Thalamocortical dysconnectivity shapes cortical hierarchy disruption across illness durations in schizophrenia

Schizophrenia is increasingly conceptualized as a disorder of circuit-level dysfunction. However, how thalamocortical abnormalities differ across cohorts with varying illness durations and relate to large-scale cortical hierarchical organization remains unclear.

We analyzed resting-state functional magnetic resonance imaging data from 1,223 patients with schizophrenia and 1,224 matched healthy controls across 12 datasets. The datasets were grouped as early-, middle-, and late-stage cohorts. Connectivity gradient mapping was applied to characterize thalamocortical organization, and computational modeling evaluated simulated hierarchical changes after modifying thalamic-salience connectivity.

We identified a schizophrenia-relevant sensorimotor-salience-association axis that captures systematic differences in thalamocortical abnormality profiles across the stage cohorts. Along this axis, case-control effects in association regions were positive in the early-stage cohort but negative in the middle- and late-stage cohorts, whereas sensorimotor regions showed the converse pattern. This cross-cohort pattern was accompanied by reduced cortical hierarchical separation in cohorts with longer illness duration. In contrast, salience-related thalamic regions showed negative case-control effects in all three stage cohorts, with larger effect sizes in the middle- and late-stage cohorts, and these alterations were associated with clinical symptoms. Computational modification of thalamic-salience connectivity increased simulated cortical hierarchical differentiation, particularly in the middle-stage cohort.

These findings indicate that thalamocortical dysconnectivity, centered on disrupted thalamic-salience interactions, is associated with systematic differences in cortical hierarchical organization across cohorts. The cross-cohort pattern of salience-related abnormalities highlights thalamic-salience coupling as a circuit-level link to cortical hierarchical differentiation and a candidate for future mechanistic and interventional investigation.