Altered Directed Connectivity Between the Posterior Limb of the Internal Capsule and Cortical Gray Matter in First-Episode Drug-Naive Schizophrenia

Background: Schizophrenia is increasingly conceptualized as a dysconnectivity disorder involving both gray-matter and white-matter systems. White-matter (WM) abnormalities have been identified early in the disease course, including in first-episode and never-medicated patients. Among these, the posterior limb of the internal capsule (PLIC) has shown structural and microstructural alterations associated with symptom severity. Resting-state functional studies have also implicated the insula, superior temporal gyrus, and superior frontal gyrus in early schizophrenia, supporting these regions as plausible targets for WM-GM directed connectivity analysis. Methods: This study investigated causal interactions between white-matter seed regions in PLIC and 48 cortical gray-matter regions in patients with first-episode drug-naive schizophrenia using resting-state functional MRI and Granger causality analysis. Group differences were evaluated with false discovery rate correction. Results: Four significant alterations in directed connectivity were identified after correction. Compared with healthy controls, patients showed reduced directed influence from the left PLIC to the insula, increased directed influence from the superior frontal gyrus to the bilateral PLIC, increased directed influence from the superior frontal gyrus to the right PLIC, and reduced directed influence from the bilateral PLIC to the anterior superior temporal gyrus. These findings indicate direction-specific reorganization of white-matter–gray-matter interactions in early schizophrenia, characterized by weakened PLIC output to salience- and temporal-related cortical regions and enhanced frontal input to the PLIC. In addition, the strength of superior frontal gyrus-to-PLIC connectivity was positively correlated with positive symptom severity. Conclusions: First-episode drug-naive schizophrenia is associated with abnormal directed functional coupling between the PLIC and specific cortical regions. The pattern of reduced PLIC efferent influence and increased frontal afferent drive suggests that early schizophrenia involves selective reorganization of white-matter–gray-matter causal interactions rather than nonspecific disconnection. Enhanced frontal-to-PLIC connectivity may be particularly relevant to psychotic symptom expression.