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bioRxiv · 10.64898/2026.06.08.730545

Prefrontal cortical pathways mediating cognitive control enhancement from internal capsule stimulation

Sretavan Wong, K.·Nagrale, S. S.·Pipia, V.·Sachse, E. M.·Dastin-van Rijn, E. M.·Kim, J.·Eiting, S.·McInnes, A. N.·Palnitkar, T.·Chandrasekaran, J.·Braun, H.·Brenny, S.·Seddighi, Y.·Patriat, R.·Harel, N.·Johnson, M. D.·Widge, A. S.
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Abstract

BackgroundDeep brain stimulation (DBS) targeting the ventral internal capsule/ventral striatum (VCVS) is an effective treatment for several psychiatric disorders, but clinical responses often vary amongst patients likely due to an incomplete mechanistic understanding of the brain pathways mediating response. VCVS DBS can improve cognitive control, a core deficit in multiple psychiatric disorders. Here, we investigated which prefrontal cortical pathway(s) in the internal capsule are associated with improving cognitive control during VCVS DBS. MethodsFour participants with bilateral VCVS DBS completed the Multi-Source Interference Task (MSIT) under 27 stimulation settings varying by side (left/right lead), electrode, amplitude, and frequency. Each condition included 100 trials and response time (RT) assessed task performance. Personalized pathway activation models quantified axonal recruitment across 11 segmented prefrontal cortical fiber bundles per brain hemisphere. Associations between pathway activation and task RT were analyzed to identify circuits linked to improved cognitive control performance. ResultsRight-sided VCVS stimulation produced greater improvements in cognitive control (reductions in MSIT RT) than left-sided stimulation. Activation of right dorsal prefrontal cortical pathways connected to the dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC) most strongly predicted faster MSIT RTs, whereas no left-sided pathways were associated with performance changes. ConclusionsThese findings suggest that the effects of VCVS DBS on cognitive control are primarily mediated by right dorsal prefrontal cortical axons projecting from the dlPFC and dmPFC. Targeting these pathways may improve stimulation strategies and outcomes for psychiatric disorders characterized by impaired cognitive control.

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Sretavan Wong, K., Nagrale, S. S., Pipia, V., Sachse, E. M., Dastin-van Rijn, E. M., Kim, J., Eiting, S., McInnes, A. N., Palnitkar, T., Chandrasekaran, J., Braun, H., Brenny, S., Seddighi, Y., Patriat, R., Harel, N., Johnson, M. D., Widge, A. S.. 2026-06-09. Prefrontal cortical pathways mediating cognitive control enhancement from internal capsule stimulation. https://doi.org/10.64898/2026.06.08.730545

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