Thalamic Reticular Nucleus Dysfunction as a Stage-Dependent Integrative Circuit Mechanism in Psychosis.

Abstract

Psychosis is increasingly conceptualized as a disorder of distributed neural circuits rather than focal brain pathology, with thalamocortical dysconnectivity emerging as one of its most consistent neurobiological features. This review argues that (TRN) dysfunction may help explain how cellular abnormalities, sleep-spindle deficits, thalamocortical dysconnectivity, and clinical symptoms become linked across the psychosis spectrum We synthesize evidence from postmortem studies, genetics, sleep spindle physiology, neuroimaging, and preclinical models to argue that TRN dysfunction may contribute to impaired sensory gating, altered thalamocortical connectivity, disrupted sleep spindles, and downstream dopaminergic dysregulation. Recent identification of molecularly and functionally distinct TRN subnetworks offers a potential framework for explaining the bidirectional connectivity pattern observed in psychosis, including reduced thalamic coupling with prefrontal/associative regions and increased coupling with sensorimotor cortex. We further propose a stage-dependent model in which early TRN dysfunction contributes to subtle sensory and cognitive disturbances in clinical high-risk states, unstable gating during first-episode psychosis supports the emergence of positive symptoms, and persistent network-level dysfunction contributes to chronic cognitive and negative symptoms. While current evidence remains largely indirect and causal relationships in humans require further testing, the TRN represents a biologically plausible and clinically underexplored convergence point for mechanistic studies of psychosis and for future biomarker and treatment development.