the striatum and the cerebellum participate to the automatization process during the late (slow) learning stage of a sequence of finger movements and that these structures also play a role in the neuronal mechanism subserving long-term retention of such a motor sequence behavior.
9711471	The effect of 3 dosages of bromazepam administered as single oral doses (1.5, 3 and 6 mg) on anxious inhibition phenomena was studied in a population of 16 young women (18-30 years) with anxiety-traits, selected on the criteria of Cattell's anxiety scale supported by two personality inventory (Eysenck's, MMPI). A double-blind, placebo study design was chosen. The main assessment criteria were based on the go/no-go test (Logan's procedure), slow response rate (SRR) and a task of forced or unforced decision (use of the CFF). Attentional processes and declarative memory were analyzed as secondary criteria. None of the three dosages modified inhibition or acting-out. Sustained attention was reduced with 1.5 mg and 6 mg, as was memory performance with 3 and 6 mg, 3.5 h after drug administration. In contradistinction with studies carried out in healthy volunteers or with other benzodiazepine compounds, bromazepam at single low dosages does not modify inhibition capacity in these subjects with traits of anxiety, in this particular procedure.
9710353	This review focuses on experiments in humans examining the regulation of the hypothalamo-pituitary-adrenal (HPA) system during nocturnal sleep. The HPA system is a most important mediator of the organism's response to stress. The early phase of nocturnal sleep dominated by extended epochs of slow wave sleep (SWS), is the only time of day in which secretory activity of this axis is subject to a pronounced and persistent inhibition resulting in minimum concentrations of ACTH and cortisol. During late sleep predominated by rapid eye movement (REM) sleep. HPA secretory activity reaches a diurnal maximum. Comparison of the response to administration of exogenous secretagogues of ACTH in men during sleep and nocturnal wakefulness indicated that early sleep, and in particular SWS, is associated with an inhibition of pituitary-adrenocortical responsiveness, which is presumably due to hypothalamic secretion of an as yet unknown release inhibiting factor of ACTH. Pituitary-adrenocortical responsiveness during early sleep was disinhibited after canrenoate which is a selective blocker of mineralocorticoid receptors (MR) located primarily in limbic-hippocampal structures. Hippocampal neuronal networks are known to integrate corticosteroid feedback via both, the MR and the classical glucocorticoid receptor (GR). Prevailing MR related activity in this network seems to act as a trigger for the inhibition of the HPA system. During early sleep, the same hippocampal network appears to be concurrently involved in the formation of declarative memory. Activation of GR after administration of dexamethasone completely blocked the formation of declarative memory during early sleep, indicating that the inhibition of HPA secretory activity is a necessary prerequisite for this memory process. Dysfunction of the described neuro-endocrine mode of regulation during early sleep is present in patients with Cushing's disease, in patients with severe depression and in aged humans. All of these groups show insufficient inhibition of HPA secretory activity particular prominent during early sleep, and reduced SWS in concert with impairments of declarative memory function. First clinical trials suggest that this trias of symptoms may benefit from intranasal treatment with neuropeptides like vasopressin and growth hormone releasing hormone.
9700804	Using the Tower of Hanoï puzzle, Butters, et al. in 1985 illustrated the difficulties in learning the procedure and questioned the suitability of this task for assessment of the cognitive procedural memory in Korsakoff's syndrome. Our objective, in the light of these criticisms, was to show preservation of cognitive procedure capacities with the Tower of Hanoï for a man (P.F.) who was suffering from alcoholic Korsakoff's syndrome. For this procedural task, some aids helped to compensate in part for the difficulties with declarative memory and with working memory. In this condition, P.F. was able to learn the cognitive procedure. This study suggests that cognitive procedure memory may be preserved in some patients suffering from Korsakoff's syndrome and that this may be shown when a suitable task is used. The result makes it possible to discuss the interaction between declarative and procedural knowledge in the solving of the Tower of Hanoï.
9683321	Neuroscience is witnessing growing interest in understanding brain mechanisms of memory formation for emotionally arousing events, a development closely related to renewed interest in the concept of memory consolidation. Extensive research in animals implicates stress hormones and the amygdaloid complex as key, interacting modulators of memory consolidation for emotional events. Considerable evidence suggests that the amygdala is not a site of long-term explicit or declarative memory storage, but serves to influence memory-storage processes in other brain regions, such as the hippocampus, striatum and neocortex. Human-subject studies confirm the prediction of animal work that the amygdala is involved with the formation of enhanced declarative memory for emotionally arousing events.
9673996	Schizophrenia affects prefrontal and temporal-limbic networks. These regions were examined by contrasting regional cerebral blood flow (rCBF) during executive (Wisconsin Card Sorting Test [WCST]), and declarative memory tasks (Paired Associate Recognition Test [PART]). The tasks, and a resting baseline, were administered to 15 patients with schizophrenia and 15 healthy controls during 10 min positron emission tomography 15O-water measures of rCBF. Patients were worse on both tasks. Controls activated inferior frontal, occipitotemporal, and temporal pole regions for both tasks. Similar results were obtained for controls matched to level of patient performance. Patients showed no activation of hypothesized regions during the WCST and activated the dorsolateral prefrontal cortex during the PART. On the PART, occipitotemporal activation correlated with better performance for controls only. Better WCST performance correlated with CBF increase in prefrontal regions for controls and in the parahippocampal gyrus for patients. Results suggest that schizophrenia may involve a breakdown in the integration of a frontotemporal network that is responsive to executive and declarative memory demands in healthy individuals.
9672817	This research investigated whether subjects with Alzheimer's disease (AD) and ischaemic vascular dementia (IVD) associated with periventricular and deep white matter alterations can be dissociated on tests of declarative and procedural memory, as well as on MRI indices of white matter alterations and the size of the hippocampal formation. The California Verbal Learning Test (CVLT) and the Pursuit Rotor Learning Tests (PRLT) were used to measure declarative and procedural memory, respectively. Subjects with IVD obtained a higher score on the CVLT recognition discriminability index; however, on the PRLT total time on target, carry-over between trial blocks, and slope calculated for all test trials was low. Subjects with AD exhibited the opposite profile. MRI studies indicated that subjects with IVD had considerably greater white matter alterations, but larger hippocampal formations than subjects with AD. Higher scores on the CVLT recognition discriminability index were correlated with increased size of the body of the hippocampus and parahippocampal gyrus. By contrast, as the severity of white matter alterations increased the slope on the PRLT declined. In sum, subjects with AD and IVD can be dissociated on the basis of differing patterns of impairment on tests of declarative and procedural memory, and MRI indices of white matter alteration and the integrity of the hippocampal formation.
9662135	Episodic memory and semantic memory are two types of declarative memory. There have been two principal views about how this distinction might be reflected in the organization of memory functions in the brain. One view, that episodic memory and semantic memory are both dependent on the integrity of medial temporal lobe and midline diencephalic structures, predicts that amnesic patients with medial temporal lobe/diencephalic damage should be proportionately impaired in both episodic and semantic memory. An alternative view is that the capacity for semantic memory is spared, or partially spared, in amnesia relative to episodic memory ability. This article reviews two kinds of relevant data: 1) case studies where amnesia has occurred early in childhood, before much of an individual's semantic knowledge has been acquired, and 2) experimental studies with amnesic patients of fact and event learning, remembering and knowing, and remote memory. The data provide no compelling support for the view that episodic and semantic memory are affected differently in medial temporal lobe/diencephalic amnesia. However, episodic and semantic memory may be dissociable in those amnesic patients who additionally have severe frontal lobe damage.
9662134	The fact that medial temporal lobe structures, including the hippocampus, are critical for declarative memory is firmly established by now. The understanding of the role that these structures play in declarative memory, however, despite great efforts spent in the quest, has eluded investigators so far. Given the existing scenario, novel ideas that hold the promise of clarifying matters should be eagerly sought. One such idea was recently proposed by Vargha-Khadem and her colleagues (Science 1997; 277:376-380) on the basis of their study of three young people suffering from anterograde amnesia caused by early-onset hippocampal pathology. The idea is that the hippocampus is necessary for remembering ongoing life's experiences (episodic memory), but not necessary for the acquisition of factual knowledge (semantic memory). We discuss the reasons why this novel proposal makes good sense and why it and its ramifications should be vigorously pursued. We review and compare declarative and episodic theories of amnesia, and argue that the findings reported by Vargha-Khadem and her colleagues fit well into an episodic theory that retains components already publicized, and adds new ones suggested by the Vargha-Khadem et al. study. Existing components of this theory include the idea that acquisition of factual knowledge can occur independently of episodic memory, and the idea that in anterograde amnesia it is quite possible for episodic memory to be more severely impaired than semantic memory. We suggest a realignment of organization of memory such that declarative memory is defined in terms of features and properties that are common to both episodic and semantic memory. The organization of memory thus modified gives greater precision to the Vargha-Khadem et al. neuroanatomical model in which declarative memory depends on perihippocampal cortical regions but not on the hippocampus, whereas episodic memory, which is separate from declarative memory, depends on the hippocampus.
26734920	We measured hippocampal volumes and cognitive functioning in crack-cocaine and crack-cocaine/alcoholdependent subjects (abstinent approximately 10-12 weeks) compared to age-matched controls. Cognitive function was evaluated using the computerized MicroCog Assessment of Cognitive Functioning (which includes tests of explicit, declarative memory subserved by the hippocampus). The hippocampal volumes were quantified on T1-weighted MRIs and were expressed as a proportion of intracranial vault volume. Both subjects and controls showed the larger right versus left hippocampal volume expected in normal anatomy, but we found no differences in hippocampal volume between any of the groups. However, both abstinent cocaine-dependent subjects and abstinent cocaine/alcohol-dependent subjects showed persistent cognitive impairments, including deficits in explicit memory. Our results suggest that either: (1) the hippocampus is resistant to structural volume loss in young and middle-aged cocaine or cocaine/alcohol-dependent subjects, (2) the hippocampal volume loss suffered by young and middle-aged cocaine or cocaine/alcohol-dependent subjects resolves after approximately 3 months of abstinence, or (3) hippocampal atrophy is obscured by the process of gliosis. Further, the cognitive impairments persisting in these abstinent cocaine and cocaine/alcohol-dependent samples may (1) be unrelated to hippocampal function or (2) be associated with abnormal hippocampal function that is not reflected in MRI measures of overall hippocampal atrophy. 
9514771	Information-processing models of childhood anxiety highlight the centrality of memory processes in the maintenance and intensification of anxiety. Recent advances in memory research allow for an increasingly fine-grained analysis of the relation between anxiety and memory. The relation between childhood anxiety and memory was examined in a sample of 160 high- and low-trait-anxious sixth through eighth grade children. Results indicated that anxiety predicted a memory bias toward negative relative to neutral information during conceptual but not perceptual tasks. Further, anxiety predicted a memory bias toward positive relative to neutral information on procedural tasks and a memory bias away from positive relative to neutral information on declarative tasks. These findings accent the complexity and multidimensionality of relations among childhood anxiety, the emotional valence of stimuli, types of cognitive processing, and memory systems in contributing to biases in children's memory functioning.
9556765	Font-specificity in visual word-stem completion priming was examined in patients with global amnesia and Patient M.S., who had a right-occipital lobectomy. Word-stems appeared in the same or different font as study words. Amnesic patients showed normal font-specific priming (greater priming for words studied in the same than different font as test), despite impaired word-stem cued recall. Patient M.S. failed to exhibit font-specific priming, despite preserved declarative memory. Therefore, perceptual specificity in visual priming depends on visual processes mediated by the right-occipital lobe rather than medial temporal and diencephalic regions involved in declarative memory.
9525860	Classical conditioning of the eye-blink response, perhaps the best studied example of associative learning in vertebrates, is relatively automatic and reflexive, and with the standard procedure (simple delay conditioning), it is intact in animals with hippocampal lesions. In delay conditioning, a tone [the conditioned stimulus (CS)] is presented just before an air puff to the eye [the unconditioned stimulus (US)]. The US is then presented, and the two stimuli coterminate. In trace conditioning, a variant of the standard paradigm, a short interval (500 to 1000 ms) is interposed between the offset of the CS and the onset of the US. Animals with hippocampal lesions fail to acquire trace conditioning. Amnesic patients with damage to the hippocampal formation and normal volunteers were tested on two versions of delay conditioning and two versions of trace conditioning and then assessed for the extent to which they became aware of the temporal relationship between the CS and the US. Amnesic patients acquired delay conditioning at a normal rate but failed to acquire trace conditioning. For normal volunteers, awareness was unrelated to successful delay conditioning but was a prerequisite for successful trace conditioning. Trace conditioning is hippocampus dependent because, as in other tasks of declarative memory, conscious knowledge must be acquired across the training session. Trace conditioning may provide a means for studying awareness in nonhuman animals, in the context of current ideas about multiple memory systems and the function of the hippocampus.
9528044	To describe the current typology and different processes involved in memory and learning, as well as adequate tests in the diagnosis of the mnesic disorders.We reviewed the most recent studies about functional and lesional neuroanatomy of memory and learning and their neurophysiological bases (cellular and biochemical), with special emphasis in studies published in the three last years. We structured a typological classification, we expose the processes involved in short-term and long-term memory, we detailed the mnesic processes of declarative and implicit type, and we expose profiles of amnesias frequent in the clinical neurology and neuropsychology.	Memory is not a diffuse and unitary process in our brain, neither amnesia is an absolute loss of memory. The multidimensional combination of two temporary memories (short- and long-term) and three mnesic processes ('working memory', explicit and implicit memory-learning) increases our capacity to memorize and learn, and it allows us to store the information in distinctive periods, with different mechanisms and covering different necessities. Patients with amnesia exhibit distinctive profiles of mnesic processes affected.	
9496622	Current knowledge is summarized about long-term memory systems of the human brain, with memory systems defined as specific neural networks that support specific mnemonic processes. The summary integrates convergent evidence from neuropsychological studies of patients with brain lesions and from functional neuroimaging studies using positron emission tomography (PET) or functional magnetic resonance imaging (fMRI). Evidence is reviewed about the specific roles of hippocampal and parahippocampal regions, the amygdala, the basal ganglia, and various neocortical areas in declarative memory. Evidence is also reviewed about which brain regions mediate specific kinds of procedural memory, including sensorimotor, perceptual, and cognitive skill learning; perceptual and conceptual repetition priming; and several forms of conditioning. Findings are discussed in terms of the functional neural architecture of normal memory, age-related changes in memory performance, and neurological conditions that affect memory such as amnesia. Alzheimer's disease, Parkinson's disease, and Huntington's disease.
9448364	Previous studies of the neuropsychological consequences of insulin dependent diabetes mellitus (IDDM) have had mixed and often contradictory results, possibly due to the heterogeneity of the samples and neuropsychological measures, and a lack of specific hypotheses. In order to address this problem, we focused on the effect of severe hypoglycemia on memory functioning in a relatively homogeneous sample of childhood-onset IDDM patients. Given the deleterious effects of hypoglycemia on medial temporal lobe structures (e.g., hippocampus) and the relationship between medial temporal damage and declarative memory functioning, we hypothesized that those patients who had experienced severe hypoglycemia would demonstrate impaired declarative memory and spared nondeclarative memory functioning. Results of the study were generally consistent with this hypothesis, although some impact of hypoglycemia was observed on perceptual priming ability.
9412524	Recent data obtained using a classic fear conditioning paradigm showed a dissociation between the retention of associations relative to contextual information (dependent on the hippocampal formation) and the retention of elemental associations (dependent on the amygdala). Furthermore, it was reported that conditioned emotional responses (CERs) could be dissociated from the recollection of the learning experience (declarative memory) in humans and from modifications of the hippocampal-septal excitability in animals. Our aim was to determine whether these two systems ("behavioral expression" system and "factual memory" system) interact by examining the consequences of amygdalar lesions (1) on the modifications of hippocampal-septal excitability and (2) on the behavioral expression of fear (freezing) resulting from an aversive conditioning during reexposure to conditional stimuli (CSs). During conditioning, to modulate the predictive nature of the context and of a discrete stimulus (tone) on the unconditional stimulus (US) occurrence, the phasic discrete CS was paired with the US or randomly distributed with regard to the US. After the lesion, the CER was dramatically reduced during reexposure to the CSs, whatever the type of acquisition. However, the changes in hippocampal-septal excitability persisted but were altered. For controls, a decrease in septal excitability was observed during reexposure to the conditioning context only for the "unpaired group" (predictive context case). Conversely, among lesioned subjects this decrease was observed in the "paired group" (predictive discrete CS case), whereas this decrease was significantly reduced in the unpaired group with respect to the matched control group. The amplitude and the direction of these modifications suggest a differential modulation of hippocampal-septal excitability by the amygdala to amplify the contribution of the more predictive association signaling the occurrence of the aversive event.
9438786	Extended exposure to study material can markedly improve subsequent recognition memory performance in amnesic patients, even the densely amnesic patient H.M. To understand this phenomenon, the severely amnesic patient E.P., 3 other amnesic patients, and controls studied pictorial material and then were given either a yes-no (Experiment 1) or a 2-alternative, forced-choice (Experiment 2) recognition test. The amnesic patients and controls benefited substantially from extended exposure, but patient E.P. consistently performed at chance. Furthermore, confidence ratings corresponded to recognition accuracy. The results do not support the idea that the benefit of extended study time is due to some kind of familiarity process made available through nondeclarative memory. It is likely that amnesic patients benefit from extended study time to the extent that they have residual capacity for declarative memory.
9344477	Three hypotheses concerning the functional source of aphasic patients' difficulty comprehending semantically reversible sentences were tested using declarative sentences in active and passive voice and sentences with center-embedded relative clauses. Each of the three hypotheses is predicated on relative patterns of impairment and sparing of patient performance on these (and other) sentence types, yet the three hypotheses make somewhat different predictions about performance patterns across these types. Results from 5 Broca's aphasic patients were not consistent with the predictions of the linguistically motivated Trace Deletion Hypothesis or of a hypothesis based on an impairment involving grammatical morphemes. The hypothesis that aphasic comprehension impairments reflect a general limitation of working memory capacity was given partial support by the ordinal pattern of difficulty for a mixed group of 10 patients, but failed to account for patterns obtained from individual patients. Results are interpreted as having relevance for methodological as well as theoretical aspects of research on aphasic sentence comprehension.
9327090	Learning and retention of procedural versus declarative memory tasks were examined with 26 young adults with mild mental retardation and 27 school children matched for MA. Results revealed a similar pattern of task performance. Performance of the young adults with mild mental retardation was inferior to that of the control subjects on both types of tasks. However, learning rate and retention over time were comparable, thereby maintaining the control group's consistent advantage throughout all repeated trials. These results are consistent with previous findings for individual's with mental retardation tested on memory and problem-solving tasks. Theoretical implications of this pattern of results for individuals with mild mental retardation were discussed.
23964593	Recent studies have challenged the notion that priming for ostensibly novel stimuli such as pseudowords (REAB) reflects the creation of new representations. Priming for such stimuli could instead reflect the activation of familiar memory representations that are orthographically similar (READ) and/or the activation of subparts of stimuli (RE, EX, AR), which are familar because they occur commonly in English. We addressed this issue in three experiments that assessed perceptual identification priming and recognition memory for novel and familiar letter strings in amnesic patients and control subjects. Priming for words, pseudowords, and orthographically illegal nonwords was fully intact in the amnesic patients following a single exposure, whereas recognition memory was impaired for the same items. Thus, priming can occur for stimuli that are unlikely to have preexisting representations. Words and pseudowords exhibited twice as much priming as illegal nonwords, suggesting that activation may contribute to priming for words and wordlike stimuli. Additional results showed that priming for illegal nonwords resulted from the formation of new perceptual associations among the component letters of each nonword rather than the activation of individual letter representations. In summary, the results demonstrate that priming following a single exposure can depend on the creation of new perceptual representations and that such priming is independent of the brain structures essential for declarative memory. 
