Disrupted cortical hierarchy and delayed connectome-based propagation in the functional connectome of schizophrenia.

Abstract

Background: Schizophrenia is associated with widespread abnormalities in large-scale brain organization; however, the mechanisms linking altered cortical hierarchy to disrupted neural communication and clinical symptoms remain unclear. By integrating functional connectivity gradient analysis and stepwise functional connectivity (SFC), we aimed to clarify how alterations in cortical hierarchy translate into disrupted connectome-based propagation in schizophrenia.

Methods: Resting-state functional MRI data from 820 participants (310 healthy controls and 510 patients with schizophrenia) were analyzed across multiple cohorts. Cortical hierarchy was characterized using functional connectivity gradients, focusing on the principal unimodal-transmodal gradient (G1). Connectome-based propagation was examined using SFC, with step counts indexing propagation efficiency across predefined hierarchical levels. Associations with clinical symptoms were assessed, including mediation analyses.

Results: Global cortical hierarchy was preserved in schizophrenia; however, selective alterations were evident. Patients with schizophrenia showed significantly reduced G1 values in the dorsal attention network (DAN), with regional alterations primarily localized to dorsal attention and somatomotor regions. SFC analysis revealed delayed propagation toward higher-order association networks in schizophrenia, reflected by increased step counts to intermediate and transmodal hierarchical levels. Among patients with illness duration <5 years, delayed propagation to higher hierarchical levels was associated with greater positive and negative symptom severity. Mediation analyses demonstrated that delayed propagation significantly mediated the relationship between DAN hierarchical positioning and clinical symptoms.

Conclusions: These findings suggest that schizophrenia is characterized by selective disruption of cortical hierarchy within attentional control systems, leading to impaired large-scale connectome-based propagation that links cortical organization to clinical symptoms.