Flexible brain state engagement predicts cognitive control transdiagnostically

Ye, J.; Mehta, S.; Khaitova, M.; Arora, J.; Tokoglu, F.; Hahn, C. A.; Lacadie, C.; Greene, A. S.; Constable, R. T.; Scheinost, D.

doi:10.64898/2025.11.30.691395

bioRxiv · 10.64898/2025.11.30.691395

Flexible brain state engagement predicts cognitive control transdiagnostically

Ye, J.·Mehta, S.·Khaitova, M.·Arora, J.·Tokoglu, F.·Hahn, C. A.·Lacadie, C.·Greene, A. S.·Constable, R. T.·Scheinost, D.

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Abstract

Cognitive control supports adaptive responses in an ever-changing world. While alterations in cognitive control have been consistently observed in a range of psychiatric disorders, the neural mechanisms giving rise to this behavioral variation remain elusive. Here, we tested whether the ability to flexibly recruit recurring brain activation patterns (i.e., brain states) may serve as an intermediate phenotype supporting cognitive control in individuals with a spectrum of clinical symptoms. We leveraged machine learning and external validation to explore this question in three independent, transdiagnostic datasets (N>600), including participants with anxiety disorders, schizophrenia, mood disorders, substance use disorders, post-traumatic stress disorder, obsessive-compulsive disorder, and neurodevelopmental disorders. To capture cognitive controls multifaceted nature, we assessed two of its components--inhibition and shift-- using both task-based and questionnaire data. Flexible brain state engagement predicted all cognitive control metrics in previously unseen individuals transdiagnostically, regardless of which dataset was used for model training. Connectome-based predictive modeling also revealed that shared brain networks underpinned flexible brain state engagement in a transdiagnostic manner. Leveraging brain network dynamics, we further observed that moments of more flexible brain state engagement aligned with moments of network connectivity related to better cognitive control within the same individual. This temporal alignment was replicated in all three datasets with heterogeneous samples. Altogether, this study suggests flexible engagement of brain states may support both inter- and intra-individual differences in cognitive control across individuals with diverse mental health profiles. Funding sourcesThis work was supported by F31AA032179 and R01MH121095. Data were provided in part by the Consortium for Neuropsychiatric Phenomics (NIH Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271, and PL1NS062410) and the Transdiagnostic Connectome Project (TCP) dataset. Datasets were accessed through OpenNeuro (https://openneuro.org/datasets/ds005237 and https://openneuro.org/datasets/ds000030/versions/00016).

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Ye, J., Mehta, S., Khaitova, M., Arora, J., Tokoglu, F., Hahn, C. A., Lacadie, C., Greene, A. S., Constable, R. T., Scheinost, D.. 2025-12-02. Flexible brain state engagement predicts cognitive control transdiagnostically. https://doi.org/10.64898/2025.11.30.691395

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