Aberrant Modular Dynamics of Functional Networks in Schizophrenia and Their Relationship with Neurotransmitter and Gene Expression Profiles

Introduction: Numerous studies have emphasized the time-varying modular architecture of functional brain networks and its relevance to cognitive functions in healthy participants. However, how brain modular dynamics change in schizophrenia and how these alterations relate to neurotransmitter and transcriptomic signatures have not been well elucidated. Methods: We harmonized resting-state fMRI data from a multi-site sample including 223 patients and 279 healthy controls and applied the multilayer network method to estimate the regional module switching rate (flexibility) of functional brain connectomes. We examined aberrant flexibility in patients relative to controls and explored its relations to neurotransmitter systems and postmortem gene expression. Results: Compared with controls, patients with schizophrenia had significantly higher flexibility in the somatomotor and right visual regions, and lower flexibility in the left parahippocampal gyrus, right supramarginal gyrus, right frontal-operculum-insula, bilateral precuneus posterior cingulate cortex, and bilateral inferior parietal gyrus. These alterations were associated with multiple neurotransmitter systems and weighted gene transcriptomic profiles. The most relevant genes were preferentially enriched for biological processes of transmembrane transport and brain development, specific cell types, and previously identified schizophrenia-related genes. Conclusions: This study reveals aberrant modular dynamics in schizophrenia and its relations to neurotransmitter systems and schizophrenia-related transcriptomic profiles, providing insights into the understanding of the pathophysiology underlying schizophrenia.