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Prefrontal cortical pathways mediating cognitive control enhancement from internal capsule stimulation.

Karianne Sretavan, Sumedh S Nagrale, Victoria Pipia

Biorxiv : the Preprint Server for Biology

|June 22, 2026

Summary

Deep brain stimulation (DBS) targeting the ventral internal capsule/ventral striatum (VCVS) improves cognitive control. Right-sided DBS activating dorsal prefrontal pathways, particularly those connected to the dorsolateral and dorsomedial prefrontal cortex, is most effective.

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Area of Science:

Neuroscience
Neurosurgery
Psychiatry

Background:

Deep brain stimulation (DBS) of the ventral internal capsule/ventral striatum (VCVS) treats psychiatric disorders.
Patient response to VCVS DBS varies due to incomplete understanding of underlying brain mechanisms.
VCVS DBS can enhance cognitive control, a key deficit in many psychiatric conditions.

Purpose of the Study:

To identify specific prefrontal cortical pathways within the internal capsule associated with improved cognitive control during VCVS DBS.
To elucidate the neural circuitry mediating cognitive control enhancement via VCVS DBS.

Main Methods:

Four participants with VCVS DBS underwent the Multi-Source Interference Task (MSIT) across 27 stimulation settings.
Task performance was measured by response time (RT).
Personalized pathway activation models analyzed axonal recruitment in prefrontal cortical fiber bundles to correlate with RT.

Main Results:

Right-sided VCVS stimulation yielded greater cognitive control improvements (faster MSIT RTs) compared to left-sided stimulation.
Activation of right dorsal prefrontal pathways, linked to the dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC), strongly predicted faster RTs.
No left-sided pathways were found to be associated with performance improvements.

Conclusions:

VCVS DBS effects on cognitive control are primarily mediated by right dorsal prefrontal cortical axons projecting from the dlPFC and dmPFC.
Targeting these specific pathways could optimize VCVS DBS strategies for psychiatric disorders with impaired cognitive control.