Investigating Connectivity Gradients in Schizophrenia: Integrating Functional, Structural, and Genetic Perspectives

Background: Schizophrenia is a complex disorder characterized by disruptions in cognition, behavior, and emotions. Extensive research has uncovered alterations in a single modality (either the brain structure or function) in schizophrenia. However, the limitation is that a single modality could not offer a synchronous result between the brain structure and function because of different samples. Here, a multiparametric approach is essential to understand the common and distinct alterations between the brain structure and function in schizophrenia. Methods: We analyzed structural and functional magnetic resonance imaging data from 146 participants (72 individuals with schizophrenia and 74 healthy controls). Individual morphological similarity and functional connectivity gradients were computed using a nonlinear dimensionality reduction technique with diffusion map embedding. Furthermore, to understand how the alterations may be related to genetic underpinnings, gene expression enrichment analyses were conducted using Allen Brain Human Atlas and GOrilla. Results: Compared with controls, patients with schizophrenia had reduced scores on the principal functional gradient of the visual network and elevated scores on the principal functional gradient of the limbic network, the frontoparietal control network, and the default mode network. Additionally, the main functional gradient in individuals with schizophrenia showed compression along the primary axis compared to the healthy control group. These changes were linked to genes involved in synaptic signaling and neuronal development. Conclusions: These results indicate connectome gradient dysfunction in schizophrenia and its linkage with gene expression profiles, supporting widespread network-level abnormalities. The integration of neuroimaging provides insight into the neurobiological underpinnings and potential biomarkers for treatment evaluation in this disorder.