9339305	A wealth of animal and human research has pointed to a significant involvement of the temporal lobes in memory processing, and yet the different functional roles of temporal cortical vs. mesial structures remain unclear. We studied verbal declarative memory, by using a word list paradigm that differentiates among learning (immediate recall), memory (delayed recall), and recognition, in epilepsy patients being considered for surgical resection of the left temporal lobe. Verbal memory was evaluated preoperatively and during the recording of intracranial event related potentials and postoperatively after selective hippocampectomy, temporal cortical lesionectomy, or anterior two-thirds en bloc temporal lobe resection procedures. Preoperative differences in verbal memory performance as a function of differences in underlying neuropathology, concurrent event-related potentials, and specific patterns of postoperative memory impairments lead to converging evidence that verbal declarative memory relies on a synergistic interaction of at least two functionally distinct brain systems. Material-specific data acquisition, or working memory, is mediated by neocortical temporal structures, whereas long-term consolidation/retrieval is particularly mediated by temporomesial structures. In contrast to the left temporal neocortex, the function of the temporomesial system appears to be material nonspecific. Apparently, its preferential involvement in verbal memory is due to its close interaction with overlying neocortical structures that are specialized for language processing.
9310091	Twenty-five older and 25 younger adults were compared on declarative (i.e., Rey Auditory-Verbal Learning Test and Visual Pair Associations) and procedural (i.e., Tower of Hanoi puzzle and Porteus mazes) learning tasks. A dissociation between learning rate on declarative and procedural tasks was demonstrated for the elderly participants. The younger group showed a steeper learning rate than the older group on the declarative tasks. By contrast, the learning rate of both groups on the procedural tasks did not differ consistently, whether the measure was number of errors/moves or time elapsed (with one exception in which the older group showed a steeper learning rate than the younger group). The younger group's baseline performance was better than that of the older group on all tasks employed in this study. These results reinforce the importance of distinguishing between baseline performance and the rate of learning on procedural learning tasks.
9302072	Recent research on the nucleus accumbens (NA) indicates that this brain region is involved in learning and memory processes in a way that is separable from its other well-known roles in behavior, such as motivation, reward, and locomotor activity. These findings have suggested that 1) the NA may be involved in declarative, or hippocampal formation-dependent learning and memory, and not in several other non-declarative forms of learning and memory, and 2) the NA may be selectively involved in certain stages of learning and memory. These characteristics suggest that the NA may be part of a larger striatal system which subserves acquisition and consolidation, but is not a site of long-term storage, of different forms of learning and memory.
9267663	Declarative memory enables conscious recollection of the past and has been proposed to be distinct from priming, a perceptual form of memory that operates nonconsciously and improves the ability to detect or identify recently presented stimuli. Yet, it has been difficult to obtain unambiguous evidence for the independence of declarative memory and priming. The authors report the first demonstration, using matched tests, of fully intact perceptual memory (priming) in a profoundly amnesic patient (E.P.), despite at-chance recognition memory. The priming and recognition tests included tests that were matched with respect to test materials, length of the study and test lists, and the kind of cues available at test. Priming appears to reflect neural changes within perceptual processing systems that occur before information reaches the brain systems that transform visual perception into conscious visual memory.
9256371	In the verb generation task, participants are presented with nouns and generate for each one an appropriate verb. Raichle et al. (Cerebral Cortex, 1994, 4, 8-26) found that when participants generated verbs to repeated nouns, generation latencies were reduced and different patterns of brain activation were present. In order to examine whether verb generation priming is dependent or independent of declarative memory, verb generation priming was compared between 13 amnesic (seven with alcoholic Korsakoff's syndrome, six with other etiologies) and 19 control participants (10 with a history of alcoholism). Both amnesic and control participants became faster across blocks on repeated nouns and slowed when novel nouns were introduced. Priming was verb specific for both groups: it was equivalent whether generated to a repeated or a novel noun. Verb generation priming, therefore, can occur independently of declarative memory.
23968216	Recall of paired-associate lists (declarative memory) and mirror-tracing skills (procedural memory) was assessed after retention intervals defined over early and late nocturnal sleep. In addition, effects of sleep on recall were compared with those of early and late retention intervals filled with wakefulness. Twenty healthy men served as subjects. Saliva cortisol concentrations were determined before and after the retention intervals to determine pituitary-adrenal secretory activity. Sleep was determined somnopolygraphically. Sleep generally enhanced recall when compared with the effects of corresponding retention intervals of wakefulness. The benefit from sleep on recall depended on the phase of sleep and on the type of memory: Recall of paired-associate lists improved more during early sleep, and recall of mirror-tracing skills improved more during late sleep. The effects may reflect different influences of slow wave sleep (SWS) and rapid eye movement (REM) sleep since time in SWS was 5 times longer during the early than late sleep retention interval, and time in REM sleep was twice as long during late than early sleep (p < 0.005). Changes in cortisol concentrations, which independently of sleep and wakefulness were lower during early retention intervals than late ones, cannot account for the effects of sleep on memory. The experiments for the first time dissociate specific effects of early and late sleep on two principal types of memory, declarative and procedural, in humans. 
9337140	Memory in the brain is organized into multiple memory systems that perform different memory functions and have different neurologic substrates. Declarative memory involves conscious memory for facts and events. The medial temporal lobe and structures in the diencephalon are essential in the establishment of new declarative memories, and these memory traces are finally stored in domain-specific regions of the cerebral cortex. The frontal lobe and basal ganglia are important in some forms of declarative memory that require reasoning about the contents of memory. Nondeclarative forms of memory (including skill learning, repetition priming, and classical conditioning) do not involve conscious recollection and are measured through changes in the way in which tasks are performed. These forms of memory rely upon the cerebral cortex, basal ganglia, and cerebellum.
9245651	Understanding the role of the medial temporal lobe (MTL) in learning and memory is an important problem in cognitive neuroscience. Memory and learning processes that depend on the function of the MTL and related diencephalic structures (e.g., the anterior and mediodorsal thalamic nuclei) are defined as declarative. We have studied the MTL activity as indicated by regional cerebral blood flow with positron emission tomography and statistical parametric mapping during recall of abstract designs in a less practiced memory state as well as in a well-practiced (well-encoded) memory state. The results showed an increased activity of the MTL bilaterally (including parahippocampal gyrus extending into hippocampus proper, as well as anterior lingual and anterior fusiform gyri) during retrieval in the less practiced memory state compared to the well-practiced memory state, indicating a dynamic role of the MTL in retrieval during the learning processes. The results also showed that the activation of the MTL decreases as the subjects learn to draw abstract designs from memory, indicating a changing role of the MTL during recall in the earlier stages of acquisition compared to the well-encoded declarative memory state.
9243961	Extending the Jacksonian principle of the hierarchical development and dissolution of function to the development and dissolution of memory, researchers have concluded that implicit (procedural) memory is a primitive system, functional shortly after birth, that processes information automatically, whereas explicit (declarative) memory matures late in the 1st year and mediates the conscious recollection of a prior event. Support for a developmental hierarchy has only been inferred from the memory performance of adults with amnesia on priming and recognition-recall tests in response to manipulations of different independent variables. This article reviews evidence that very young infants exhibit memory dissociations like those exhibited by adults with normal memory on analogous memory tests in response to manipulations of the same independent variables. These data demonstrate that implicit and explicit memory follow the same developmental timetable and challenge the utility of conscious recollection as the defining characteristic of explicit memory.
9220087	This study was designed to examine the role of the striatum, cerebellum, and frontal lobes in the implicit learning of a visuomotor sequence. The performance of patients with idiopathic Parkinson's disease (PD), with damage to the cerebellum, or with a circumscribed lesion to the frontal lobes was thus compared to that of separate groups of matched normal control subjects on an adapted version of the Repeated Sequence Test. This paradigm consists of a visual reaction-time task with a fixed embedded sequence of finger movements to be performed based on presentation of visual stimuli. Subjects received four blocks of trials (i.e., 40 presentations of a 10-item sequence) per day over 6 training days. Following the last experimental session, subjects were also given two tests measuring their declarative knowledge of the sequence. Only PD patients with a bilateral striatal-dysfunction or patients with lesions to the cerebellum failed to improve their performance in the last three training sessions, hence suggesting an impairment late in the acquisition process. Further analyses revealed that such impairment was mainly implicit in nature, and that it could not be ascribed to a general decline in cognitive functioning, to mood disturbances, or to the severity of the motor symptoms. By contrast, the level of declarative knowledge of the sequence did not differ between the three clinical groups and their respective groups of normal subjects. These findings suggest that, unlike declarative memory, the incremental acquisition of a new visuomotor skill depends upon the integrity of both the striatum and the cerebellum, but not of the frontal lobes.
9215274	A group of 14 healthy elderly subjects was submitted to a nonstressful (attentional task) and a stressful (public speaking task) condition. Declarative (conscious recollection of learned information) and nondeclarative (retrieved information without conscious or explicit access) memory as well as salivary cortisol levels were measured before and after each condition. The results showed that the stressful condition significantly decreased declarative memory performance, whereas the nonstressful condition did not. Nondeclarative memory performance was not affected by either condition. Further analyses separating the subjects into responders and nonresponders in terms of stress-induced cortisol changes revealed a very different pattern of cortisol secretion and declarative memory performance in both populations. We showed that the responders presented increased cortisol levels 60 min before the actual stressor, whereas the nonresponders presented increased cortisol levels 25 min before the actual stressor. Although the responders did not differ from the nonresponders in declarative memory performance before and after the nonstressful condition, they presented a lower declarative memory performance when measured before and after the stressful condition. The early increase in cortisol levels observed in the responder group suggests that the anticipation of the stress, rather than the actual stressor per se, may have played a more significant role in the stress-induced declarative memory deficits observed in this subgroup. Together, these results show that the cortisol response to anticipation of stress and/or to stress in the elderly specifically affects those memory functions that are dependent on hippocampal activity. They also suggest that an altered cortisol responsivity to acute and/or chronic stress, with its detrimental effects on memory, could be an important factor explaining the genesis of memory deficits in aged populations.
9213065	Motor, perceptual, and cognitive skill learning abilities of mild Alzheimer's disease (AD) patients were compared to sex-, age-, and education-matched controls. We excluded patients who were unable to perform each skill learning task with a predetermined criterion. In those who completed the task, skill learning was as good as in normal controls. On the cognitive and perceptual skill learnings, some of the AD patients, whose cognitive but not declarative memory functions were more severely impaired than in those who completed the whole session, failed to complete the task, while all patients could complete the motor task. These results support that view that patients with mild AD can acquire motor, perceptual, and cognitive skills and that the neural system subserving procedural skill is not related to the neural systems for declarative memory.
9192700	Human declarative memory involves a systematic organization of information that supports generalizations and inferences from acquired knowledge. This kind of memory depends on the hippocampal region in humans, but the extent to which animals also have declarative memory, and whether inferential expression of memory depends on the hippocampus in animals, remains a major challenge in cognitive neuroscience. To examine these issues, we used a test of transitive inference pioneered by Piaget to assess capacities for systematic organization of knowledge and logical inference in children. In our adaptation of the test, rats were trained on a set of four overlapping odor discrimination problems that could be encoded either separately or as a single representation of orderly relations among the odor stimuli. Normal rats learned the problems and demonstrated the relational memory organization through appropriate transitive inferences about items not presented together during training. By contrast, after disconnection of the hippocampus from either its cortical or subcortical pathway, rats succeeded in acquiring the separate discrimination problems but did not demonstrate transitive inference, indicating that they had failed to develop or could not inferentially express the orderly organization of the stimulus elements. These findings strongly support the view that the hippocampus mediates a general declarative memory capacity in animals, as it does in humans.
23965010	Event-related brain potentials (EMS) were recorded while normal German subjects read either simple declarative sen- tences made up from real German words, or sentences that contained German pseudo-words instead of nouns and verbs. The verb (pseudo-verb) of the sentences disagreed in number with the subject noun (pseudo-noun) in 50% of the sentences. The subjects had the task either to read the sentences for an interspersed memory test (memory condition, pseudeword sentences only) or to make a syntactic judgment after each real-word/pseudo-word sentence. While in the real-word condition a late and widespread positivity resembling the previously described syntactic positive shift was found for the disagreeing verbs, a negativity with an onset latency of about 300 msec was seen for the disagreeing pseudo-verbs. In the pseudo-word conditions no positivity followed the initial negativity. This dissociation of negative and positive waves occurring in response to morphosyntactic mismatches by the pseudo/real-word manipulation suggests that the positive shift is a concomitant of a recomputation routine initiated to account for the number incongruency. This routine is based upon the semantics of the sentence and therefore is not observed in the pseudo-word conditions. The earlier negativity, on the other hand, appears to be a more direct index of morphosyntactic incongruency. 
9152991	Recently published work using MRI to image the human brain has revealed that the hippocampal formation undergoes a selective atrophy in diverse conditions such as Cushing's syndrome, post-traumatic stress disorder, recurrent depressive illness, normal aging preceding dementia and in Alzheimer's disease. Hippocampal shrinkage is usually accompanied by deficits in declarative, episodic, spatial and contextual memory performance and the hippocampal changes provide a neural substrate for changes in cognitive function that have been recognized to accompany these various conditions. The hippocampus has long been known as a target of stress hormones, and it is an especially plastic and vulnerable region of the brain. However, the prominence of the hippocampus as a glucocorticoid target has obscured the fact that other factors besides glucocorticoid hormones are involved in the process of hippocampal atrophy. Excitatory amino acids and NMDA receptors are prominent in their involvement in an animal model of hippocampal atrophy as well as in neuronal death. Further-more, the finding of hippocampal atrophy does not necessarily imply a permanent loss of cells, and this aspect deserves careful investigation, both to analyze the underlying anatomical changes and to investigate the possibility of pharmacological treatment to reverse the process. In cases where atrophy is due to cell loss, the time course of the disease process will provide much useful information about mechanism and offer the possibility of early intervention to arrest or slow the pathological process.
9150509	Awareness of cognitive deficits may rely on the implicit learning of intellectual limitations, and anosognosia in Alzheimer's disease (AD) may result from deficits in implicit learning. To examine this hypothesis, a consecutive series of 55 patients with probable AD were divided into groups with mild (n = 13), severe (n = 12), or no anosognosia (n = 30) and were assessed with a neuropsychological battery that included tests of declarative and procedural learning. Whereas there were no significant between-group differences in tests of declarative learning (the Buschke Selective Reminding Test and the Benton Visual Retention Test), patients with severe anosognosia showed a significantly worse performance on procedural learning (as measured with the Maze Learning Test) and a test assessing set shifting abilities (the Wisconsin Card Sorting Test) than AD patients without anosognosia. The authors' results suggest that deficits in procedural learning and anosognosia in AD may result from dysfunction in habit-learning systems.
9110329	Functional and anatomical relationships between working and declarative memory were investigated by contrasting regional cerebral blood flow (rCBF) change during standard working (Wisconsin Card Sorting Test, WCST) and declarative memory (Paired Associate Recognition Test, PART) tasks using identical stimulus-response modalities. The tasks and a resting baseline were administered to 30 participants (16 men, 14 women) during successive 10-min positron emission tomography 15O-water measures of rCBF. For both tasks, rCBF increased over baseline in inferior frontal and occipitotemporal regions, with more consistent dorsolateral prefrontal activation for WCST than PART. Additional orbitofrontal increases and dorsomedial decreases were seen for the PART. Activation patterns diverged when performance was considered. For the WCST, high performers activated dorsolateral and inferior frontal regions, whereas top PART performers activated only the occipitotemporal region. These results suggest operation of a frontotemporal network subserving both types of memory function that becomes more focal as performance increases.
23962016	Language comprises a lexicon for storing words and a grammar for generating rule-governed forms. Evidence is presented that the lexicon is part of a temporal-parietalhnedial-temporal "declarative memory" system and that granlmatical rules are processed by a frontamasal-ganglia "procedural" system. Patients produced past tenses of regular and novel verbs (looked and plagged), which require an -ed-suffixation rule, and irregular verbs (dug), which are retrieved from memory. Word-finding difficulties in posterior aphasia, and the general declarative memory impairment in Alzheimer's disease, led to more errors with irregular than regular and novel verbs. Grammatical difficulties in anterior aphasia, and the general impairment of procedures in Parkinson's disease, led to the opposite pattern. In contrast to the Parkinson's patients, who showed sup pressed motor activity and rule use, Huntington's disease patients showed excess motor activity and rule use, underscoring a role for the basal ganglia in grammatical processing. 
9173034	The contents of long-term memory will influence behaviour, even if the acquired knowledge or the original learning episode are not remembered. These phenomena have been termed "non-declarative" or "implicit" memory, and they are contrasted with "declarative" or "explicit" memory which is characterised by conscious search and retrieval procedures. Non-declarative memory encompasses non-associative learning, simple conditioning, priming effects as well as motor, perceptual and cognitive skill acquisition. The dissociation of both forms of memory is documented by studies in health subjects which indicated that experimental manipulations or drugs may differentially affect declarative and non-declarative memory processes. Damage to the medial temporal or the medial thalamic regions is known to result in declarative memory deficits whereas non-declarative memory is largely unaffected by such lesions. Animal research and clinical findings indicate that several components of non-declarative memory such as motor and cognitive skill acquisition or certain types of classical conditioning are dependent upon the integrity of the basal ganglia or the cerebellum. These issues are therefore of increasing importance for the understanding of extrapyramidal and cerebellar diseases. This paper presents recent neuropsychological findings and neuroanatomical data relating to the issue of non-declarative memory.
9126860	Some persons with Alzheimer's disease (AD) lose the ability to recognize themselves, as when they cannot overtly recognize their reflection in a mirror. There is evidence, however, that covert or unconscious self-recognition might be displayed in such individuals. In this study, 3 persons with AD lacking the ability to overtly self-recognize demonstrated multiple instances of unconscious or covert self-recognition. A variety of interventions, inspired by research with prosopagnosics, was implemented to remediate this loss. Interventions enabled all participants to exhibit overt self-recognition, though each did so with the aid of a different intervention. In addition, successful overt self-recognition required a verbal probe and was entirely intervention-dependent: When the intervention was removed, overt self-recognition was lost. Results support a dissociation between explicit-declarative versus implicit-nondeclarative memory systems, and extends this dissociation into the realm of self-recognition in AD.
25420138	A comparison of learning rates between schizophrenia patients and normals on measures tapping different memory systems may provide clues about relatively preserved areas of learning in schizophrenia. The present study assessed declarative (nonsense syllable list learning) and procedural (pursuit rotor tracking) learning in a group of chronic schizophrenia inpatients and a group of normal adults. Approximately equivalent baselines were obtained for the two groups on both measures. The results revealed a significant group trial interaction on the declarative memory measure, exemplified by a shallower learning slope for the patient group. For the procedural learning measure, there was no significant group block interaction; that is, both groups showed similar learning slopes. These findings suggest a relative preservation of selected procedural aspects of learning in schizophrenia. 
9147851	The term memory expresses the ability of the human or animal CNS to store information. Memory can be classified according to different principles. Short-term memory and long-term memory represent the basic classification. Within the long-term memory, a declarative and a nondeclarative form can be distinguished. The declarative memory provides a consciously accessible record of individual previous experiences. Nondeclarative memory includes motor skills, perceptual procedures and simple conditioned reactions. It is characteristic for nondeclarative knowledge, that the individual is not well aware what exactly he learned. Formation of the declarative memory traces requires processing in the hippocampus, while nondeclarative learning does not. Studies on animals suggest that declarative memory is stored by changes in synaptic strength at contacts involving NMDA receptors in the hippocampus. The ion channel associated with the NMDA receptor is usually blocked by Mg2-. It becomes unblocked only when the postsynaptic cell is depolarized, for instance during simultaneous activation of NMDA and nonNMDA receptors. Resulting Ca2+ influx into the postsynaptic cell initiates activation of second-messenger kinases followed by strengthening the synapses that were activated during depolarization. The molecular substrate of nondeclarative memory in unknown. Both forms of memory can be modelled in laboratory animals and analyzed experimentally. An analogy of declarative memory requires memory-stored cognitive maps of the outside world and lists of expected consequences of various actions. Motor learning can serve as a suitable model of complex nondeclarative (procedural) memory.
