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bioRxiv · 10.1101/2025.09.30.679557

Diagnosis-Optimized Dynamic Feature Learning Reveals Altered Default Mode Network Connectivity in Schizophrenia

Seraji, M.·Ellis, C. A.·Ma, L.·Turner, J. A.·Preda, A.·Mathalon, D. H.·van Erp, T. G. M.·Sendi, M. S. E.·Calhoun, V. D.
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Abstract

Schizophrenia (SZ) is characterized by widespread neural dysconnectivity, with particularly pronounced alterations in the default mode network (DMN)--a set of brain regions involved in self-referential thought and mind-wandering. We investigated dynamic functional connectivity within the DMN in SZ by analyzing resting-state fMRI data from two independent cohorts (FBIRN and COBRE). Using a novel iterative feature-removal clustering approach focusing on DMN independent components, we identified distinct recurring connectivity states while iteratively removing dominant connectivity features to reveal subtler network patterns. This approach iteratively refines the set of features considered, ensuring a more balanced representation and facilitating the identification of significant interactions that would otherwise be overlooked. Cluster centroids for the four connectivity states were highly similar across both datasets, reflecting stable shared DMN patterns. State occupancy was compared between participants with SZ and healthy controls, and associations with clinical symptom severity were examined. The SZ group exhibited significant alterations in DMN connectivity dynamics, spending more time than controls in certain connectivity states characterized by atypical DMN coupling and less time in a state reflecting a normative DMN configuration. A comparison between the FBIRN and COBRE datasets reveals both similarities and differences in occupancy rate (OCR) states. Overall, the pattern of group effects converged while state-specific divergences likely reflected protocol/sample differences rather than conflicting biology. Crucially, the explainability pipeline yielded a highly similar feature-removal order across datasets, indicating that the same DMN edges drive the diagnostic signal in both cohorts. Several OCR effects also tracked symptom ratings, linking abnormal DMN dynamics to clinical expression. Our findings suggest that SZ is characterized by reproducible disturbances in the temporal organization of DMN connectivity. These dynamic DMN features may serve as potential biomarkers for SZ, offering diagnostic and clinical utility by capturing network dysfunction that static connectivity measures could overlook.

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Seraji, M., Ellis, C. A., Ma, L., Turner, J. A., Preda, A., Mathalon, D. H., van Erp, T. G. M., Sendi, M. S. E., Calhoun, V. D.. 2025-10-01. Diagnosis-Optimized Dynamic Feature Learning Reveals Altered Default Mode Network Connectivity in Schizophrenia. https://doi.org/10.1101/2025.09.30.679557

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