Buccini, M. C. | bioRxiv Science

bioRxiv2026

mPFC axons drive cognitive control enhancement during striatal stimulation

Deep brain stimulation (DBS) of the ventral internal capsule/ventral striatum (VCVS) can alleviate symptoms of mental illness and may work in part by improving cognitive control, a feature of healthy decision making. The human VCVS DBS target and its mid-striatum analog in our preclinical rodent model contain both cortical axons and local striatal cell bodies. However, the specific neural components that stimulation acts on to mediate cognitive effects remain unclear. We addressed this by delivering high frequency optogenetic stimulation ("opto-DBS") to either medial prefrontal cortex (mPFC) axons or local mid-striatal (midSTR) neurons in a rodent Set-Shift task. Opto-DBS of mPFC axons reduced response times, effectively replicating the cognitive enhancement observed in a previous study that used electrical stimulation. Conversely, we observed cognitive impairment from sustained (>10 min) opto-DBS of midSTR neurons. In addition, the cognitive benefit from axonal opto-DBS exhibited time-dependent declines that were not observed with electrical stimulation. The improvement in response times declined within a session and was associated with attenuated magnitude of local midSTR evoked-response potentials. Across-testing days, we linked this decline to diminished mPFC responsiveness, evidenced by a reduction in the post-DBS functional strength of the circuit, suggesting a neuroplastic-like mechanism. These results demonstrate that mPFC-originating axons, rather than local neurons, are the primary drivers of cognitive control enhancements from electrical stimulation, providing insight into therapeutic mechanisms of VCVS DBS.

neuroscience↗

bioRxiv2025

Unilateral striatal deep brain stimulation improves cognitive control

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VCVS) can treat obsessive-compulsive disorder (OCD) and other psychiatric conditions. Yet, optimizing its clinical efficacy is a major challenge, often hindered by incomplete knowledge of how stimulation parameters and targets affect neural activity and behavior. VCVS DBS is thought to work in part by improving cognitive control, an important decision-making component that is impaired in OCD and other illnesses. The magnitude of this cognitive control enhancement was shown to be lateralized, with right-unilateral stimulation being the most effective. Prior work developed a preclinical model of VCVS DBS by leveraging the cognitive control construct, which can be measured in humans and rodents and is modulated by analogous brain circuits. However, this work did not address laterality effects observed in humans or examine left/right stimulation differences. These effects may be critical for maximizing therapeutic benefit while avoiding aversive outcomes. This study aimed to investigate lateralization in the rodent model, where bilateral stimulation of the mid-striatum was previously shown to improve cognitive control. Right and left-unilateral stimulation reduced response times without changing accuracy, replicating the cognitive control improvement from bilateral stimulation. With computational modeling, we show that bilateral and unilateral stimulation modifies the same decision-making variables to drive this behavior change. We also establish that females have the same cognitive control improvement from stimulation as males. These findings increase our understanding of cognitive control circuits and strengthen the validity of the rodent model as a translational platform to study VCVS DBSs therapeutic mechanisms. Significance StatementHere, we demonstrate that stimulating just one side of the brain (e.g. unilaterally) can be as effective as bilateral stimulation for improving cognitive control, the ability to adjust thoughts and decisions in response to environmental changes. These findings in rodents match results from prior human deep brain stimulation (DBS) studies, highlighting the validity of this preclinical model to study DBSs therapeutic mechanisms. We hypothesize that unilateral stimulation may be preferable to maximize cognitive benefits without causing off-target effects, while also reducing surgical invasiveness. Further, we demonstrate that females have the same cognitive control improvement from stimulation as males. Overall, this work answers important outstanding clinical questions regarding laterality and sex in DBS therapies for psychiatric illnesses.

neuroscience↗