9250622	Clinical and experimental observations indicate that the hippocampus is critical in the formation of declarative memories. Interestingly, electrophysiological studies have demonstrated that the region also has a particularly low seizure threshold, where globally synchronous synaptic activity can occur. By using a detailed biophysical model of area CA3, it is shown how septal cholinergic modulation, through three distinct mechanisms, can interact with intrinsic and synaptic conductances to influence population behavior. A dissection of each mechanism demonstrates a variety of population firing activity ranging from fully synchronized behavior to a mixture of repetitive bursting and oscillations in reduced subsets of neurons, ideal for forming accurate associations during a learning and recall task.
9156098	Although most analyses of amnesia have focused on the loss of explicit declarative and episodic memories following hippocampal-region damage, considerable insights into amnesia can also be realised by studying hippocampal function in simple procedural, or habit-based, associative learning tasks. Although many simple forms of associative learning are unimpaired by hippocampal damage, more complex tasks which require sensitivity to unreinforced stimuli, configurations of multiple stimuli, or contextual information are impaired by hippocampal damage. In several recent papers we have developed a computational theory of hippocampal function which argues that this brain region plays a critical role in the formation of new stimulus representations during learning (Gluck & Myers, 1993, 1995; Myers & Gluck, 1996; Myers, Gluck, & Granger, 1995). We have applied this theory to a broad range of empirical data from studies of classical conditioning in both intact and hippocampal-lesioned animals, and the model correctly accounts for these data. The classical conditioning paradigm can be adapted for use in humans, and similar results for acquisition are obtained in both normal and hippocampal-damaged humans. More recently, we have begun to address an important set of category learning studies in both normals and hippocampal-damaged amnesics. This work integrates experimental studies of amnesic category learning (Knowlton, Squire, & Gluck, 1994) with theoretical accounts of associative learning, and builds on previously established behavioural correspondences between animal conditioning and human category learning (Gluck & Bower, 1988a). Our work to date illustrates some initial progress towards a more integrative understanding of hippocampal function in both animal and human learning, which may be useful in guiding further empirical and theoretical research in human memory and amnesia.
9156097	A major area of research in memory and amnesia concerns the item specificity of implicit memory. In this paper we address several issues about the nature of implicit memory phenomena and about what constitutes an "item", using the procedural/declarative memory theory to guide us. We consider the nature of memory for items and of memory for relations among items, within the context of the procedural/declarative framework, providing us with the foundation necessary to analyse the basis for item-specific implicit memory phenomena. We review recent work from our laboratories demonstrating the fundamentally relational and flexible nature of declarative memory representation, in both humans and animals, and the essential role of the hippocampal system in relational memory processing. We show, further, that the memory representations supporting implicit memory phenomena are inflexible and nonrelational, and are tied to specific processing modules. Finally, we introduce empirical approaches that blur the distinction between skill learning and repetition priming, and show computational modelling results that demonstrate how these two implicit memory phenomena can be mediated by a single incremental learning mechanism, in accord with the claims of the procedural-declarative theory. Taken together, these various analyses of memory for items and memory for relations help to illuminate the nature of the functional deficit in amnesia and the memory systems of the brain.
9138665	We present a conceptual framework for the role of the hippocampus and its afferent and efferent structures in rodent navigation. Our proposal is compatible with the behavioral, neurophysiological, anatomical, and neuropharmacological literature, and suggests a number of practical experiments that could support or refute it. We begin with a review of place cells and how the place code for an environment might be aligned with sensory cues and updated by self-motion information. The existence of place fields in the dark suggests that location information is maintained by path integration, which requires an internal representation of direction of motion. This leads to a consideration of the organization of the rodent head direction system, and thence into a discussion of the computational structure and anatomical locus of the path integrator. If the place code is used in navigation, there must be a mechanism for selecting an action based on this information. We review evidence that the nucleus accumbens subserves this function. From there, we move to interactions between the hippocampal system and the environment, emphasizing mechanisms for learning novel environments and for aligning the various subsystems upon re-entry into familiar environments. We conclude with a discussion of the relationship between navigation and declarative memory.
9058062	The cerebellum has been implicated in higher-order behavior. Blood flow studies (SPECT) have shown that cerebral diaschisis can appear after cerebellar lesions and this phenomenon could serve as a basis for a potential neuropsychological derangement after cerebellar insults. Our objectives in this study were to delineate the neuropsychological profile after cerebellar stroke, to evaluate cerebral diaschisis as measured by SPECT and to correlate the findings. We prospectively studied 26 patients with cerebellar stroke and 16 subjects matched for age, sex and educational level as a control group. A neuropsychological battery test, MRI and cerebral SPECT were performed in both groups. We found that cerebellar stroke results in motor control impairment and mild naming deficit, whereas no dysfunction in declarative memory, language, visuospatial or executive abilities is evident. The anatomical distribution of the lesion does not seem relevant in terms of neuropsychological impairment or diaschisis. Both ipsilateral and contralateral diaschisis as a result of a cerebellar stroke are found, but this phenomenon does not seem to result in overt neuropsychological derangement.
9046568	The discovery of declarative memory as distinct from other forms of memory is a major recent achievement in cognitive science. Basic issues about the nature of declarative memory are considered in this review from the perspective of studies on its underlying brain mechanisms. These studies have shown that declarative memory is mediated by a specific brain system including areas of the cerebral cortex and hippocampal region that make distinct functional contributions to memory processing. These processing mechanisms mediate the organization of memories in ways that can support the special properties of declarative or explicit memory expression. Furthermore, the basic properties of declarative memory in human beings can be viewed as evolving from a capacity for organized memory representation and flexible memory expression in animals.
9030402	In this study, the functional properties of the dorsomedial prefrontal cortex (dmPFC) of the rat were examined in two olfactory tasks. In a successive cue olfactory discrimination task, dmPFC lesioned animals improved performance across sessions more rapidly than operated control animals. In an olfactory task using fixed interval training, animals with similar lesions were impaired. Both effects, although opposite, can be explained by a temporal processing deficit. The present results seem to indicate that the dmPFC is required for timing, classified as part of non-declarative memory. As reference memory improved in the lesioned animals, the finding is that the dmPFC supports non-declarative memory and thus interacts with declarative memory in the long-term formation of the associations between a particular stimulus (olfactory cue) and particular responses.
9010405	This case study describes post-traumatic stress disorder (PTSD) and head injury after a road traffic accident involving a pedestrian. Previous studies have proposed two mechanisms by which this dual diagnosis may occur: (1) when post-traumatic amnesia and retrograde amnesia are small or non-existent and (2) when non-declarative memory systems for the traumatic event are in operation. This case study demonstrates a third mechanism--"islands" of memory within post-traumatic amnesia.
9049070	Skill-learning, i.e., anterograde memory of 'procedures' has been separated from conventional declarative memory, or event- or data-related memory. This type of memory requires a concerted activity of various neural structures which are not assigned to the acquisition of declarative memory. We employed mirror reading task as a paradigm of skill acquisition memory and tried to elucidate possible neurological mechanisms involved in the procedural memory process. Ten normal control subjects, 10 early, non-treated Parkinson's, and 9 relatively early spinocerebellar degeneration patients participated in our study. The results showed a clear dissociation between declarative memory and mirror reading skill acquisition capacity. Thus, the Parkinson's patients as well as the spinocerebellar patients showed retardation in acquiring mirror reading skills, while both groups showed normal performance in auditory verbal learning tests and word recognition tests. The facts suggest a possible role of the nigro-striatal system and fronto-ponto-cerebellar system in forming these skill-related memory.
9000297	A battery of cognitive tasks designed to assess information-processing speed, working memory capability, and declarative learning was administered to a cross-sectional sample of 477 adults ranging in age from 17 to 86 years. Results showed significant age-related decrements in all three constructs. A variety of structural equation models was fit to the results. The preferred model on empirical and conceptual grounds was one that showed (a) working memory capability as the most important mediator of age effects in declarative learning; (b) working memory capability as the mediator for the effects of general processing speed on declarative learning; and (c) differentiation among verbal, numeric, and spatial processing speed and between verbal and spatial working memory capability.
8975682	This group study examined the role of residual declarative memory and task-specific cognitive abilities for cognitive procedural learning in amnesia. 20 amnesic patients and 40 control subjects were studied, using four new cognitive tasks, as well as the Tower of Hanoi and a Mirror Reading task. On the cognitive tasks, but not on Mirror Reading, the learning of amnesic patients was significantly impaired relative to controls. Between- and within-group differences in learning were found to be statistically related to cognitive abilities that are involved in the processing of the procedural tasks. In amnesic patients, significant effects of residual declarative memory on learning scores were not observed, but there was indirect evidence for a role of memory in two tasks. The analysis of the correlative relationship between absolute procedural task performances and cognitive abilities indicated a prolonged dependence on nonspecific intellectual abilities in amnesic patients, suggesting a retarded transition to more advanced stages of skill acquisition.
8942968	The effects upon memory of normal aging and two age-related neurodegenerative diseases, Alzheimer disease (AD) and Parkinson disease, are analyzed in terms of memory systems, specific neural networks that mediate specific mnemonic processes. An occipital memory system mediating implicit visual-perceptual memory appears to be unaffected by aging or AD. A frontal system that may mediate implicit conceptual memory is affected by AD but not by normal aging. Another frontal system that mediates aspects of working and strategic memory is affected by Parkinson disease and, to a lesser extent, by aging. The aging effect appears to occur during all ages of the adult life-span. Finally, a medial-temporal system that mediates declarative memory is affected by the late onset of AD. Studies of intact and impaired memory in age-related diseases suggest that normal aging has markedly different effects upon different memory systems.
8942965	This article reviews recent studies of memory systems in humans and nonhuman primates. Three major conclusions from recent work are that (i) the capacity for nondeclarative (nonconscious) learning can now be studied in a broad array of tasks that assess classification learning, perceptuomotor skill learning, artificial grammar learning, and prototype abstraction; (ii) cortical areas adjacent to the hippocampal formation, including entorhinal, perirhinal, and parahippocampal cortices, are an essential part of the medial temporal lobe memory system that supports declarative (conscious) memory; and (iii) in humans, bilateral damage limited to the hippocampal formation is nevertheless sufficient to produce severe anterograde amnesia and temporally graded retrograde amnesia covering as much as 25 years.
8942963	In humans declarative or explicit memory is supported by the hippocampus and related structures of the medial temporal lobe working in concert with the cerebral cortex. This paper reviews our progress in developing an animal model for studies of cortical-hippocampal interactions in memory processing. Our findings support the view that the cortex maintains various forms of memory representation and that hippocampal structures extend the persistence and mediate the organization of these codings. Specifically, the parahippocampal region, through direct and reciprocal interconnections with the cortex, is sufficient to support the convergence and extended persistence of cortical codings. The hippocampus itself is critical to the organization cortical representations in terms of relationships among items in memory and in the flexible memory expression that is the hallmark of declarative memory.
8959234	This study aimed to determine the specific aspects of cognitive functioning which are related to geriatric rehabilitation treatment-outcome, and was based on a within-subject repeated measures design. In the setting of the inpatient Geriatric Rehabilitation Program (GRP) of the SCO Hospital in Ottawa, Canada 40 patients underwent six weeks of physiotherapy treatment for mobility training, on a twice daily schedule. Measurements were performed by the Clinical Outcome Variables Scale (COVS) and a mental status battery composed of five neuropsychological tests. Patients with a poorer mobility status at admission were significantly more depressed, more apraxic, less educated and had greater memory problems than their counterparts. The extent of treatment gains achieved by discharge was significantly related to a single aspect of cognition, namely procedural memory. Longer-term maintenance of treatment gains, however, was predicted by cognitive functioning more globally, including measures of praxis, declarative memory and reasoning. Together, the measures of cognition explained 52% of the variance in functional mobility outcome. In conclusion, patients with mild-to-moderate difficulties of cortically-based higher-order cognitive functions may still achieve significant gains in mobility function following geriatric rehabilitation. However, these patients may not be able to maintain their gains over time to the same extent as their cognitively healthier counterparts. Thus, from an empirical viewpoint, the decision to include or exclude cognitively impaired patients in GRPs varies with the definition of "treatment success" selected (i.e., short-term vs long-term gains). Alternatively, cognitively impaired patients may require more frequent follow-up rehabilitation services in order to maintain their gains.
8921303	In humans and monkeys, memory consists of various components which were initially revealed through neuropsychological studies of amnesic patients. One memory component, the long-term memory about facts and events (declarative memory), has been shown to require the integrity of the medial temporal lobe and the neocortex. To investigate a map of gene expression during declarative memory formation in the primate, we monitored expression of immediate early genes in the temporal lobe of macaque monkeys. We trained the monkeys to learn visual associative memory tasks, and immunohistochemically analysed the expression of protein products of immediate early genes. We found that Zif268, a transcription factor regulated by neuronal activity, accumulated in patches in the anterior temporal lobe during visual stimulus-stimulus association learning, whereas other transcription factors, c-Fos and JunD, were not. By contrast, the patchy expression of Zif268 was not observed during another type of learning, visual discrimination learning. These results suggest that Zif268 activates a gene cascade related to the formation of long-term memory in the primate.
8918990	Amnesic patients (n = 8), who have severely impaired declarative memory, learned a probabilistic classification task at the same rate as normal subjects (n = 16) but subsequently were impaired on transfer tests that required flexible use of their task knowledge. A second group of controls (n = 20) rated the questions on the transfer tests according to whether the questions simply reinstated the training conditions or required flexible use of task knowledge. The amnesic patients tended to be impaired on the same items that were rated as requiring indirect or flexible use of knowledge. Thus, control subjects acquired declarative knowledge about the task that could be applied flexibly to the transfer tests. The nondeclarative memory available to amnesic patients was relatively inflexible and available only in conditions that reinstantiated the conditions of training. These findings show that declarative memory has different operating characteristics than nondeclarative memory.
8703077	Amnesic patients and nondemented patients with Parkinson's disease were given a probabilistic classification task in which they learned which of two outcomes would occur on each trial, given the particular combination of cues that appeared. Amnesic patients exhibited normal learning of the task but had severely impaired declarative memory for the training episode. In contrast, patients with Parkinson's disease failed to learn the probabilistic classification task, despite having intact memory for the training episode. This double dissociation shows that the limbic-diencephalic regions damaged in amnesia and the neostriatum damaged in Parkinson's disease support separate and parallel learning systems. In humans, the neostriatum (caudate nucleus and putamen) is essential for the gradual, incremental learning of associations that is characteristic of habit learning. The neostriatum is important not just for motor behavior and motor learning but also for acquiring nonmotor dispositions and tendencies that depend on new associations.
8906404	Phenomenal reports were obtained immediately after participants retrieved information from long-term memory. Data were gathered for six basic forms of memory (semantic, generic perceptual, recollective, motor skill, rote skill, cognitive skill) and for three forms of memory that asked for declarative information about procedural tasks (motor-declarative, rote-declarative, cognitive-declarative). The data show consistent reports of mental imagery during retrieval of information from the generic perceptual, recollective, motor-declarative, rote-declarative, and cognitive-declarative categories; much less imagery was reported for the semantic, motor, rote, and cognitive categories. Overall, the data provide support for the theoretical framework outlined in Brewer and Pani (1983).
8893311	In this article, three experiments in which single-trial associative priming for nonwords was investigated in young and older adults in a pronunciation task are reported. During an encoding task, associative priming was observed for young and older adults, although cued recall was near zero for both groups. Associative priming for young and older adults was found under full attention conditions, but when attention was divided at study, associative priming was observed in Experiment 3, but not in Experiment 2. Divided attention also disrupted recognition memory for new associations in young and older adults. The results limit the generality of findings of age-related decrements in associative priming by showing an absence of such decrements in tasks that do not require elaborative processing during encoding. They also argue against G. Musen and L. Squire's (1993) suggestion that formation of new connections in implicit memory requires multiple study opportunities, whereas declarative memory is specialized for rapid acquisition of new associations.
8690148	To test the hypothesis that glycemic thresholds for hypoglycemic cognitive dysfunction, like those for neuroendocrine responses to and symptoms of hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia, 16 healthy young adult subjects (7 women and 9 men) were studied on two separate occasions in random sequence, once with hyperinsulinemic hypoglycemia (2.6 +/- 0.1 mmol/l, 47 +/- 1 mg/dl) and once with otherwise identical hyperinsulinemic euglycemia (4.8 +/- 0.1 mmol/l, 86 +/- 5 mg/dl) between 1430 and 1630. Neuroendocrine, symptomatic, and cognitive responses to hyperinsulinemic stepped hypoglycemic (4.7, 4.2, 3.6, 3.0, 2.8, 2.5, and 2.2 mmol/l; 85, 75, 65, 55, 50, 45, and 40 mg/dl) clamps were quantitated the following morning on both occasions. Cognitive function tests included measures of information processing (Serial Addition), attention (Stroop Arrow Word), pattern recognition and memory (Delayed Non-Match to Sample), and declarative memory (Paragraph Recall). As expected, plasma glucagon (P = 0.0094), epinephrine (P = 0.0063), and pancreatic polypeptide (P = 0.0046) responses to stepped hypoglycemia were reduced significantly, and symptomatic responses tended to be reduced after afternoon hypoglycemia. Performance on the cognitive function tests deteriorated (P < 0.0001) during stepped hypoglycemic clamps, but there were no significant overall effects of antecedent hypoglycemia on hypoglycemic cognitive dysfunction. Although deterioration was reduced (P < 0.05) from the 2.8 mmol/l (50 mg/dl) to the 2.5 mmol/l (45 mg/dl) steps on the Serial Addition and Delayed Non-Match to Sample tasks after afternoon hypoglycemia, comparable differences were not found on the Stroop Arrow Word or Paragraph Recall tasks. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, unlike those for neuroendocrine responses to and symptoms of hypoglycemia, do not seem to shift to substantially lower plasma glucose concentrations after recent antecedent hypoglycemia in nondiabetic humans.
23968151	The concepts of declarative memory and procedural memory have been used to distinguish two basic types of learning. A neural network model suggests how such memory processes work together as recognition learning, reinforcement learning, and sensorimotor learning take place during adaptive behaviors. To coordinate these processes, the hippocampal formation and cerebellum each contains circuits that learn to adaptively time their outputs. Within the model, hippocampal timing helps to maintain attention on motivationally salient goal objects during variable task-related delays, and cerebellar timing controls the release of conditioned responses. This property is part of the model's description of how cognitive-emotional interactions focus attention on motivationally valued cues, and how this process breaks down due to hippocampal ablation. The model suggests that the hippocampal mechanisms that help to rapidly draw attention to salient cues could prematurely release motor commands were not the release of these commands adaptively timed by the cerebellum. The model hippocampal system modulates cortical recognition learning without actually encoding the representational information that the cortex encodes. These properties avoid the difficulties faced by several models that propose a direct hippocampal role in recognition learning. Learning within the model hippocampal system controls adaptive timing and spatial orientation. Model properties hereby clarify how hippocampal ablations cause amnesic symptoms and difficulties with tasks which combine task delays, novelty detection, and attention toward goal objects amid distractions. When these model recognition, reinforcement, sensorimotor, and timing processes work together, they suggest how the brain can accomplish conditioning of multiple sensory events to delayed rewards, as during serial compound conditioning. 
8998272	Recent psychopathological studies consistently identified a delusional, a negative, and a disorganized subsyndrome in chronic schizophrenia. The aim of the present study was to investigate these subsyndromes with respect to declarative, procedural and working memory deficits. While the delusional subsyndrome was associated with an impaired delayed recognition, the negative subsyndrome showed a marked deficit in delayed recall. In addition, the delusional and the negative subsyndrome shared procedural memory changes. The disorganized subsyndrome was associated with neurological soft signs and a poor working memory performance. These results do not seem to be effected by severity of illness, degree of chronicity, nor attentional deficits. Our findings support the differentiation of three subsyndromes in chronic schizophrenia and suggest that memory impairment in schizophrenia may reflect the involvement of different memory systems rather than an unspecific, global deficit.
