Transdiagnostic connectome-based predictive modeling of many behavioral phenotypes reveals brain network mediators of clinical-cognitive relationships

Simon, A. J.; Samardzija, A.; Iannone, S.; Parra Rodriguez, F.; Mehta, S.; Arora, J.; Tokoglu, F.; Qiu, M.; Tang, K. Y.; Flanagan, A. Q.; Katz, R.; Sanacora, G.; Woods, S. W.; Srihari, V. H.; Shen, X.; Scheinost, D.; Constable, R. T.

doi:10.1101/2025.10.02.680080

bioRxiv · 10.1101/2025.10.02.680080

Transdiagnostic connectome-based predictive modeling of many behavioral phenotypes reveals brain network mediators of clinical-cognitive relationships

Simon, A. J.·Samardzija, A.·Iannone, S.·Parra Rodriguez, F.·Mehta, S.·Arora, J.·Tokoglu, F.·Qiu, M.·Tang, K. Y.·Flanagan, A. Q.·Katz, R.·Sanacora, G.·Woods, S. W.·Srihari, V. H.·Shen, X.·Scheinost, D.·Constable, R. T.

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Abstract

A key assumption of the NIMHs RDoC framework is that disordered circuits in the brain should manifest in observable behaviors, including psychiatric symptomatology and cognitive deficits. However, how disordered circuitry impacts multiple behaviors remains poorly understood. Connectome-based predictive modeling (CPM) applied to functional MRI connectivity data can identify networks associated with specific behavioral measures across individuals. Prediction strength reflects how closely a measure relates to network connectivity, while derived networks provide evidence of where an individuals disordered circuits are located. Using CPM, we predicted a broad range of self-reported clinical and objective cognitive measures in a large, transdiagnostic sample with extensive fMRI data (n = 317). Prediction performance varied substantially across instruments, with objective cognitive tests yielding stronger models than self-reported clinical measures (p < 0.001). To test whether circuits underlying cognitive deficits related to symptomatology reside in regions where networks overlap, we examined the prediction strength of these sparsely shared circuits. Their connectivity strongly predicted cognitive performance and were primarily localized within the frontoparietal network and between the frontoparietal and default mode networks. These findings reveal how much various behavioral measures reflect brain networks and how circuits within the shared network space contribute to cognitive deficits associated with symptomatology.

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Simon, A. J., Samardzija, A., Iannone, S., Parra Rodriguez, F., Mehta, S., Arora, J., Tokoglu, F., Qiu, M., Tang, K. Y., Flanagan, A. Q., Katz, R., Sanacora, G., Woods, S. W., Srihari, V. H., Shen, X., Scheinost, D., Constable, R. T.. 2025-10-02. Transdiagnostic connectome-based predictive modeling of many behavioral phenotypes reveals brain network mediators of clinical-cognitive relationships. https://doi.org/10.1101/2025.10.02.680080

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