The Prefrontal Astrocyte-Vascular Supply Interface: A Systems Architecture and Its Failure Modes in Ehlers-Danlos Syndrome, Autism, and ADHD

Cortical computation is constrained by metabolic supply routed through a layered astrocyte-vascular interface. This paper specifies the interface as a six-layer transduction stack — from extracellular matrix substrate through integrin mechanosensing, cytoskeletal control, adhesion fidelity, calcium computation, to vascular and gliotransmitter output coupling — and identifies three structurally distinct failure modes producing the clinical phenotypes of hypermobile Ehlers-Danlos syndrome (constitutional substrate compliance), autism (atypical neuronal connectivity via CADM1), and ADHD (intermittent astrocyte gating via SynCAM1). Three parallel pathways from substrate to the same downstream observable — degraded theta-gamma phase-amplitude coupling with preserved channel power — converge on a preregistered discriminating prediction: stimulant treatment response in ADHD correlates more strongly with prefrontal cerebral blood flow change than with dopamine transporter occupancy change.