8660785	Two experiments which require subjects to hold a digit span while solving an equation and then recall the digit span are performed. The size of the memory span and the complexity of the equation are manipulated as well as whether the subject is required to substitute items from the digit span for constants in the equation. As either task (digit span recall or equation solving) gets more complex there are performance decrements (accuracy or latency) not only in that task but also in the other task. It is also shown that the majority of the errors are misretrievals. These results are consistent with the proposal that working memory load has its impact on retrieval from memory. These results are fit by the ACT-R theory (Anderson, 1993) which assumes that there is a limit on source activation and that this activation has to be divided between the two tasks. As either task increases in complexity there is less activation for retrieval of information from declarative memory. Subjects' misretrievals of associatively related information could be predicted by assuming a partial matching process in ACT-R.
8632799	The human hippocampus has been implicated in memory, in particular episodic or declarative memory. In rats, hippocampal lesions cause selective spatial deficits, and hippocampal complex spike cells (place cells) exhibit spatially localized firing, suggesting a role in spatial memory, although broader functions have also been suggested. Here we report the identification of the environmental features controlling the location and shape of the receptive fields (place fields) of the place cells. This was done by recording from the same cell in four rectangular boxes that differed solely in the length of one or both sides. Most of our results are explained by a model in which the place field is formed by the summation of gaussian tuning curves, each oriented perpendicular to a box wall and peaked at a fixed distance from it.
8843488	1. Findings in cognitive psychology and neuropsychology have led to consider the existence of several mnestic systems. This study focuses on a now clearly established distinction between the procedural and the declarative memories. 2. The aim of the present study was to try and determine which of the two acquisition steps (learning and automation) is affected by Parkinsonians' mnestic difficulties, and to verify if these difficulties are linked to the skill content (declarative or motor). 3. To answer these questions, 20 Parkinsonians under treatment underwent specific tests: the maze test and the arithmetic alphabet test. 4. Results show that, by comparison with 20 matched healthy individuals, the deficiencies observed in Parkinson's disease affect both the declarative and the motor skills. In addition, Parkinsonians suffer difficulties in both acquisition steps: learning and automation. 5. These results could account for the cognitive and motor disturbances observed in Parkinson's disease; these abnormalities should be among the pharmacological targets in future.
8612256	Learning and memory can be impaired by sleep loss during specific vulnerable "windows" for several days after new tasks have been learned. Different types of tasks are differentially vulnerable to the loss of different stages of sleep. Memory required to perform cognitive procedural tasks is affected by the loss of rapid-eye-movement (REM) sleep on the first night after learning occurs and again on the third night after learning. REM-sleep deprivation on the second night after learning does not produce memory deficits. Declarative memory, which is used for the recall of specific facts, is not similarly affected by REM-sleep loss. The learning of procedural motor tasks, including those required in many sports, is impaired by the loss of stage 2 sleep, which occurs primarily in the early hours of the morning. These findings have implications for the academic and athletic performance of students and for anyone whose work involves ongoing learning and demands high standards of performance.
8723304	The Paired Associate Recognition Test (PART) was developed to measure declarative memory using Wisconsin Card Sorting Test (WCST) stimuli, so that both tasks could be administered during functional neuroimaging to differentiate memory and executive function, and associated frontal and temporal lobe activation in schizophrenia. The current study was designed to compare PART and WCST performance in schizophrenic patients and to examine effects of medication and symptomatology. The PART, WCST, and standard declarative memory tasks were administered to 30 chronic schizophrenic patients and 30 matched healthy control subjects. Supporting task validity was the finding that patients were equally impaired on the PART and the WCST. Neuroleptics did not appear to affect performance. The effect of anticholinergic medication correlated negatively with WCST performance in a small subsample. Severity of schizophrenia-specific symptoms measured at intake on the Brief Psychiatric Rating Scale correlated negatively with performance on the WCST. These results support the application of the PART and WCST in future functional neuroimaging studies.
8645769	This study examined whether the neuropsychological deficits observed in patients with schizophrenia were related to cortical gray matter volume deficits in these patients. All subjects were men and included 34 patients with DSM-III-R Schizophrenia and 47 age-matched healthy controls. Subjects received a battery of 21 tests, assessing four different functional domains: executive functions, short-term memory and production, declarative memory, and motor ability. MRI volumes were corrected for normal variation in head size and age, and neuropsychological test scores were corrected for normal variation in age. The schizophrenic group had significantly smaller cortical gray matter volumes (p < .05) and lower test scores in all functional domain than the control group (p = .0001). Within the schizophrenic group, lower scores in each domain were significantly correlated with smaller total cortical gray matter volumes; however, no predictable relationships were observed between neuropsychological test performance and the volumes of specific cortical regions.
8538790	The hippocampus is critical to declarative memory in humans. This kind of memory involves associations among items or events that can be accessed flexibly to guide memory expression in various and even new situations. In animals, there has been controversy about whether the hippocampus is specialized for spatial memory or whether it mediates a general memory function, as it does in humans. To address this issue we trained normal rats and rats with hippocampal damage on non-spatial stimulus-stimulus associations, then probed the nature of their memory representations. We report here that normal rats demonstrated two forms of flexible memory expression, transitivity, the ability to judge inferentially across stimulus pairs that share a common element, and symmetry, the ability to associate paired elements presented in the reverse of training order. Rats with neurotoxic damage limited to the hippocampus demonstrated neither form of flexible expression, indicating that non-spatial declarative processing depends specifically on the hippocampus in animals as it does in humans.

9246447	The cognitive and neuroanatomical work described here should be viewed as a first step in analyzing how the brain has organized its memory functions, which can open the door to more detailed neurobiological analysis. With respect to declarative memory, it should soon be possible to study representations directly in neocortex with the technique of single-cell recording, to observe directly the development of neuronal plasticity important for declarative memory, and to determine how the medial temporal lobe interacts with neocortex during learning, consolidation, and retrieval. In this regard, the paradigms developed by Miyashita and his colleagues appear to hold particular promise (Sakai and Miyashita 1991; Higuchi and Miyashita 1996). With respect to nondeclarative memory, it is now possible to identify particular brain systems that are essential for particular kinds of memory. An important next step will be to determine whether these systems are essential for the acquisition, storage, or expression of memory, and to identify exactly where the synaptic changes occur that support each kind of memory.
8891321	Despite considerable consensus on what is known and unknown about delayed traumatic recall in adults, this topic remains one of the most polarized issues within both forensic psychiatry and society as a whole. Competing priorities of values contribute to this polarization. So do often subtle confusions of categories: experiential with substantive realities; clinical with legal priorities and criteria; distinctions between explicit and implicit with declarative and procedural memory; conditioned avoidance with declarative knowledge; and prediction of traumatic sequelae from known traumatic events with postdiction of possible traumatic events from symptoms that may imply prior traumatization. Memories are rendered more vulnerable to falsification through social influence and intrinsic suggestibility-- and probably more so when suggestive input bypasses conscious scrutiny. Legal, clinical, and forensic guidelines are proposed to sort out these complexities, balance conflicting professional duties and priorities, balance protection of children with defending legitimate social structures such as the family, and better use our growing knowledge about the vicissitudes of human memory.
8648284	The contributions of exemplar-specific and abstract knowledge to artificial grammar learning were examined in amnesic patients and controls. In Experiment 1, grammatical rule adherence and chunk strength exerted separate effects on grammaticality judgments. Amnesic patients exhibited intact classification performance, demonstrating the same pattern of results as controls. In Experiment 2, amnesic patients exhibited impaired declarative memory for chunks. In Experiment 3, both amnesic patients and controls exhibited transfer when tested with a letter set different than the one used for training, although performance was better when the same letter sets were used at training and test. The results suggest that individuals learn both abstract information about training items and exemplar-specific information about chunk strength and that both types of learning occur independently of declarative memory.
8637437	We have studied three groups of subjects with a working memory paradigm, using 18FDG-PET. Controls show the greatest increase on uptake in dorsolateral prefrontal cortex, basal forebrain and angular gyrus. A group of subjects with focal frontal epilepsy did not show increases compared to a control task of attention. Primary generalized epilepsy subjects show the greatest changes in angular gyrus, dorsal temporal, medial frontal and parietal regions. Factor and regression analyses extend these observations and show reliance of both patient groups on the medial and inferior temporal lobe. We propose that the normal network of working memory is disrupted by these two forms of epilepsy and different networks are accessed. Declarative memory may be used as a compensatory system, which results in decreased performance.
8622574	Two studies investigated the association between cortisol levels and memory performance in healthy adults. In a first study, 13 subjects were exposed to a brief psychosocial laboratory stress ("Trier Social Stress Test") with a subsequent test of declarative memory performance. Results indicated a significant negative relationship between stress-induced cortisol levels and performance in the memory task, i.e. subjects with high cortisol response to the stressor showed poorer memory performance. In a second experiment it was investigated if cortisol, alone, i.e. independent of psychological stress, would also impair memory function. In this study, 40 healthy subjects received either 10 mg cortisol or placebo orally. One hour later they were tested for procedural and declarative memory and spatial thinking. Subjects who received cortisol showed impaired performance in the declarative memory and spatial thinking tasks but not in the procedural memory task. From these results we conclude that in healthy adults elevated free cortisol levels are associated with impaired memory function.
8573654	A neural mechanism for control of dynamics and function of associative processes in a hierarchical memory system is demonstrated. For the representation and processing of abstract knowledge, the semantic declarative memory system of the human brain is considered. The dynamics control mechanism is based on the influence of neuronal adaptation on the complexity of neural network dynamics. Different dynamical modes correspond to different levels of the ultrametric structure of the hierarchical memory being invoked during an associative process. The mechanism is deterministic but may also underlie free associative thought processes. The formulation of an abstract neural network model of hierarchical associative memory utilizes a recent approach to incorporate neuronal adaptation. It includes a generalized neuronal activation function recently derived by a Hodgkin-Huxley-type model. It is shown that the extent to which a hierarchically organized memory structure is searched is controlled by the neuronal adaptability, i.e. the strength of coupling between neuronal activity and excitability. In the brain, the concentration of various neuromodulators in turn can regulate the adaptability. An autonomously controlled sequence of bifurcations, from an initial exploratory to a final retrieval phase, of an associative process is shown to result from an activity-dependent release of neuromodulators. The dynamics control mechanism may be important in the context of various disorders of the brain and may also extend the range of applications of artificial neural networks.
8618923	A fundamental question about memory and cognition concerns how information is acquired about categories and concepts as the result of encounters with specific instances. We describe a profoundly amnesic patient (E.P.) who cannot learn and remember specific instances--i.e., he has no detectable declarative memory. Yet after inspecting a series of 40 training stimuli, he was normal at classifying novel stimuli according to whether they did or did not belong to the same category as the training stimuli. In contrast, he was unable to recognize a single stimulus after it was presented 40 times in succession. These findings demonstrate that the ability to classify novel items, after experience with other items in the same category, is a separate and parallel memory function of the brain, independent of the limbic and diencephalic structures essential for remembering individual stimulus items (declarative memory). Category-level knowledge can be acquired implicitly by cumulating information from multiple training examples in the absence of detectable conscious memory for the examples themselves.
8847390	Declarative and procedural learning were assessed in patients with probable Alzheimer's Disease (AD) and major depression, patients with AD and no depression, patients with major depression but no dementia, and a group of age-comparable nondemented and nondepressed normal controls. AD patients showed significant deficits in declarative but not in procedural learning, while depressed nondemented patients showed the opposite pattern (i.e., a significantly worse procedural than declarative learning). Patients with both AD and major depression showed a similar learning pattern to the AD nondepressed group (relatively preserved procedural learning but severe deficits in declarative memory). These findings provide further evidence for the independence between declarative and procedural learning, and demonstrate their different vulnerability in dementia and depressive-like states.
8748954	In 2 experiments, the acquisition of new declarative knowledge was examined in amnesic patients and in 7 groups of controls, with a study-only procedure that delayed testing until the conclusion of training. The study-only procedure was compared with a standard procedure in which study and test trials alternated (study-test). The amnesic patients acquired new factual (declarative) knowledge at an abnormally slow rate, learning more with the study-only procedure than with the study-test procedure. Controls exhibited the opposite pattern. The advantage of the study-only procedure for amnesic patients was related to the presence of frontal lobe dysfunction. The 2 groups exhibited a similar ability to use their knowledge flexibly, suggesting that the information acquired by amnesic patients was based on their residual capacity for declarative memory. In addition, the capacity for factual learning in amnesia was proportional to the capacity to recollect specific events in the learning session.
8554707	The status of classical conditioning in human amnesia was examined by comparing conditioning of the eyeblink response (the unconditional response) to a tone conditioned stimulus (CS) paired with an airpuff unconditioned stimulus (US) in the delay paradigm between 7 amnesic and 7 age- and education-matched normal control participants. Amnesic patients exhibited normal baseline performance in pseudoconditioning and normal acquisition and extinction of conditioned responses in terms of the number, latency, and magnitude of eyeblinks. These results indicate that in humans, as in rabbits, brain structures critical for declarative memory are not essential for the acquisition of elementary CS-US associations.
7562107	The hippocampal formation (HF) is involved in higher brain functions including learning and declarative memory. The possibility that dietary copper has a role in the morphological development, and therefore the function of the HF, has received little attention. A rat model of tiered copper deficiency, initiated during gestation, was employed to determine the susceptibility of the HF, regions of which develop postnatally, to copper deficiency. At postnatal 23, pups whose dams had received either 1.8 or 1.4 mg Cu/kg diet during both gestation and lactation, compared with offspring of a group that had received 4.3 mg Cu/kg diet during both periods had, significantly more cell nuclei in the infrapyrimidal arm of the dentate gyrus. Offspring of rats fed 1.4 mg Cu/kg diet, but not those fed 1.8 mg/kg, compared with those fed 4.3 mg/kg, exhibited smaller, shorter, and narrower cell nuclei in the infrapyrimidal and suprapyrimidal arms of the dentate gyrus and smaller cell nuclei in region CA3c of the hippocampus. A fourth group (gestation, 1.8 mg Cu/kg diet; lactation, 0.9 mg Cu/kg diet) exhibited alterations less marked than those exhibited by the group fed 1.4 mg Cu/kg diet. All alterations in the groups fed low copper diets were consistent with slowed cell nuclear maturation. The findings indicate that copper is required for maturation of the dentate gyrus and hippocampus. Also, copper supplied at or below 1.8 mg/kg is insufficient for morphological maturation of the dentate gyrus and hippocampus. Because the HF is important for higher brain functions, further research is needed to determine whether the copper deficiency-induced alterations in dentate gyrus and hippocampus development are transient or permanent.
7472442	Classical fear conditioning was used in the present study as a model for investigating emotional learning and memory in human subjects with lesions to the medial temporal lobe. Animal studies have revealed a critical role for medial temporal lobe structures, particularly the amygdala, in simple and complex associative emotional responding. Whether these structures perform similar functions in humans is unknown. On both simple and conditional discrimination tasks, unilateral temporal lobectomy subjects showed impaired conditioned response acquisition relative to control subjects. This impairment could not be accounted for by deficits in nonassociative sensory or autonomic performance factors, or by differences in declarative memory for the experimental parameters. These results show that temporal lobe structures in humans, as in other mammals, are important components in an emotional memory network.
8527062	This study used classical conditioning as a measure of nondeclarative learning and compared it with verbal learning as a declarative measure. Eighty participants were tested using 1 of 2 paradigms (400-ms and 750-ms delay) for eyeblink classical conditioning (EBCC) and the California Verbal Learning Test (CVLT). Large age differences were observed in the nondeclarative EBCC task, even in the 750-ms paradigm, which is more optimal for older adults. Age differences in the nondeclarative EBCC task were larger in the 400-ms paradigm and equal in the 750-ms paradigm to the magnitude of age differences in the declarative CVLT task. Partial correlations (removing the variance that was due to age) showed no relation between performance on the nondeclarative and declarative tasks. The results contradict the common assumption that, in the same participants, nondeclarative learning and memory are more resistant to the effects of aging than are declarative learning and memory and suggest that nondeclarative learning and memory are not unitary.
8539301	Social scientists are currently being pressed upon by the legal and scientific communities to provide more definitive explanations regarding the nature and functions of memory (Loftus 1993). At the forefront of this debate is autobiographical memory. Autobiographical memory is a subclassification of memory within the declarative memory system and signifies memory for one's own personal life experiences in the recent and/or remote past. This study investigates the relationship between early trauma and memory for childhood events in adult psychiatric patients. The findings suggest that patients with an alleged history of trauma have a measurably different pattern of recall for early events than the patient and nonpatient comparison groups.
7638234	We tested amnesic patients, patients with frontal lobe lesions, and control subjects with the deferred imitation task, a nonverbal test used to demonstrate memory abilities in human infants. On day 1, subjects were given sets of objects to obtain a baseline measure of their spontaneous performance of target actions. Then different event sequences were modeled with the object sets. On day 2, the objects were given to the subjects again, first without any instructions to imitate the sequences, and then with explicit instructions to imitate the actions exactly as they had been modeled. Control subjects and frontal lobe patients reproduced the events under both uninstructed and instructed conditions. In contrast, performance by the amnesic patients did not significantly differ from that of a second control group who had the same opportunities to handle the objects but were not shown the modeled actions. These findings suggest that deferred imitation is dependent on the brain structures essential for declarative memory that are damaged in amnesia, and they support the view that infants who imitate actions after long delays have an early capacity for long-term declarative memory.
7557739	Discoveries of long-term potentiation and immediate early gene in the central nervous system have enabled new developments in experiments on learning and memory. These experiments are conducted in many kinds of animals with different procedures, physiology, chemistry and pharmacology. However, there is still some confusion when these various procedures are discussed. Memory is defined as information storage of an animal's previous experiences. The memory induces changes in behavioral performance. This means that memory must be observed in whole animals, and one question that can occur is how does long-term potentiation, for example, correlate with memory. Furthermore, memory has been divided into two major classifications, declarative and non-declarative, from the comparison of amnesias observed in humans and animals. The declarative memory can be observed in human subjects, but not in animals. This article presents a neuronal circuit concerning memory formation and some results obtained from benzodiazepines, and it discusses some problems encountered executing when experiments on learning and memory. In addition, the discussion speculates over the possibility for an "anti-dementia drug".
7583258	The administration of glucose has been shown to improve memory for various learning tasks in rodents. In humans, glucose also increases declarative memory performance in elderly people and in some patients with mild Alzheimer's disease. One of the possible physiological bases for the effect of glucose on memory processes is a facilitation of cholinergic function through increased synthesis. In support of this hypothesis, glucose was shown to attenuate the amnesia induced by scopolamine and, in similar conditions, glucose increased extracellular levels of acetylcholine following a scopolamine injection. To further examine the interaction between glucose and cholinergic function, the present experiment measured the effects of combined injections of glucose and scopolamine on hippocampal sodium-dependent high-affinity choline uptake, an indirect index of cholinergic activity. Results showed that the injection of 3 g/kg glucose enhanced the increase in high affinity choline uptake in hippocampal synaptosomes produced by scopolamine. A regression analysis revealed the existence of a positive correlation between plasma blood glucose level and hippocampal choline uptake particularly in the animals receiving a combined injection of scopolamine and glucose. These data further support the hypothesis that glucose administration can facilitate acetylcholine synthesis under certain conditions and that this action could explain how glucose attenuates scopolamine-induced amnesia.
