Structural Synaptogenesis Superior to Functional Modulation in a Pruning-Based Recurrent Network Model of OCD

Background: Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive behaviors, with incomplete response to current treatments suggesting limitations in prevailing neurotransmitter-focused models. Emerging evidence implicates dysregulated synaptic pruning—mediated by microglial and complement pathways—as a core neurodevelopmental mechanism, potentially explaining persistent circuit immaturity and high relapse rates.

Methods: We developed a gated recurrent unit network approximating cortico-striato-thalamo-cortical dynamics, trained on a rule-switching task sensitive to perseveration. Excessive pruning (95% sparsity, recurrent-biased) induced an OCD-like phenotype. From identical pruned baselines, three mechanistically distinct interventions were simulated: rapid gradient-guided synaptogenesis (ketamine-like), prolonged low-learning-rate adaptation with noise annealing (SSRI-like), and tonic inhibitory scaling (neurosteroid-like). An iso-dose pipeline equated network alteration via L1 weight change norms, with parameter sweeps enabling fair cross-mechanism comparison of acute efficacy and relapse vulnerability (secondary pruning).

Results: Pruning alone produced marked rigidity (perseverative errors ~0.73). Ketamine-like structural repair dramatically reduced perseveration (~0.23) and restored accuracy, with moderate relapse resistance. SSRI- and neurosteroid-like functional modulations yielded milder, more reversible gains. At matched doses, ketamine-like intervention consistently outperformed others in acute symptom reduction and durability, with highest efficiency at lower doses.

Conclusions: These findings support excessive synaptic pruning as a primary driver of OCD-related cognitive inflexibility and demonstrate that treatments promoting structural synaptogenesis offer inherent advantages over functional approaches. The iso-dose framework provides a novel tool for mechanistic therapy ranking, with implications for prioritizing rapid plastogens in clinical guidelines and personalizing care via pruning-related biomarkers.