Biology subjects

Mensinger, M. E.

Publications and source records attributed to Mensinger, M. E..

3 recordsLinked to original sources

bioRxiv2025

Real-time Bayesian optimization of deep brain stimulation for personalized cognitive control enhancement

BackgroundIdentifying effective deep brain stimulation (DBS) parameters for psychiatric disorders has historically been a time-consuming and error prone process due to a lack of an objective and rapid readout of target circuit engagement. Cognitive control may have use as a biomarker of treatment efficacy but it has yet to be shown that DBS parameters can be reliably optimized to produce cognitive control improvements in individual subjects. ObjectiveWe sought to leverage a rat model of DBS-driven cognitive control improvements to determine whether state of the art optimization algorithms could consistently identify effective stimulation amplitudes to enhance cognition. MethodsWe delivered periods of active and inactive DBS-like stimulation at variable parameters while rats performed a Set-Shifting task that we previously showed to be stimulation-sensitive. We tested both predefined settings of interest and settings that were personalized to individual animals using Bayesian Optimization. Measurements of task performance including reaction time and accuracy were compared between acute, optimized, and traditional settings to evaluate effects on cognitive control. ResultsAcute stimulation reduced reaction times without hindering accuracy (N=15), replicating the effects previously observed with chronic stimulation. In a second cohort (N=6), optimization of stimulation amplitude successfully reduced reaction times in all animals with comparable effect size to historically best settings. ConclusionThese findings confirm that optimization techniques can be effective for improving symptomatically-relevant cognitive markers supporting the feasibility of personalized, quantitatively-informed approaches to neuromodulation and target engagement for psychiatric and/or cognitive disorders. HighlightsProving target engagement is a substantial challenge across brain stimulation modalities, and objective, rapid behavioral read-outs may be a solution to that challenge. Reaction times in cognitive control tasks are an example of a behavioral measure that changes rapidly in response to changes in stimulation parameters, and that also may predict clinical outcomes. Individually optimal stimulation amplitudes for reducing reaction time by stimulating corticofugal fibers passing through the striatum can be determined using Bayesian Optimization. Individually optimized settings discovered in an acute preparation demonstrate consistent effects when applied chronically.

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↗

bioRxiv2024

Cross-species modeling and enhancement of cognitive control with striatal brain stimulation

Brain disorders, particularly mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. We show a path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result, showing that DBS-like stimulation of the mid-striatum improves cognitive control in rats. Using this model, we identify a mechanism, improvement in domain-general cognitive control, and rule out competing hypotheses such as impulsivity. The rat findings explain prior human results and have immediate implications for clinical practice and future trial design. One Sentence Summary: Developing a reliable animal model of a human brain stimulation therapy reveals that this therapy works by enhancing the brains ability to process conflicting pieces of evidence.

neuroscience↗