7568522	This article, basing on experimental analysis and clinical observations, focuses on the role of subcortical structures in memory processes. It explained terminological problems and defined terms of memory: immediate, delayed, recent, remote, declarative and procedural. The present article pointed out functional hemispheric specialization as a predicator of material-specific forms of memory. Neuroanatomical basis was revealed, especially limbic system with its connections to prefrontal, cortical and brain stem regions. Amnesic Korsakoff and Wernicke syndromes, transient global amnesia, memory loss after bilateral damage of temporal lobes and after anterior communicating artery aneurysm rupture, were also discussed. Next part exhibited current knowledge about definition of dementia which may be caused by many multi-focal brain diseases like multiinfarct (vascular) dementia, Parkinson disease, Huntington disease, and sclerosis multiplex, and compared to Alzheimer disease. Term of dementia was defined, according to Cummings and Benson, as syndrome of acquired intellectual dysfunction when three of the following mental functions are impaired: language, memory, visuospatial skills, emotion, and cognition (abstraction, calculation, judgement). There is little doubt that various subcortical diseases are characterised by similar, no specific dysfunctions of cognitive processes including: disturbed attention and concentration, slowness of mental processing, forgetfulness, personality alterations and mood disturbances as well as motivational impairment, visuospatial disturbances, absence of symptoms of cortical dysfunction such as aphasia, agnosia and apraxia and associated motor disorder. Review of the literature suggests that rapid forgetting and retrieval deficits are most often symptoms of memory deficits observed after subcortical brain injuries.
7546305	Evidence for the involvement of rapid eye movement (REM) sleep or paradoxical sleep (PS) with memory processing continues to accumulate. In animals, there is continuing evidence of relatively small, vulnerable paradoxical sleep windows (PSWs) following successful acquisition. These PSWs, which manifest as increases in PS over normal levels, appear to exhibit shorter latencies to onset when the amount of material presented during acquisition is increased. Prevention of the PSW results in memory deficits. In humans, there is now evidence that different types of tasks are differentially sensitive to rapid eye movement sleep deprivation (REMD). Memory for declarative or explicit types of tasks appear not to be affected by REM sleep loss, while memory for cognitive procedural or implicit types of material are impaired by REMD. Using post training auditory stimulation during REM sleep, memory enhancement of the procedural material is also possible. The memory for a fine motor task appears to be sensitive to post training stage 2 sleep loss. The important neural structures are generally not yet identifiable, although the hippocampus would appear to be important for place learning in the Morris water maze.
7673466	Projections of the entorhinal cortex to the hippocampus are well known from the classical studies of Cajal (Ramon y Cajal, 1904) and Lorente de Nó (1933). Projections from the entorhinal cortex to neocortical areas are less well understood. Such connectivity is likely to underlie the consolidation of long-term declarative memory in neocortical sites. In the present study, a projection arising in layer V of the entorhinal cortex and terminating in a polymodal association area of the superior temporal gyrus has been identified with the use of retrograde tracing. The dendritic arbors of neurons giving rise to this projection were further investigated by cell filling and confocal microscopy with computer reconstruction. This analysis demonstrated that the dendritic arbor of identified projection neurons was largely confined to layer V, with the exception of a solitary, simple apical dendrite occasionally ascending to superficial laminae but often confined to the lamina dissecans (layer IV). Finally, immunoreactivity for glutamate-receptor subunit proteins GluR 5/6/7 of the dendritic arbor of identified entorhinal projection neurons was examined. The solitary apical dendrite of identified entorhinal projection neurons was prominently immunolabeled for GluR 5/6/7, as was the dendritic arbor of basilar dendrites of these neurons. The restriction of the large bulk of the dendritic arbor of identified entorhinal projection neurons to layer V implies that these neurons are likely to be heavily influenced by hippocampal output arriving in the deep layers of the entorhinal cortex. Immunoreactivity for GluR 5/6/7 throughout the dendritic arbor of such neurons indicates that this class of glutamate receptor is in a position to play a prominent role in mediating excitatory neurotransmission within hippocampal-entorhinal circuits.
7669991	We designed the present study to investigate the hypothesis that progression of hippocampal pathology may decrease the therapeutic effects of anti-cholinesterase drug, tetrahydroaminoacridine, on memory functioning in Alzheimer's disease (AD) patients. Memory, visuoconstructive, executive and vigilance functions were assessed after administration of placebo (p.o.; two placebo sessions) and tetrahydroaminoacridine (one session for 25 and 75 mg, p.o.). Eight patients performed better on list learning test during tetrahydroaminoacridine 75 mg than after placebo or tetrahydroaminoacridine 25 mg. The responders performed during baseline examination better than the non-responders in executive and some declarative memory functions, and had higher MMSE scores than the non-responders. The responders had larger left and right hippocampi than the non-responders. The hippocampal volume correlated with list learning performance. The results suggest that severe hippocampal atrophy may block memory improving effect of an anticholinesterase drug, tetrahydroaminoacridine.
7622990	Long-term recall memory was assessed using a nonverbal method requiring subjects to reenact a past event from memory (deferred imitation). A large sample of infants (N = 192), evenly divided between 14- and 16-months old, was tested across two experiments. A delay of 2 months was used in Experiment 1 and a delay of 4 months in Experiment 2. In both experiments two treatment groups were used. In one treatment group, motor practice (immediate imitation) was allowed before the delay was imposed; in the other group, subjects were prevented from motor practice before the delay. Age-matched control groups were used to assess the spontaneous production of the target acts in the absence of exposure to the model in both experiments. The results demonstrated significant deferred imitation for both treatment groups at both delay intervals, and moreover showed that infants retained and imitated multiple acts. These findings suggest that infants have a nonverbal declarative memory system that supports the recall of past events across long-term delays. The implications of these findings for the multiple memory system debate in cognitive science and neuroscience and for theories of infantile amnesia are considered.
7620531	A detailed analysis of the mnestic deficits associated with Parkinson's disease (PD) contributes to explaining the cognitive disorders and their well documented consequences. This study was designed to show that, in PD declarative as well as procedural memory is severely impaired. Three tests designed to explore this aspect of mnestic functioning were proposed to a group of 16 parkinsonian patients whose motoricity was controlled: inverted reading, braille reading, sound form association. The results obtained, compared with those of young and aged controls, show that PD is associated with marked deficits in both declarative and procedural memory. Declarative memory impairment was similar to that observed in the control population (healthy elderly subjects, age-matched with the PD patients) but more marked in PD subjects. The procedural memory deficit was linked with age and pathology. Procedural memory involves a variety of processing modules dedicated to the type of information (visual, auditive, tactile codes). The deficits observed were more like a loss of automatism than procedural impairment stricto sensu ('knowing how'). It would be worth pursuing research by studying akinesia and motor disorders from the angle of automatic memory impairment.
7602267	Amnesic patients and a control group were given a recognition test 10 min after studying words. For each recognized word, participants indicated whether they remembered it (R) or whether simply they knew that the word was presented but had no recollections about it (K). The patients were impaired for both R and K responses, performing like a control group tested after 1 week. Another control group was tested both 10 min and 1 week after study. The proportion of words initially eliciting an R response and later eliciting a K response exceeded the proportion of K responses that shifted to R responses. These data are accounted for if items initially eliciting R responses can also elicit K responses. We conclude that the R-K distinction does not reflect the operation of explicit and implicit memory but reflects instead a distinction within declarative memory. Thus, K responses depend on brain structures damaged in amnesia; R responses depend on these same structures and also on the frontal lobes for contextual information.
7620309	Stress affects cognition in a number of ways, acting rapidly via catecholamines and more slowly via glucocorticoids. Catecholamine actions involve beta adrenergic receptors and also availability of glucose, whereas glucocorticoids biphasically modulate synaptic plasticity over hours and also produce longer-term changes in dendritic structure that last for weeks. Prolonged exposure to stress leads to loss of neurons, particularly in the hippocampus. Recent evidence suggests that the glucocorticoid- and stress-related cognitive impairments involving declarative memory are probably related to the changes they effect in the hippocampus, whereas the stress-induced catecholamine effects on emotionally laden memories are postulated to involve structures such as the amgydala.
24487423	Memory dysfunction is a frequent concomitant of Parkinson's disease (PD). Historically, two classes of hypotheses, focusing on different cognitive mechanisms, have been advanced to explain this memory impairment: one postulating retrieval deficits (common to several neurodegenerative disorders involving the basal ganglia), and the other postulating frontally mediated executive deficits as fundamental to memory impairment. After outlining empirical support for the retrieval deficit hypothesis, research on the more recent "frontal executive deficit hypothesis" is reviewed, and major challenges to this hypothesis are identified. It is concluded that the frontal executive deficit hypothesis cannot adequately account for all memory impairments in PD, and that a more parsimonious theoretical account might invoke a distinction between prospective and declarative memory impairments. It is suggested that there may be three subgroups of PD patients: one demonstrating prospective memory dysfunction only, one with declarative memory dysfunction only, and one with both prospective and declarative memory dysfunction. Consequently, PD might provide a useful model within which to investigate the relationship between prospective and declarative memory. 
7885356	The performances of 12 patients with Parkinson's disease (PD), 16 with Huntington's disease (HD), and young and old healthy controls were assessed on a number of tests of verbal and nonverbal declarative memory, on a test of nonmotor conditional associative learning (words and colors), and on a number of reaction time (RT) tasks. The RT tasks consisted of cued simple and choice reactions. The relationship between the precue and the imperative stimulus in the S1-S2 paradigm was nonarbitrary in the first series and arbitrary in the second series. The series with arbitrary S1-S2 associations was repeated across two successive blocks of trials. The rationale of the study was to investigate the function of the basal ganglia "complex loop," and it was postulated that HD patients would show greater deficits because of greater involvement of the caudate nucleus. The patients with HD had the slowest RTs. Across the two blocks with arbitrary S1-S2 associations, the patients with HD but not PD nevertheless showed evidence of learning in their precued RTs. In contrast, the patients with PD were better able to remember the associations in free recall than were the HD patients. It is concluded that patients with PD have relatively greater deficits in procedural learning, whereas those with HD have relatively more impairments in declarative memory, and the greater level of cognitive impairment in HD overall is interpreted as being due to more serious damage to the caudate loop.
7669937	One of the aims of cognitive psychology is to breakdown complex tasks into their most basic components. The components of explicit (declarative) and implicit (procedural) memory were thus analyzed in undemented, non-depressed Parkinsonian patients under anti-Parkinsonian treatment, and compared with young and elderly healthy subjects. Three series of experiments were conducted in 61 patients in total. Statistically significant results revealed an impairment of explicit memory (verbal recall of words and drawings) with preserved recall of faces, in Parkinsonians. Implicit memory was also deficient, only in association tests (sound-form; arithmetical alphabet) and maze tests. Braille reading tests and Toronto tower tests did not discriminate between Parkinsonians and elderly subjects. Lastly, analyzing learning and automation revealed a dysfunctioning in Parkinsonian patients. All these data indicate a dysregulation of the cortical-sub-cortical systems, not essentially pre-frontal, and not necessarily dopaminergic. Cognitively, it appears that procedural and implicit memories should be dissociated conceptually.

7661935	This study examined the neuropsychological deficits associated with schizophrenia and the interrelationships among multiple dissociable cognitive and motor functions. The tests were selected for their previously demonstrated sensitivity to circumscribed brain pathology and included four functional domains: executive functions, short-term memory and production, motor ability, and declarative memory. Each test composite was divided according to verbal versus nonverbal material or left- versus right-hand performance; this distinction permitted functions principally subserved by the left or right cerebral hemispheres to be tested separately. Data reduction was theoretically driven by the test selection and was achieved first by standardizing the scores of each test for age-related differences observed in the normal control group, and then by calculating test composite scores as an average of the age-corrected Z-scores of the tests comprising a functional composite. The schizophrenic group was impaired equivalently on all composites for both cerebral hemispheres; on average, the Z-scores of the patients were 1 standard deviation below those of the control group. The cognitive test composite scores were highly intercorrelated but showed only weak associations with motor ability. Multiple regression analyses suggested that symptom severity was a significant predictor of the Declarative Memory and Short-Term Memory/Production composite scores after accounting for disease duration, whereas disease duration uniquely contributed to the Executive Functions composite scores after controlling for symptom severity. Even though the schizophrenics as a group showed an equivalent level of deficit across all test composites, 1) the deficits were associated with different aspects of psychiatric symptomatology, 2) the motor deficit was independent of the cognitive deficits, and 3) each neuropsychological domain contributed independently to the deficit pattern. Thus, what appears to be a generalized functional deficit in schizophrenia may actually be, at least in part, combinations of multiple specific deficits.
10467599	A fundamental issue about memory and its different forms is whether learning can occur without the development of conscious knowledge of what is learned. Amnesic patients and control subjects performed a serial reaction time task, exhibiting equivalent learning of an imbedded repeating sequence as measured by gradually improving reaction times. In contrast, four tests of declarative (explicit) knowledge indicated that the amnesic patients were unaware of their knowledge. Moreover, after taking the tests of declarative memory, all subjects continued to demonstrate tacit knowledge of the repeating sequence. This dissociation between declarative and nondeclarative knowledge indicates that the parallel brain systems supporting learning and memory differ in their capacity for affording awareness of what is learned.
7969972	We report a pathologically documented case of infarction of the dominant thalamus with extensive involvement of the ventral lateral, ventral posterolateral, and lateral posterior nuclei and some involvement of the pulvinar. This patient exhibited linguistic impairment with features fairly typical for thalamic lesions. He also demonstrated a severe ideomotor apraxia. The preservation of repetition, syntax, and implicit memory despite severe naming deficits in patients with thalamic lesions suggests the possibility that thalamic involvement in cognitive function involves processes underlying declarative as opposed to nondeclarative (eg, implicit or procedural) memory. The occurrence of apraxia with thalamic lesions may be consistent with this hypothesis if it is accepted that only actual tool use approaches a pure skill that involves only nondeclarative memory, while other aspects of praxis implicate declarative memories.
7958619	Memory processes and long-term potentiation (LTP) are blocked at the time of their initiation by antagonists of glutamate NMDA or metabotropic receptors, by drugs that hinder the activity of carbon monoxide or the platelet-activating factor, and by GABA type A receptor agonists. In the next 2 h, memory and LTP are accompanied by an enhancement of the activity of calcium/calmodulin-dependent protein kinase II and of protein kinase C, and are blocked by inhibitors of these enzymes. At the time of expression, memory and LTP are blocked by antagonists of glutamate AMPA receptors. The effects of drugs on memory are seen upon their infusion into areas of the brain known to be responsible for the storage and retrieval of declarative memories (hippocampus, amygdala, medial septum, entorhinal cortex) and are both task- and structure-specific. When put together with other pharmacologic findings, with lesion and recording studies, and with data on transgenic animals showing deficits of both memory and LTP, the data reviewed here lend strong support to the hypothesis that LTP in these brain areas underlies memory processes.
10467594	We investigated sensorimotor skill learning, a form of nondeclarative (implicit) memory, in 28 subjects with declarative (explicit) memory defects caused by either mesial temporal (n = 15) or basal forebrain (n = 13) damage and in 66 normal control subjects. All 28 amnesics had normal learning of a rotor pursuit task. We also studied in detail the sensorimotor skill learning of patient Boswell. As a result of bilateral damage to both mesial and lateral aspects of the temporal lobes and to the basal forebrain, Boswell has one of the most severe impairments ever reported for learning of all types of declarative knowledge. Compared to matched controls, Boswell acquired and retained normally the skills associated with performing motor tasks. We conducted a long-term (2-year) followup study of Boswell's retention of the rotor pursuit task, and we found that he retained the skill as well as normal controls. Our study builds on previous work in the following respects: (1) It provides evidence, for the first time, that skill learning is normal in basal forebrain amnesics; (2) it shows that patient Boswell has normal learning and long-term retention of sensorimotor skills, in spite of his extensive damage; and (3) it offers additional evidence that mesial temporal lobe damage spares skill learning. These findings demonstrate unequivocally that sensorimotor skill learning does not require structures in mesial and lateral temporal regions nor in basal forebrain.
7808868	This manuscript presents a neuropsychological model of the development and stability of human character. We define character as those things which people do routinely, automatically, and unconsciously--those which make people knowable and predictable. According to the model, the substrate of character is comprised of one's phenotypically based temperamental predispositions. This substrate is modified as a result of experience. Research has indicated the existence of multiple, relatively independent memory systems, and we are particularly interested in the distinction that has been made between declarative and procedural learning. Declarative memory involves recall of information and events, while procedural memory involves the learning of skills and other processes. In neurologically intact persons, these systems work in concert, yet they are relatively independent of one another. This model constrains the concept of character in a manner that allows researchers to address several issues, including (1) the manner in which character develops over time, (2) the mechanisms involved in the stability of character, and (3) the processes likely to be associated with character change.
10467589	Amnesic patients and control subjects participated in a study of probabilistic classification learning. In each of three tasks, four different cues were each probabilistically associated with one of two outcomes. On each trial, the cues could appear alone or in combination with other cues and subjects selected the outcome they thought was correct. Feedback was provided after each trial. In each task, the amnesic patients learned gradually to associate the cues with the appropriate outcome at the same rate as control subjects, improving from 50% correct to approximately 65% correct. Presumably because the cue-outcome associations were probabilistic, declarative memory for the outcomes of specific trials was not as useful for performance as the information gradually accrued across trials. Nevertheless, declarative memory does appear to make a contribution to performance when training is extended beyond approximately 50 trials, because with further training control subjects eventually outperformed the amnesic patients. It was also demonstrated that performance on the probabilistic classification task was not the result of holding knowledge of cue-outcome associations in short-term memory, because both control subjects and amnesic patients demonstrated significant savings when testing was interrupted by a 5-min delay (experiment 2). Probabilistic classification learning appears to provide an analog in human subjects for the habit learning tasks that can be acquired normally by animals with hippocampal lesions.
7919210	Rats with bilateral electrolytic lesions of the perirhinal cortex and sham operated control rats were tested in a spatially guided, delayed non match to sample task. Although perirhinal lesioned animals showed no deficit in acquisition of the task, a performance deficit was observed across longer delay intervals. These results indicate that the perirhinal cortex is a critical component of the network subserving working or declarative memory in the rat.
8043268	Measures of procedural and declarative memory were administered to 88 children forming two groups, aged 8 and 12. Two measures of priming, Gollin Figures and Degraded Words, were compared to declarative measures of recall. Strong support for a developmental dissociation between priming tasks and declarative memory was found. Both age groups showed a similar amount of priming facilitation, yet a significant age effect was observed for the declarative recall tasks. Current findings demonstrate that the level of procedural memory performance stabilizes during a period of development when declarative memory continues to improve.
8198631	Glucocorticoids (GCs) have a variety of effects on the brain including site-preferential, inhibitory effects on hippocampal neurons. In the case of dexamethasone (DEX), extended rather than single-dose treatment in vivo may be required for binding to brain rather than peripheral (e.g., pituitary) GC receptors and for maximizing other biologic effects in hippocampus (e.g., GC receptor downregulation, inhibition of glucose transport). Based on the contributory role of hippocampal neurons in declarative memory performance, we investigated the cognitive consequences of DEX treatment in normal adult human subjects, hypothesizing a decrease in declarative memory performance after extended but not overnight treatment. Double-blind, placebo-controlled treatment with DEX was given at 2300 hr for four consecutive days (0.5, 1, 1, 1 mg, respectively). Plasma sampling (0800 and 1600 hr) and cognitive testing (1600 hr) were performed on study days 0 (baseline), 1, and 4, and 7 d posttreatment. Repeated-measures ANOVA found a significant interaction between study day and treatment condition for correct recall during a paragraph recall task [F(3,51) = 3.52, p = 0.02]. DEX (n = 10) in comparison to placebo (n = 9) treatment decreased correct paragraph recall on study day 4 [F(1,17) = 5.01, p = 0.04] and study day 11 [F(1,17) = 5.82, p = 0.03], with the lowest level of performance occurring on day 4 followed by a return toward baseline performance level by day 11. In the placebo-treated subjects, correct paragraph recall improved over the course of treatment, consistent with practice.(ABSTRACT TRUNCATED AT 250 WORDS)
8050857	The case of a 63-year-old woman who suffered bilateral ischemic damage in the region of blood supply of the paramedian thalamic arteries is reported. She displayed severe deficits on immediate and delayed recall of both verbal and visuospatial material in the presence of intact IQ and attentional abilities. Performance on tests of all major components of nondeclarative memory (skill acquisition, perceptual priming, classical conditioning) was also preserved. The present report, thus, provides a further example for dissociations of declarative and nondeclarative memory functions following bilateral thalamic damage.
