Distinct and common subcortical functional connectivity revealed across three major psychiatric disorders

BACKGROUND: Subcortical nuclei - including the thalamus, basal ganglia, and hippocampus-amygdala complex - are key regions in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). While cortical-subcortical connectivity is well studied, fine intra- and inter-subcortical patterns are less known. This study aimed to identify shared and distinct functional connectivity alterations across SZ, BD, and MDD using a high-resolution subcortical atlas. METHODS: Resting-state functional magnetic resonance imaging data from 800 participants (200 per group: SZ, BD, MDD, and healthy controls) in a single-site cohort were analyzed. Subcortical structures were parcellated into 27 regions per hemisphere - thalamus (8 regions), hippocampus (5 regions), amygdala (2 regions), and striatum (12 regions) - based on the a priori atlas. Pairwise functional connectivity among the 54 regions was computed for each participant, and group differences were assessed using general linear models. RESULTS: Patients with SZ exhibited significantly reduced intra-thalamic connectivity and increased intra-striatal connectivity, as well as enhanced connectivity between the thalamus, striatum, and limbic regions. Patients with BD showed reduced intra-thalamic and intra-striatal connectivity, along with decreased thalamus-amygdala and thalamus-striatum connectivity. In MDD, the predominant finding was reduced intra-limbic connectivity, accompanied by mild reductions in intra-thalamic and striatum-limbic connectivity. CONCLUSION: The results suggest that intra-thalamic hypoconnectivity appears common to SZ, BD, and MDD, with graded degrees of severity. In contrast, distinct alterations in intra-striatal and striatum-limbic connectivity may differentiate mood disorders from SZ. These shared and disorder-specific subcortical connectivity patterns enhance the understanding of psychiatric neurobiology and may guide the development of targeted, disorder-tailored interventions.