8192849	This study hypothesized that verbal memory decline following anterior temporal lobectomy (ATL) is associated with a lack of significant neuropathology in resected left, but not right, hippocampus and is limited to measures of episodic memory only. Tests of immediate (digit span), semantic (visual naming), and episodic memory as measured by the California Verbal Learning Test (CVLT) were administered before and 6 months after resection of the anterior left (n = 36) or right (n = 26) temporal lobe. There were no effects of hippocampal pathology on measures of immediate or semantic memory for either ATL group or for episodic memory for the right ATL group. Left ATL patients who demonstrated no/mild hippocampal sclerosis exhibited significantly greater postoperative decline in episodic memory compared with those with moderate/marked hippocampal sclerosis on multiple CVLT indices (recall measures, learning characteristics, and contrast measures).
9384857	Ever since people's responses to overwhelming experiences have been systematically explored, researchers have noted that a trauma is stored in somatic memory and expressed as changes in the biological stress response. Intense emotions at the time of the trauma initiate the long-term conditional responses to reminders of the event, which are associated both with chronic alterations in the physiological stress response and with the amnesias and hypermnesias characteristic of posttraumatic stress disorder (PTSD). Continued physiological hyperarousal and altered stress hormone secretion affect the ongoing evaluation of sensory stimuli as well. Although memory is ordinarily an active and constructive process, in PTSD failure of declarative memory may lead to organization of the trauma on a somatosensory level (as visual images or physical sensations) that is relatively impervious to change. The inability of people with PTSD to integrate traumatic experiences and their tendency, instead, to continuously relieve the past are mirrored physiologically and hormonally in the misinterpretation of innocuous stimuli as potential threats. Animal research suggests that intense emotional memories are processed outside of the hippocampally mediated memory system and are difficult to extinguish. Cortical activity can inhibit the expression of these subcortically based emotional memories. The effectiveness of this inhibition depends, in part, on physiological arousal and neurohormonal activity. These formulations have implications for both the psychotherapy and the pharmacotherapy of PTSD.
8170623	A network model with some general properties of hippocampal area CA3, and the results of its simulation on a massively parallel processor, are described. This network performs the tasks of recent declarative memory including recovery of complete traces from partial cues and recognition of familiarity. Immediate recurrent inhibition is essential for providing sensitivity to small cues while preventing spurious recall. Tonic inhibition seems to set the retrieval speed/accuracy trade-off. Delayed inhibition resets hippocampal activity. The behavior under excessive or deficient inhibition resembles that of amnesics with lesions in brainstem areas known to modulate hippocampal inhibition. The rate of recall and dynamics of inhibition by the model are similar to those inferred to occur in the human hippocampus from unit and evoked potential recordings. The model suggests a mechanism whereby the hippocampus can control its own plasticity. These simulations demonstrate that the retrieval mechanism in several hippocampal models is feasible and that the theta rhythm and the cognitive evoked potentials may be generated by synaptic events modulating network parameters.
8019524	Evoked potentials (EPs) were used to help identify the timing, location, and intensity of the information-processing stages applied to faces and words in humans. EP generators were localized using intracranial recordings in 33 patients with depth electrodes implanted in order to direct surgical treatment of drug-resistant epilepsy. While awaiting spontaneous seizure onset, the patients gave their fully informed consent to perform cognitive tasks. Depth recordings were obtained from 1198 sites in the occipital, temporal and parietal cortices, and in the limbic system (amygdala, hippocampal formation and posterior cingulate gyrus). Twenty-three patients received a declarative memory recognition task in which faces of previously unfamiliar young adults without verbalizable distinguishing features were exposed for 300 ms every 3 s; 25 patients received an analogous task using words. For component identification, some patients also received simple auditory (21 patients) or visual (12 patients) discrimination tasks. Eight successive EP stages preceding the behavioral response (at about 600 ms) could be distinguished by latency, and each of 14 anatomical structures was found to participate in 2-8 of these stages. The earliest response, an N75-P105, focal in the most medial and posterior of the leads implanted in the occipital lobe (lingual g), was probably generated in visual cortical areas 17 and 18. These components were not visible in response to words, presumably because words were presented foveally. A focal evoked alpha rhythm to both words and faces was also noted in the lingual g. This was followed by an N130-P180-N240 focal and polarity-inverting in the basal occipitotemporal cortex (fusiform g, probably areas 19 and 37). In most cases, the P180 was evoked only by faces, and not by words, letters or symbols. Although largest in the fusiform g this sequence of potentials (especially the N240) was also observed in the supramarginal g, posterior superior and middle temporal g, posterior cingulate g, and posterior hippocampal formation. The N130, but not later components of this complex, was observed in the anterior hippocampus and amygdala. Faces only also evoked longer-latency potentials up to 600 ms in the right fusiform g. Words only evoked a series of potentials beginning at 190 ms and extending to 600 ms in the fusiform g and near the angular g (especially left). Both words and faces evoked a N150-P200-PN260 in the lingual g, and posterior inferior and middle temporal g.(ABSTRACT TRUNCATED AT 400 WORDS)
8259522	A fundamental question about cognition concerns how knowledge about a category is acquired through encounters with examples of the category. Amnesic patients and control subjects performed similarly at classifying novel patterns according to whether they belonged to the same category as a set of training patterns. In contrast, the amnesic patients were impaired at recognizing which dot patterns had been presented for training. Category learning appears to be independent of declarative (explicit) memory for training instances and independent of the brain structures essential for declarative memory that are damaged in amnesia. Knowledge about categories can be acquired implicitly by cumulating information from multiple examples.
8124078	Bilateral damage of the medial temporal lobe system prevents the formation of new declarative memories but leaves intact knowledge that was acquired before damage. For motor learning, no structure has been identified that plays a comparable role for the consolidation of motor memories. The deficits of motor learning are focal and show a similar allocation to the various sensorimotor subsystems, as do the corresponding non-mnemonic functions. The involvement of sensorimotor circuitries changes during motor learning so that association areas are preferentially activated in the early stages, and cerebello- and striato-motor-cortical loops are preferentially activated in the late stages of motor learning. Recent neuroanatomical and neurophysiological findings on the effects of brain lesions in human and non-human primates are discussed.
7507594	The cholinergic neurotoxin AF64A (ethylcholine mustard aziridinium) produced alterations in a spatial but not a nonspatial cognitive task following ICV injection. AF64A impaired acquisition and performance in the standard Morris water maze task, evidenced by significantly longer latencies to find the submerged platform. However, the AF64A group exhibited shorter latencies and more direct paths to the target at the end of training, which suggests acquisition of efficient search strategies and a sparing of procedural memory. However, the AF64A group spent significantly less time in the target quadrant during the probe trial than the CSF group. This suggests a failure to learn the specific location of the target and impaired declarative memory processes. In contrast, AF64A did not affect performance of a cued MWM task that did not involve spatial memory processing, demonstrating the absence of motoric, sensory, or motivational impairments. The AF64A-induced behavioral deficits were associated with a) a significant decrease in high affinity choline transport (HAChT), b) reduced concentrations of 5-HT and 5-HIAA, and c) an increased ratio of 5-HIAA/5HT, in the HPC. There were no changes in choline uptake in the gustatory cortex, the amygdala, or the striatum. Percent time in the target quadrant during the probe trial was significantly correlated with HAChT in the HPC. There were no correlations between any of the behavioral measures and HAChT in the striatum, gustatory cortex, or the amygdala, or between serotonergic or noradrenergic parameters in the HPC. These data suggest that AF64A produces cognitive deficits in spatial tasks that are correlated with the cholinergic hypofunction induced by the compound.
8215247	We compared procedural learning, translation of procedural knowledge into declarative knowledge, and use of declarative knowledge in age-matched normal volunteers (n = 30), patients with Parkinson's disease (n = 20), and patients with cerebellar degeneration (n = 15) by using a serial reaction time task. Patients with Parkinson's disease achieved procedural knowledge and used declarative knowledge of the task to improve performance, but they required a larger number of repetitions of the task to translate procedural knowledge into declarative knowledge. Patients with cerebellar degeneration did not show performance improvement due to procedural learning, failed to achieve declarative knowledge, and showed limited use of declarative knowledge of the task to improve their performance. Both basal ganglia and cerebellum are involved in procedural learning, but their roles are different. The normal influence of the basal ganglia on the prefrontal cortex may be required for timely access of information to and from the working memory buffer, while the cerebellum may index and order events in the time domain and be therefore essential for any cognitive functions involving sequences.
8276926	The case of a patient with above-average intelligence and educational background, high motivation, and an approximate IQ-MQ difference of 40 points is documented. The patient has been examined repeatedly for nearly a decade. Extensive neuroradiological material of his focal bilateral brain damage in the dorsal diencephalon is available. A widespread range of cognitive tests was used to investigate his actual performance on all relevant aspects of intelligence, attention, subjective memory, immediate retention, learning, skill and problem solving abilities, concept formation, cognitive flexibility, priming, constructional ability, retrograde memory, and long-term retention. The total of more than 50 tests included German-language forms of the revised Wechsler Memory Scale and of the Rivermead Behavioural Memory Test. The patient's short-term memory and attention were, in spite of his advanced years, average or well above average. He gave a number of examples of still intact skills and implicit memory abilities, though there was no uniformity in his performance on implicit memory tests (e.g., with respect to stored vs. new implicit information). He had no awareness of his severe anterograde and retrograde amnesia, documented over a large range of verbal and figural tests. Taken together, the results from our patient confirm the principal dichotomy between declarative and nondeclarative mnestic functions, but give evidence for some restrictions as well. They furthermore demonstrate that focal diencephalic damage may result in profound anterograde and selective retrograde amnesia, especially with respect to data-based material, and that disconnecting portions of the medial and basolateral limbic circuits has devastating consequences on memory.
8261027	General cognitive function and specific language and memory processing abilities were compared in dementia of the Alzheimer type (DAT), depressed and normal control subjects. Several tests clearly differentiated between DAT and depressed subjects including a verbal fluency task, several components of a word memory test, an IQ deterioration index, and the Mini-Mental State Examination. The inability of DAT subjects to take advantage of semantic cues in both the verbal fluency and in the memory test contrasted with the performance of depressed and normal subjects, who were able to benefit from semantic cues. Depressed patients displayed deficits compared with normal controls on the more effortful verbal fluency task but not on the memory test. Tasks that are least effortful, rely on semantic associations, and require declarative memory are most likely to discriminate between DAT and depression.
8252610	Hippocampal structures are a major target for adrenal steroid hormones, and hence these neural regions are some of the most likely mediators of the effects of adrenocortical steroids on behavior. Memory disturbance, in particular biasing toward negative contents, are part of the symptomatology presented by depressive patients. In turn, a sizeable subset of depression also presents with hypercortisolemia. Adrenocortical hormones are also known to affect memory processes. Hippocampal formation is essential for declarative memory. We thought it appropriate then to study the effects of adrenal steroids on long-term potentiation, a putative memory mechanism in the hippocampus. Two clearly distinguished components of the evoked response to perforant path stimulation can be studied in the hippocampus: the excitatory postsynaptic potential (EPSP) which denotes the graded depolarization of the somatodendritic region of the neuron and the population spike (PS), a manifestation of the all-or-none-discharge of the cell action potential. Corticosterone had a significant depressant effect on the EPSP component of the evoked response immediately and 15 min after injection. Thereafter EPSP amplitudes were within normal values. Corticosterone significantly decreased the PS immediately after the train, the component remaining low 30 min after the train. 5 alpha-Dihydrocorticosterone (a ring A-reduced metabolite of corticosterone) significantly reduced the PS component of the response at all times after injection. 18-Hydroxydeoxycorticosterone and deoxycorticosterone significantly decreased both EPSP and PS components of the evoked response from the time of infusion. Contrary to expectation, tetrahydrodeoxycorticosterone was ineffective in decreasing and if anything, enhanced the development of long-term potentiation. 18-Hydroxydeoxycorticosterone 21-acetate behaved like vehicle, except for the first 30 min after injection when the EPSP was decreased. Allotetrahydroprogesterone decreased all EPSP's values and had no effect in the PS development in comparison with vehicle. The suggestion is made that the study of steroidal effects on hippocampal LTP can serve as a preclinical model of some aspects of depression in a specific subset of the disease.
8350733	Amnesic patients and normal subjects read the names of nonfamous persons. Then, after being told that all the names were nonfamous, subjects judged the fame of names on a mixed list of new famous names, old nonfamous names, and new nonfamous names. Finally, they took a recognition memory test involving old and new nonfamous names. In this way, declarative (explicit) memory and nondeclarative (implicit) memory were placed in opposition. That is, recollection that a name had been recently presented (and was therefore nonfamous) opposed the facilitatory effect by which prior presentation ordinarily increases the tendency to judge that name as famous. Normal subjects exhibited good recognition memory and no fame-judgment effect--that is, no difference in fame judgments for new and old nonfamous names. By contrast, for the amnesic patients recognition memory was poor, but a strong fame-judgment effect occurred--that is, amnesic patients judged old nonfamous names as famous. The results provide additional evidence that the fame-judgment effect is supported fully by nondeclarative (implicit) memory and is independent of the limbic/diencephalic brain structures damaged in amnesia.
8216164	An overview of lesion experiments concerned with the involvement of the hippocampus in learning and memory in the rat is presented. Multiple injections of small amounts of ibotenic acid were used to selectively remove the hippocampus (dentate gyrus, hilar cells, CA1-CA3 pyramidal cells). Similar selective, axon-sparing ibotenate lesions of hippocampus were used in a series of learning and memory experiments employing tasks that are thought to be important in hippocampal function. The performance of rats with the hippocampus removed was compared with that of control animals in the acquisition and retention of spatial versus nonspatial information, forgetting of spatial and nonspatial information, contextual learning, recognition memory and concurrent discrimination learning, and complex representational learning (conditional discrimination and negative patterning learning). The general finding that rats without a hippocampus were impaired on those tasks that required the utilization of spatial and contextual information stands in contrast with the spared performance that was found in learning about and handling (even complex) nonspatial information. Rather than support for views that emphasize a role for the hippocampus in specific memory processes (working memory, declarative memory, temporary memory buffer, configural learning), the present results are more compatible with the idea that the hippocampus plays an especially important role in processing and remembering spatial and contextual information. The limited data that are available using more selective lesions of related hippocampal formation structures (entorhinal cortex, subiculum) suggest that these structures also make important contributions to learning and memory, and that some of these contributions may be different from those made by the hippocampus.
8321585	Concept mapping was developed by Novak and Gowin in 1984 as a technique to examine an individual's knowledge-base in a given domain. In the motor domain, however, with a heavy emphasis on automated and tacit knowledge there may not be a base of information which can be verbally reported. 52 subjects with similar academic backgrounds were asked to explain all they knew about the concept of movement, and these reports were transcribed and assessed by four judges. Subjects also completed a pattern-recognition task related to procedural knowledge for movement. Over-all, the judges were able to identify a clear hierarchy in the levels of movement-related knowledge, suggesting that this technique may be useful in research on movement. However, this declarative knowledge appeared to be distinct from associated procedural knowledge, supporting Anderson's (1982) theory and the need for several tools to provide a more complete reflection of the knowledge base in a particular domain.
8491847	Previous research has produced conflicting evidence concerning transfer of new learning by amnesic patients. The present experiment investigated the hypothesis that different numbers of learning trials account for differences in transfer, such that the greater the number of repetitions of material in identical stimulus contexts the poorer the transfer. Six memory-impaired patients and six control subjects attempted to learn the names of business-related documents in response to descriptive definitions. Learning continued until one of the following criteria was reached: 50% correct, 100% correct, 100% correct plus 10 trials. In a transfer task, subjects were then asked to produce the target responses to altered definitional cues. The results of the experiment demonstrated that, contrary to prediction, transfer improved with numbers of learning trials. Results are consistent with the view that continued study of information allows better integration of new learning with prior knowledge and correspondingly higher levels of transfer. The theoretical implications of the findings are discussed in terms of the declarative/procedural and the episodic/semantic memory distinction. It is suggested that memory-impaired patients are capable of acquiring new semantic information although not at a normal rate. Implications for memory rehabilitation are also outlined.
8454964	In the visual paired-comparison task, which has been used to demonstrate memory abilities in human infants, Ss view pairs of pictures and then view new pictures paired with old ones. Memory is demonstrated when Ss spend more time looking at new pictures than at old ones. In a series of studies involving amnesic patients and normal Ss, the authors evaluated what kind of memory is exhibited in this task. The results suggest that performance ordinarily depends on the brain structures essential for declarative memory. These and other findings suggest that the visual paired-comparison test also depends on declarative memory when the task is given to human infants. Thus, successful performance on this task by infants probably reflects an early capacity for declarative memory. The relevance of these findings to the phenomenon of infantile amnesia is discussed.
8469418	This study was aimed to clarify in how far ontogenetic development is different for declarative/explicit compared to procedural/implicit learning. These two memory subsystems are differentially affected in a number of pathological conditions. Sixty-one children between the age of 5 and 10 years were tested on a verbal story recall and non-verbal pictorial recall task, representing explicit memory. To test for implicit memory, a motor mirror tracking task and a non-motor tower-of-hanoi puzzle were used. Both explicit memory tasks showed a clear developmental profile with an increase in the number of recalled items for immediate, late and delayed recall with adult values not reached before the age of 9-10 years. In contrast, there were no age differences for both implicit memory tasks. The study demonstrates that explicit and implicit memory follow different maturational trends and further corroborate the notion of two different memory systems.
8475218	Learning and memory were assessed in 24 monozygotic (MZ) pairs of individuals discordant for schizophrenia or delusional disorder and seven normal pairs of MZ twins. On declarative memory tasks, the affected group displayed a pattern that might best be characterized as dysmnesic in that they performed significantly worse than the discordant unaffected group on story recall, paired associated learning, and visual recall of designs, but they learned over time, had relatively preserved recognition memory, and did not show profoundly accelerated rates of forgetting. Effortful, volitional retrieval from the lexicon, measured by verbal fluency, was also compromised in the affected group. On the other hand, procedural learning of the motor skill in a pursuit rotor task was relatively intact in the affected group. Comparisons of the normal group and unaffected group indicated that the latter group had very mild impairments in some aspects of episodic memory, namely, immediate and delayed recall of stories and delayed recall of designs. It is highly unlikely that the impairments observed in the affected group can be attributed to differences in genome, family environment, socioeconomic circumstance, or educational opportunity, as all of these were controlled by the twin paradigm. Rather, the impairments appear to be related to the intercession of disease. The neuropsychological profile is consistent with frontal lobe and medial temporal lobe dysfunction, as noted in this sample as well as other samples of schizophrenic singletons. Significant correlations between many measures of memory and global level of social and vocational functioning within the discordant group were also found. Thus difficulties in rapidly acquiring new information and propitiously retrieving old information may burden patients with schizophrenia in many of the transactions of everyday life.
8428073	Memory is composed of dissociable systems that accomplish different forms of learning and that are mediated by distinct neural networks. Knowledge about the psychological nature and neural basis of specific memory systems has come primarily from lesion analysis, but this year functional brain imaging has provided a new source of convergent evidence. Recent findings are reviewed that provide new information about a limbic-diencephalic system critical for learning new declarative information, a temporal lobe system that stores long-term semantic knowledge in a domain-specific fashion, an occipital system that subserves visuoperceptual implicit memory, and a fronto-thalamo-neostriatal system that mediates the executive component of working memory and that plays an important role in some forms of sensorimotor skill learning.
7907201	Different approaches to integrate emotion and cognition can be differentiated. On the one hand emotions can be part of an associative network of long-term memory (Bower, 1981; Bower & Cohen, 1982; Lang, 1979, 1984). On the other hand emotions are said to function as mediators that instigate different processing strategies (Fiedler, 1988; Isen, 1984, 1987; Kuhl, 1983 b). Both approaches can be integrated within the framework of ACT* (Anderson, 1983) assuming emotion nodes as parts of the declarative memory and emotion related productions as parts of the procedural memory (Spies & Hesse, 1986). A third approach claims that emotions change the amount of processing capacity available for task related processes (Ellis & Ashbrook, 1988; Kuhl, 1983 b; Spies & Hesse, 1986). The theoretical positions as well as related empirical results are discussed by referring to the literature as well as to some of our own data.
1457394	Two kinds of procedural learning, viz. learning of a sequence of simple motor responses and learning to solve a rather complex problem (Tower of Hanoi), as well as declarative learning (word list learning) were investigated in a group of psychotic inpatients (n = 67) and a control group of non-psychotic psychiatric inpatients (n = 19). Within the psychotic group, correlations of the task variables with positive and negative symptoms were explored. There was no difference between both groups in motor procedural learning. Psychotic patients were less efficient than controls in solving the Tower problem, but both groups again showed an equal amount of procedural learning. Consistent with the literature, however, a clear difference between both groups was found in declarative learning. The memory tasks did not correlate significantly with psychotic symptoms. These findings are interpreted as another indication that automatic information processing in psychotic patients is intact. The results are discussed with reference to neuropsychological research on procedural learning in neurological patients.
1436436	Previous research demonstrated that a single amnesic patient could acquire complex knowledge and processes required for the performance of a computer data-entry task. The present study extends the earlier work to a larger group of brain-damaged patients with memory disorders of varying severity and of various etiologies and with other accompanying cognitive deficits. All patients were able to learn both the data-entry procedures and the factual information associated with the task. Declarative knowledge was acquired by patients at a much slower rate than normal whereas procedural learning proceeded at approximately the same rate in patients and control subjects. Patients also showed evidence of transfer of declarative knowledge to the procedural task, as well as transfer of the data-entry procedures across changes in materials.
23964880	Abstract The topic of multiple forms of memory is considered from a biological point of view. Fact-and-event (declarative, explicit) memory is contrasted with a collection of non conscious (non-declarative, implicit) memory abilities including skills and habits, priming, and simple conditioning. Recent evidence is reviewed indicating that declarative and non declarative forms of memory have different operating characteristics and depend on separate brain systems. A brain-systems framework for understanding memory phenomena is developed in light of lesion studies involving rats, monkeys, and humans, as well as recent studies with normal humans using the divided visual field technique, event-related potentials, and positron emission tomography (PET). 
23964879	Abstract Theoretical arguments and empirical data are presented in favor of the hypothesis that the hippocampal system supports a declarative memory capacity in animals as well as humans. This view is advanced by identifying two prominent characteristics of human declarative memory and by operationalizing and evaluating them using both experimental lesion and single unit recording studies on animals. First, hippocampal processing is not selective to any particular category of learning materials; instead, it supports comparisons among all kinds of information in memory, resulting in a representation of critical relations between items. Conversely, individual representations are supported outside the hippocampal system. Second, hippocampal-dependent, relational memory representations involve a flexible organization that permits inferences from memory in novel situations. Conversely, hippocampal-independent individual representations can support only repetition of procedures acquired during original learning. Correspondences between the neuropsychological and neurophysiological findings presented serve to indicate how these properties of hippocampal representation support declarative memory across behavioral paradigms and across species. 
1385610	The relationship between recall and recognition has been a central topic for the study of memory. A test of alternative views about recall and recognition was arranged by studying amnesic patients. In amnesia, damage has occurred to a brain system important for declarative (conscious) memory, but skill learning, priming, and other forms of nonconscious memory are intact. Recall and recognition were found to be proportionately impaired in amnesic patients, and confidence ratings for the recognition judgments were commensurate with the level of impaired performance. The results are contrary to views that either recognition memory or associated confidence judgments are ordinarily supported significantly by nonconscious memory. The results favor the view that recall and recognition are related functions of declarative memory and equivalently dependent on the brain system damaged in amnesia.
1643196	Measures of the degree of motor, psychiatric, and declarative memory disability were made in neurologically impaired and neurologically asymptomatic patients with Wilson's disease. All three types of disability were significantly greater in the neurologically impaired than in the asymptomatic patients. There was no significant interaction between these disabilities in the impaired patients suggesting that motor, psychiatric, and memory symptoms are three relatively independent sequelae of the copper-induced central nervous system (CNS) damage that underlies Wilson's disease.
1594723	This article considers the role of the hippocampus in memory function. A central thesis is that work with rats, monkeys, and humans--which has sometimes seemed to proceed independently in 3 separate literatures--is now largely in agreement about the function of the hippocampus and related structures. A biological perspective is presented, which proposes multiple memory systems with different functions and distinct anatomical organizations. The hippocampus (together with anatomically related structures) is essential for a specific kind of memory, here termed declarative memory (similar terms include explicit and relational). Declarative memory is contrasted with a heterogeneous collection of nondeclarative (implicit) memory abilities that do not require the hippocampus (skills and habits, simple conditioning, and the phenomenon of priming). The hippocampus is needed temporarily to bind together distributed sites in neocortex that together represent a whole memory.
1308182	The CA3 network in the hippocampus may operate as an autoassociator, in which declarative memories, known to be dependent on hippocampal processing, could be stored, and subsequently retrieved, using modifiable synaptic efficacies in the CA3 recurrent collateral system. On the basis of this hypothesis, the authors explore the computational relevance of the extrinsic afferents to the CA3 network. A quantitative statistical analysis of the information that may be relayed by such afferent connections reveals the need for two distinct systems of input synapses. The synapses of the first system need to be strong (but not associatively modifiable) in order to force, during learning, the CA3 cells into a pattern of activity relatively independent of any inputs being received from the recurrent collaterals, and which thus reflects sizable amounts of new information. It is proposed that the mossy fiber system performs this function. A second system, with a large number of associatively modifiable synapses on each receiving cell, is needed in order to relay a signal specific enough to initiate the retrieval process. This may be identified, we propose, with the perforant path input to CA3.
1349833	Explicit consolidation of memory, or fixation of declarative belief, appears to be physically represented in changes of synaptic conductances of neurons in the parietal-temporal-occipital association cortex (PTO) of the mammalian forebrain. This fixation of belief in PTO is postulated to be critically dependent on a diffuse reinforcement signal via the inferior temporal cortex (ITC) ultimately caused by an increased output of the CA1 pyramidal cells of hippocampus. Analogous to the reinforcing mechanisms of other forebrain systems, this updating of the connection weights of the neural nets in PTO by the output of the critical neurons in CA1 is directly related to concentrations of dopamine (DA). We propose that the delusions (i.e., unreasonable beliefs) of paranoid schizophrenia are caused by a hyperactivity of the same DA-sensitive CA1 neurons that are responsible for the fixation of normal beliefs. The dramatic reduction in delusions with administration of neuroleptics, as DA D2 blockers, in schizophrenics may thus be explained by their acting to ameliorate the hyperactivity of these CA1 DA D2 receptors.
1605325	Research conducted by Sternberg (1969) has suggested that there is a transfer process, a cognitive process for activating stored knowledge. His research and that of those who have replicated and extended it have concentrated on distinct declarative lists of information. In two experiments, we have sought to extend this area by studying the cognitive processes for activating an action plan, a sequence of mental operations executed to achieve a goal. Results showed that (a) longer action plans took more time to activate, and (b) when the activation process was interrupted before completion, the process had to be restarted from its beginning after the interruption had been dealt with. These results were interpreted as evidence for a time-consuming transfer process in which the elements of action plans are transferred from long-term store to short-term store. These results are compared with other current data on the transfer process, and implications for the use of controlled knowledge in cognitive tasks are discussed.
1779028	This study examined retention of procedural learning, using the serial reaction time (SRT) task, over a 1- or 2-week delay in Alzheimer's disease (AD) patients and elderly control (EC) subjects. The SRT task is a four-choice reaction-time task consisting of blocks of 100 trials. A 10-item repeating sequence was embedded in the first four blocks of trials in session one and the first two blocks of session two. Sequence-specific learning was assessed in session one by comparing reaction time (RT) in the fourth block with a repeating sequence to a fifth block in session one in which the stimuli were randomly arranged. After excluding subjects with deficient session one learning, there were eight AD patients and 14 EC subjects who showed robust sequence-specific learning in session one. In these subjects, retention of sequence-specific learning over the 1- to 2-week delay was examined. The AD patients and EC subjects showed an equivalent change in RT across sessions, and all the AD patients lacked any declarative knowledge of the repeating sequence within the task. Individually, two of the eight AD patients appeared to deviate substantially from the others and from the EC subjects in their excess slowing of RT across sessions. Since six AD patients did show retention similar to the EC subjects, it is concluded that at least some AD patients show normal retention of implicitly acquired knowledge over a long delay. Preserved retention in some of the AD patients implies that it is mediated by brain structures that are not affected by the Alzheimer neuropathological process.
1896849	Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent, anatomically related cortex, including entorhinal, perirhinal, and parahippocampal cortices. These structures, presumably by virtue of their widespread and reciprocal connections with neocortex, are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However, the role of this system is only temporary. As time passes after learning, memory stored in neocortex gradually becomes independent of medial temporal lobe structures.
1669313	The hippocampus has sometimes been proposed to function as a cognitive map, a memory system that stores information about allocentric space. Work with experimental animals and memory-impaired patients has raised difficulties with this view by showing that the hippocampus is not performing an exclusively spatial function. However, the possibility has remained that the hippocampus plays a special role in spatial memory or a disproportionately large role in spatial memory compared to other kinds of memory. This study compared spatial and nonspatial memory in amnesic patients with lesions of the hippocampal formation or diencephalon. Subjects studied an array of 16 toy objects and were subsequently tested for object recall, object recognition, and memory for the location of the objects. Control subjects were tested after long retention intervals in order to equate their object memory performance with that of the patients. The main finding was that, when the performance of amnesic patients on the object memory tests was matched to the object memory performance of control subjects, spatial memory performance of the amnesic patients also matched the spatial memory performance of the control subjects. The results were the same for the two groups of patients. These findings suggest that the hippocampus is not especially involved in spatial memory. Spatial memory is simply one instance of a broader category of memory that requires the hippocampus. While cognitive mapping in its most abstract sense may describe hippocampal function, our results support alternative formulation, suggesting that the hippocampus is necessary for the rapid acquisition of relational, configural, or declarative (as opposed to purely spatial) information.
2041988	Amnesic syndromes are rare, but they constitute very useful models to study the neurobiological substrates of human memory. The causes and semiological formulae of these syndromes are varied, but they are all characterized by anterograde amnesia combined with a retrograde amnesic disorder and by elective damage of episodic and declarative memories, the semantic and procedural memories, as well as intelligence, being usually spared. Amnesic syndromes are divided into two main types: the simplest one, type 1, is thought to be a defective storage, whilst the more complex type 2 is regarded as defective encoding associated with disturbances in retrieval dependent on more diffuse meso-diencephalic, septal, hypothalamic and sometimes frontal lesions. The lesional substrate of amnesic syndromes comprises the hippocampo-mammilo-thalamo-cingulum axial complex and its connections with the mesencephalon and the basal forebrain.
28147905	How are solutions of complex water jar problems influenced by starting with the simplest or the next simplest problem? The problems have been described as difficult variants of our water jar problems and as belonging to the class of MOVE problems that includes the Tower of Hanoi task. They were presented on a computer to 200 college students tested under eight conditions. With the simpler problem presented first rather than second, there were significant influences on the results: more solutions of each of five problems; more use of an illustrated initial direction; different preferences for initial left- or right-path solutions; shorter solutions; and reversed effects of the computer display of all the student's steps or only the most recent step. The results were discussed in terms of previous findings, memory processes, Einstellung and primacy effects, influences of timing, stress, and failure, declarative and proc6edural distinction, and educational implications.
24487577	The most common clinical sign of Alzheimer's disease (AD) is progressive memory loss. Presented here is a case of AD who, despite ultimate profound dementia with severe amnesia, showed retention of a perseverative response she developed during 26 encounters, over 4.5 years, with the Brown-Peterson distractor test. From Test 9 onwards, she responded from the first distractor-filled trial with one consonant trigram, appearing in none of the seven test forms given her. At Test 26, she could not repeat heard trigrams yet faithfully responded with her perseverative trigram. The trigram, ostensibly declarative information, apparently became part and parcel of the task's procedure. Although perseveration is a form of impairment probably resulting from Alzheimer pathology involving frontal and parietal cortex, it may also reflect a form of preserved memory, albeit distorted, supported by posterior cortical regions spared in AD. 
1944862	Evidence supports the view that "memory traces" are formed in the hippocampus and in the cerebellum in classical conditioning of discrete behavioral responses (e.g. eyeblink conditioning). In the hippocampus, learning results in long-lasting increases in excitability of pyramidal neurons that appear to be localized to these neurons (i.e. changes in membrane properties and receptor function). However, these learning-altered pyramidal neurons are distributed widely throughout CA3 and CA1. Although it plays a key role in certain aspects of classical conditioning, the hippocampus is not necessary for learning and memory of the basic conditioned responses. The cerebellum and its associated brain stem circuitry, on the other hand, does appear to be essential (necessary and sufficient) for learning and memory of the conditioned response. Evidence to date is most consistent with a localized trace in the interpositus nucleus and multiple localized traces in cerebellar cortex, each involving relatively large ensembles of neurons. Perhaps "procedural" memory traces are relatively localized and "declarative" traces more widely distributed.
2095766	Recently, Wood and his colleagues (1989) presented a case of childhood amnesia as evidence against the distinction between declarative and procedural memory that has sometimes been applied to human amnesia. Their argument was based on the observation that their patient showed some progress in school over the years, i.e., acquired some declarative knowledge, despite severely impaired day-to-day memory ability. We briefly review their case, together with a carefully studied second case of childhood amnesia not mentioned by Wood et al. Their argument is wrong in several ways. First, the utility of the declarative/procedural distinction for amnesia, or the utility of any other distinction between memory systems, depends on whether or not one kind of memory is impaired selectively, not on the severity of the impairment. In particular there is no requirement that one kind of memory be totally absent. Second, they have not provided the data necessary to support their argument; namely, data showing that the amount of declarative knowledge accumulated during years in school was better than would have been expected given the capacity for moment-to-moment or day-to-day memory. Indeed, the patient's moment-to-moment memory ability is better than represented, and the patient's progress in school was abnormally slow. Third, it is not clear that academic achievement scores provide a direct measure of declarative memory abilities (skill learning and recovery of function may also have contributed). We conclude that the evidence from childhood amnesia is fully consistent with the proposal that amnesia reflects a selective impairment in the formation of long-term declarative memory.
2341560	A current model proposes that memory consists of two functionally separate systems that have different neurological substrates. Declarative memory appears to be dependent on the diencephalic medial temporal lobe system whereas some speculate that the basal ganglia may be a neurological substrate for procedural memory. This study tested the role of the basal ganglia in regulating different types of procedural skills by comparing performance on a motor and a visuoperceptual skill learning task. Twenty Parkinson's (PD) patients and 20 normal control subjects performed two procedural learning tasks (rotary pursuit and mirror reading) and one declarative learning task (paired associates) over 3 days. The results showed that PD patients were not impaired on mirror reading or paired associate learning. On rotary pursuit, performance levels on day 1 were similar between groups, but the PD group showed less improvement across days than controls. However, only patients with more advanced symptoms of PD showed impaired rotary pursuit learning, and this could not be attributed directly to deficits in primary motor or general cognitive function. These findings suggest that the underlying processes/procedures for procedural learning are specific to the task, and are supported by different neuroanatomical systems.
2331737	In the 8-10th decade of life, people can be found who are not demented in the sense of WHO definition, but who are amnestic ("a memory problem only"). This defect is probably a result of the lesion of recent declarative memory. Immediate and remote memory are almost intact. Neuropathology of 17 such brains found numerous plaques and tangles in amygdalas and especially tangles in the IIth and IIIth strata of the entorhinal cortex and in subicula of hippocampi in 11 out of them. The number of plaques and tangles in frontal, parietal and temporal neocortex in these cases was not significant. In two other cases no significant ó "alzheimer-like" changes were found, but there was numerical atrophy of neurons of CA 1 sector of hippocampi in their caudal half perhaps due to chronic ischaemic lesion in one of them. In the other one there was an infarction of the left isthmus collateralis and retrosplenic cortex. In four cases no unequivocal structural basis for the amnesia was found--except slight numerical atrophy of large neurons of the nucleus basalis Meynerti. No significant diencephalic pathology was found. Severe "binswanger-like" changes were found in two cases of amnesia and in one case of control group, all of them were hypertonics. There exists a possibility that a part of "isolated" and relatively "benign" amnestic defects in old people is not a result of the aging of the brain but a sign of evolution of Alzheimer's disease and/or ischaemic vascular lesion of the brain destroying or disconnecting some of its information bottlenecks.
2303775	In this chronometric study of mental arithmetic, problems with sums greater than 20 and less than 100 were presented to third-grade subjects (age 8-9). It is argued that such problems are calculated by using procedures in which the problem is broken down into subproblems for which solutions are retrieved from a declarative knowledge base. Important bottlenecks in this process are the processing capacity (since only one subproblem can be handled at a time) and the storage capacity of working memory (since the original problem and all outcomes of subproblems have to be retained). Therefore it can be hypothesized that arithmetic procedures and types of problems that necessitate more subproblems will lead to longer solution times. Both hypotheses were confirmed. Significant interactions between types of problems and arithmetic procedures show an increasing difference in solution time between the procedures with increasing problem difficulty. It can be concluded that for the type of problems studied, arithmetic procedures requiring a smaller number of subproblems lead to better performance.
2234608	This paper proposes a new theory addressing the neural mechanism of declarative memory consolidation and retrieval. The premise of the theory is that the cortex is responsible for the storage of declarative memory while the medial temporal lobe is responsible for the consolidation and retrieval of declarative memory. The theory suggests that the medial temporal lobe can only accomplish its functions related to memory by hierarchically and cooperatively regulating the descending limbic system, including the hypothalamus, epithalamus, septum, mammillary bodies and the bed nucleus of the stria terminalis. These descending limbic structures, together with the amygdala, further send efferents to the four ascending NA, 5-HT, DA and ACh systems. It is these four ascending extrathalamic regulatory systems that provide the feedback neural pathways to the cortex and regulate the processes of memory consolidation and retrieval in the cortex. Therefore, the coupling of these descending limbic structures to the ascending NA, 5-HT, DA and ACh systems completes the neural circuits responsible for the consolidation and retrieval of new declarative memories. This neural mechanism of declarative memory consolidation and retrieval is universal to all species in higher mammals.
2530305	Amnesic patients demonstrate by their performance on a serial reaction time task that they learned a repeating spatial sequence despite their lack of awareness of the repetition (Nissen & Bullemer, 1987). In the experiments reported here, we investigated this form of procedural learning in normal subjects. A subgroup of subjects showed substantial procedural learning of the sequence in the absence of explicit declarative knowledge of it. Their ability to generate the sequence was effectively at chance and showed no savings in learning. Additional amounts of training increased both procedural and declarative knowledge of the sequence. Development of knowledge in one system seems not to depend on knowledge in the other. Procedural learning in this situation is neither solely perceptual nor solely motor. The learning shows minimal transfer to a situation employing the same motor sequence.
2757532	To investigate the possibility that learning of skills (ie, procedural memory) is preserved during posttraumatic amnesia, 16 amnesic survivors of severe closed head injury and 16 control subjects were studied. Procedural learning tasks included mirror reading, mazes, and a pursuit rotor task that involved tracking a rotating target. Declarative memory was assessed by testing recognition of the words used in mirror reading and a questionnaire concerning details of the previous testing session. Learning was evaluated on 3 consecutive days and a fourth session was scheduled after resolution of posttraumatic amnesia. Despite stable impairment of declarative memory during posttraumatic amnesia, the performance of head-injured patients improved across sessions on all procedural tasks and showed transfer to testing after resolution of posttraumatic amnesia.
2713146	In attempting to explain observed dissociations between impaired and preserved memory functioning in amnesia, various dichotomous memory systems (e.g., procedural versus declarative, episodic versus semantic, working versus reference memory) have often been employed. In such cases, the assumption has been that memory subserved by one system is preserved, while that of the other system is impaired. Cohen and Squire have suggested that in amnesia, declarative memory is impaired, although procedural memory is preserved. Long-term follow-up of a densely amnesic patient refutes this view by demonstrating significant anterograde learning of school subjects including reading, vocabulary, spelling, and arithmetic, all of which include some component of declarative memory. It appears that the procedural/declarative dichotomy is not adequate to explain preserved memory in amnesia.
3208061	The pattern of preserved learning abilities is described in a severely amnesic patient after bilateral thalamic infarction. Experimental findings cannot be accounted for both by the view that only episodic memory is impaired in amnesia, while semantic memory is spared, and by the theory that what is spared in amnesia is procedural learning contrasted with impaired declarative memory. In agreement with Warrington and Weiskrantz (1982), diencephalic amnesia is considered to be a disconnection syndrome between the frontal and temporal lobes. The conditions for showing spared and impaired memory in amnesics are specified on the basis of the performance of the patient and of the data available in the literature. This allows us to derive practical suggestions for programmes aimed at remediation of memory defects.
2969762	Patients with early stage Parkinson's disease are shown to be selectively impaired in a cognitive task of procedural learning while remaining intact in recall and recognition tests of declarative memory. In contrast, amnestic patients showed the opposite set of deficits, thus demonstrating a double dissociation. Patients with early Huntington's disease were either comparable to the parkinsonian patients or to amnestics. In the advanced Huntington's group, both procedural learning and declarative memory were impaired. It is argued that cognitive procedural learning depends on the establishment of heuristic strategies through the action of a circuit which involves the neostriatum and the prefrontal cortex.
3401382	Four of five patients with marked global amnesia, and others with new learning impairments, showed normal processing facilitation for novel stimuli (nonwords) and/or for familiar stimuli (words) on a word/nonword (lexical) decision task. The data are interpreted as a reflection of the learning capabilities of in-line neural processing stages with multiple, distinct, informational codes. These in-line learning processes are separate from the recognition/recall memory impaired by amygdalohippocampal/dosomedial thalamic damage, but probably supplement such memory in some tasks in normal individuals. Preserved learning of novel information seems incompatible with explanations of spared learning in amnesia that are based on the episodic/semantic or memory/habit distinctions, but is consistent with the procedural/declarative hypothesis.
3146767	Drug effects on human memory are usually assessed by overt recall or recognition tests. Covert tests which do not explicitly assess memory but which indirectly elicit previously presented information may be more sensitive to low levels of learning than overt tests. Three covert tests and corresponding overt recall tests were given to 16 men and 16 women breathing 30% nitrous oxide in oxygen or 100% oxygen to see if the covert tests resisted the memory-impairing effects of nitrous oxide. Nitrous oxide impaired performance on the overt tests. Performance in two covert tests, Constrained Associations and Word Completion, showed resistance to memory impairment. In the least resistant covert test, Free Associations, nitrous oxide altered associative processes. Performance in an additional test involving recognition and preferences for nonsense words repeated with varying frequencies also showed some resistance to memory impairment. The results support the distinction between declarative and procedural memory. Constrained Associations, Word Completion, and Nonsense Words tests may be useful for assessing low levels of learning during drug states.
3064086	A complete understanding of human memory will necessarily involve consideration of the active processes involved at the time of learning and of the organization and nature of representation of information in long-term memory. In addition to process and structure, it is important for theory to indicate the ways in which stimulus-driven and conceptually driven processes interact with each other in the learning situation. Not surprisingly, no existent theory provides a detailed specification of all of these factors. However, there are a number of more specific theories which are successful in illuminating some of the component structures and processes. The working memory model proposed by Baddeley and Hitch (1974) and modified subsequently has shown how the earlier theoretical construct of the short-term store should be replaced with the notion of working memory. In essence, working memory is a system which is used both to process information and to permit the transient storage of information. It comprises a number of conceptually distinct, but functionally interdependent components. So far as long-term memory is concerned, there is evidence of a number of different kinds of representation. Of particular importance is the distinction between declarative knowledge and procedural knowledge, a distinction which has received support from the study of amnesic patients. Kosslyn has argued for a distinction between literal representation and propositional representation, whereas Tulving has distinguished between episodic and semantic memories. While Tulving's distinction is perhaps the best known, there is increasing evidence that episodic and semantic memory differ primarily in content rather than in process, and so the distinction may be of less theoretical value than was originally believed.(ABSTRACT TRUNCATED AT 250 WORDS)
3442997	Recent studies have underlined the importance of the distinction between "declarative" and "procedural" aspects of memory functioning. The purpose of the present study is to evaluate the relative deficits in these two aspects of anterograde memory in an amnesic population with midline diencephalic lesions, and to determine whether this apparently fundamental distinction in memory types is honored even under real-world conditions. Eight alcoholic Korsakoff patients were examined for their lexical acquisition capacity, including both their application of word-learning procedures to a new lexical domain and their eventual recall of the facts represented by the new word. The findings revealed that each Korsakoff patient successfully applies at least some of the procedures subserving the word-learning process to the new lexical domain. By comparison, the Korsakoff patients subsequently acquire little of the factual knowledge represented by the new word. Specifically, almost all of the patients recognize only the object used during the exposure period to demonstrate the new word. Quantitative and qualitative features of the patients' declarative and procedural memory deficits are discusses in the context of real-world processing advantages and limitations.
3685069	The effects of diazepam on several tests of memory were investigated in a double-blind study of 24 healthy young adults. Following a single oral administration of 0.3 mg/kg diazepam or placebo, subjects in the diazepam group showed marked impairment in immediate free recall of words as compared to placebo control subjects. However, diazepam-treated subjects demonstrated performance benefits from prior exposure to the same words on tests of memory priming using word completion and category-generation tasks. The two types of memory tests differ in their demand for conscious recollection. Tests of free recall have explicit (declarative) memory demands whereas the priming test places only implicit (procedural) demands upon memory. The results demonstrate that diazepam spares some forms of memory as does amnesia induced by neurological impairment.
3315145	Disruption of neural activity within the basal ganglia of experimental animals causes selective learning deficits in tasks requiring switching between response strategies. These data along with reports of both general and specific intellectual impairment in patients with neurodegenerative disorders such as Parkinson's disease, appear to support the theory of cognitive functions of the basal ganglia. Recent studies have failed to confirm general cognitive or memory deficits in parkinsonian patients, but have identified deficiencies in devising and executing certain cognitive strategies. Following the lead of theorists such as Squire and Mishkin, this brief review emphasizes the distinction between procedural and declarative knowledge and examines the possible role of the basal ganglia in the acquisition and retention of procedural knowledge.
3574678	The administration of scopolamine, an anticholinergic drug, reduced the ability to recall and recognize stimuli presented previously--abilities thought to require declarative memory. In contrast, measures of procedural memory were unaffected by scopolamine: performance on a serial reaction time task incorporating a repeating stimulus and response sequence showed no difference in acquisition and retention of the sequence after scopolamine or saline. These results suggest that the cholinergic system is required for declarative but not procedural memory.
3580879	To investigate the roles individual hippocampal cell groups play in processing of spatial information for memory, we administered low-intensity electrical stimulation to the granule cells, CA3 and CA1 pyramidal cells of the dorsal hippocampus at selected times before and after acquisition of the solution to a radial maze win-stay task. Stimulation of any of the 3 cells populations yielded a variable duration anterograde disruption of memory performance, while stimulation of dentate gyrus granule cells alone produced a declarative memory-specific retrograde amnesia. The amnestic effect of granule cell stimulation was not associated with after discharges in the hippocampus and was prevented by systemic administration of the opiate antagonist naloxone. Our results support the view that this electrical stimulus does not disrupt, but rather, activates the normal function of the granule cell system, resulting in erasure of information held in declarative memory. In contrast, similar activation of the pyramidal cell system does not yield retrograde amnesia, suggesting a normal role for these cells in promoting memory for spatial information.
3588200	In this report, we describe the "fractionation of memory systems" in a 62-yr.-old woman following a left anterior stroke. Despite the presence of a significant, persistent declarative memory (verbal learning) deficit, this patient exhibited relatively intact procedural learning. The latter was manifested over a 4-day period by improved performance on a maze task executed under "mirror-tracing" conditions. By the final set of trials, the patient's performance approximated that of a normal control subject with respect to speed, although not errors. The selective preservation of particular learning abilities in brain-damaged patients has implications for rehabilitative interventions.
3571141	A review of the literature on hyperlexia suggests that the disorder is frequently associated with autism, that hermetic readers reach the lexicon via both the phonological and orthographic routes, and that the children derive meaning from print (notably, single words). In hyperlexia, as in other savant syndromes, the skills seemingly arise without a practice period and are not integrated with other areas of knowledge. A theory was advanced to account for the findings: Savants have dysfunctional procedural memory systems, though their declarative memories are relatively intact. The deficit in procedures is reflected in the difficulties savants have with routinized activities and in a dissociation of accessible knowledge from action. A disconnected declarative system manifests itself in the savant skill.
3622311	In an uncontrolled clinical trial of 6 weeks' duration conducted in 20 male patients, aged 49 to 68 years, with memory disorders, cyclandelate 1200 to 1600 mg daily was found to be effective in improving memory as reflected by psychiatric, psychometric and psychophysiological measurements. Treatment with cyclandelate produced clinical effects which were selective for the Wechsler Memory Scale items of visual reproduction and orientation--indicators of the declarative memory. Moreover, the improvements seen in the average auditory reaction and critical flicker fusion frequency demonstrates its effect on procedural memory. Thus, our results indicate that this drug may be therapeutically useful in memory disorders of various aetiology, and that further exploration of the place of cyclandelate in this clinical area is needed.
3574658	In three separate experiments, we assessed the strength and duration of word completion effects in amnesic patients and two control groups. In Experiment 1 subjects studied words under a semantic orienting condition and were given tests of word completion and recognition memory after an immediate, 2-hr or 4-day delay. In the word completion test for Experiment 1, we presented three-letter word stems that could be completed to form several common words, one of which had been presented previously (e.g. MOT for MOTEL), and subjects completed each stem with the first word that came to mind. Priming effects were equivalent in amnesic patients and control subjects and they reached baseline levels within 2 hr. In Experiments 2 and 3, subjects studied words under either a semantic or a nonsemantic orienting condition, and word completion was tested at the same three delays using cues that uniquely specified the study words (e.g. JUI for JUICE; or A--A--In for ASSASSIN). In these experiments, amnesic patients exhibited both smaller and shorter lasting word completion effects than control subjects. Specifically, amnesic patients exhibited word completion effects that seldom lasted as long as 2 hr, whereas control subjects usually exhibited completion effects lasting 4 days. An important additional finding was that control subjects exhibited larger and longer-lasting word completion effects when tested under the semantic orienting condition than when tested under the nonsemantic orienting condition. Amnesic patients were not affected by this manipulation. Moreover, under the nonsemantic orienting condition, control subjects and amnesic patients performed similarly. The results show that word completion performance is not always fully intact in amnesic patients. Long-lasting word completion effects found in normal subjects may be mediated by declarative or elaborative retrieval processes, which are impaired in amnesic patients. If so, priming as measured by word completion methods is shorter lasting than recent studies of normal subjects would suggest.
3114178	When mental operations share input and output mechanisms, it is necessary to resort to neuropsychological evidence to determine whether they belong to the same or different systems. That multiple memory systems exist is suggested by dissociation between memory performances by normal people, and proven by dissociations in memory performances induced by focal brain damage. The pathological forgetting of the amnesic syndrome is limited to memory for events ("episodic memory") and appears to be due to the patient's inability in escape from control of his present internal and external environment in order to recollect (consciously, by reexperience) a prior event. Effects of prior experience on subsequent performance that does not involve conscious recollection ("semantic memory") remains intact. The distinction between episodic and semantic memory is an instance of a broader distinction between conscious and unconscious mental operations, in humans and possibly other mammals also. However, the further subdivision of semantic memory into procedural and declarative lacks empirical basis, and indeed seems impossible to operationalize. Amnesics' difficulty in recollecting events (and partially learned facts) from before the onset of their disease (retrograde amnesia) is explicable in terms of interference between current events and prior events in similar contexts in patients who are unduly controlled by their current context. Consolidation theory is incoherent, and not needed to explain retrograde amnesia.
2980690	The neurology of memory has been illuminated by parallel studies of patients with circumscribed memory impairment and animal models of human amnesia. Human amnesia can occur as an isolated cognitive deficit that impairs the ability to learn new facts and episodes. In addition, memory can be affected for material learned many years prior to the onset of amnesia. The finding that some memory abilities are intact in amnesia (e.g., skill learning, word priming, and adaptation-level effects) has suggested that memory can be divided into two or more separate processes. Declarative memory affords the ability to store information explicitly and to retrieve it later as a conscious recollection. This form of memory depends on the integrity of the structures damaged in amnesia. Other, non-declarative kinds of memory afford the ability to change as the result of experience, but the information is available only through performance. Recent studies of a favorable human case provided strong evidence that the hippocampus is a critical component of the declarative memory system. Extensive convergent and divergent projections link the hippocampus to many areas of neocortex where processing and storage of new information is likely to occur. It is perhaps by way of these connections that the hippocampus operates upon and participates in declarative representations.
3760945	Learning and retention of 3 types of information were examined in patients with Alzheimer's disease (AD) and in normal controls. While patients were unable to learn series of frequent words and unfamiliar faces, they improved significantly in a motor skill, showing a learning curve similar to controls. Furthermore, no significant loss of the motor skill was evident in a 20 min delay trial. Such dissociation in learning has not been noted previously in AD, although it has been noted in amnesias caused by other disease processes. The results support the existence of two, relatively independent, learning systems related to "declarative" knowledge and "procedural" knowledge. Judging from the pathologic correlates of these amnesias, the declarative knowledge system appears to be associated with corticotemporo/limbic structures, while the procedural system is likely to depend on corticocerebellar/striatal structures. The data also offer additional cognitive correlates for the selective damage to neural systems recently identified in AD.
3734866	Recent evidence of preserved skill learning in patients with "global" amnesia has led to the postulation of a qualitative distinction between functionally separate memory systems, one of which may remain preserved when the other is profoundly impaired. On one account, the separate memory systems support either the learning of declarative knowledge, i.e., facts and associations, or the learning of procedural knowledge, i.e., knowledge that permits the expression of skilled performance without reference to specific facts or associations. In an effort to develop a rodent model of amnesia that illustrates the same distinction between memory systems, rats were trained in a series of discrimination and reversal problems using olfaction, a sensory modality in which they rapidly learn new associations. Rats with bilateral fornix, amygdala, or combined fornix and amygdala damage learned successive two-odor discriminations as quickly as normal and sham-operated control subjects. Furthermore, all groups rapidly acquired the skills of discrimination as revealed in the development of a learning set. Subsequent presentation of a reversal of one discrimination elicited a marked dissociation among groups: Normal rats and rats with amygdala lesions required many more trials to acquire the reversal than to acquire a new discrimination problem, whereas rats with fornix lesions learned the reversal rather easily. A detailed analysis of response strategies suggested that normal rats and rats with amygdala lesions first extinguished the prior response tendencies and then abandoned the learning set skills and treated the reversal much as they did the initial discrimination problem.(ABSTRACT TRUNCATED AT 250 WORDS)
3086978	Recent studies of animals with complex nervous systems, including humans and other primates, have improved our understanding of how the brain accomplishes learning and memory. Major themes of recent work include the locus of memory storage, the taxonomy of memory, the distinction between declarative and procedural knowledge, and the question of how memory changes with time, that is, the concepts of forgetting and consolidation. An important recent advance is the development of an animal model of human amnesia in the monkey. The animal model, together with newly available neuropathological information from a well-studied human patient, has permitted the identification of brain structures and connections involved in memory functions.
4062614	Persistent memory problems were reported by a 39-year-old man who suffered a penetrating brain wound while serving in Vietnam 15 years earlier. Neuropsychological testing indicated an unusually isolated memory impairment. Computed tomography revealed transection of the columns of the fornix cerebri with no temporal-lobe involvement and minimal thalamic damage. We suggest that the fornix cerebri has a role in the maintenance of information accessibility to both encoding and recall during post-working memory processing and in the organization of verbal information during encoding and/or retrieval for declarative (recall) purposes. These processes are not essential for verbal recognition but can result in decrements on specific laboratory tasks and in social adjustment.
3987843	A series of 4 experiments examined the performance of rats with retrohippocampal lesions on a spatial water-maze task. The animals were trained to find and escape onto a hidden platform after swimming in a large pool of opaque water. The platform was invisible and could not be located using olfactory cues. Successful escape performance required the rats to develop strategies of approaching the correct location with reference solely to distal extramaze cues. The lesions encompassed the entire rostro-caudal extent of the lateral and medial entorhinal cortex, and included parts of the pre- and para-subiculum, angular bundle and subiculum. Groups ECR 1 and 2 sustained only partial damage of the subiculum, while Group ECR+S sustained extensive damage. These groups were compared with sham-lesion and unoperated control groups. In Expt 1A, a profound deficit in spatial localisation was found in groups ECR 1 and ECR+S, the rats receiving all training postoperatively. In Expt 1B, these two groups showed hyperactivity in an open-field. In Expt 2, extensive preoperative training caused a transitory saving in performance of the spatial task by group ECR 2, but comparisons with the groups of Expt 1A revealed no sustained improvement, except on one measure of performance in a post-training transfer test. All rats were then given (Expt 3) training on a cueing procedure using a visible platform. The spatial deficit disappeared but, on returning to the normal hidden platform procedure, it reappeared. Nevertheless, a final transfer test, during which the platform was removed from the apparatus, revealed a dissociation between two independent measures of performance: the rats with ECR lesions failed to search for the hidden platform but repeatedly crossed its correct location accurately during traverses of the entire pool. This partial recovery of performance was not (Expt 4) associated with any ability to discriminate between two locations in the pool. The apparently selective recovery of aspects of spatial memory is discussed in relation to O'Keefe and Nadel's (1978) spatial mapping theory of hippocampal function. We propose a modification of the theory in terms of a dissociation between procedural and declarative subcomponents of spatial memory. The declarative component is a flexible access system in which information is stored in a form independent of action. It is permanently lost after the lesion. The procedural component is "unmasked" by the retrohippocampal lesion giving rise to the partial recovery of spatial localisation performance.

6488030	Albino rats received 10 s of sub-seizure electrical stimulation applied to the dentate gyrus granule cells immediately after acquisition of information on trial 1 of a 2-trial radial maze spatial memory task. Granule cell stimulation selectively reduced the probability of accessing information held in declarative memory ('knowing that' a particular maze location contains food) while leaving procedural memory intact ('knowing how' to search for food in the maze). This specific memory impairment was prevented by pretreatment with the opiate antagonist naloxone. Naloxone also improved memory performance when given to non-stimulated subjects.
7414331	Amnesic patients acquired a mirror-reading skill at a rate equivalent to that of matched control subjects and retained it for at least 3 months. The results indicate that the class of preserved learning skills in amnesia is broader than previously reported. Amnesia seems to spare information that is based on rules or procedures, as contrasted with information that is data-based or declarative--"knowing how rather than "knowing that." The results support the hypothesis that such a distinction is honored by the nervous system.