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Nagrale, S. S.

Publications and source records attributed to Nagrale, S. S..

2 recordsLinked to original sources

Bayesian methods for optimizing deep brain stimulation to enhance cognitive control

ObjectiveDeep brain stimulation (DBS) of the ventral internal capsule/striatum (VCVS) is a potentially effective treatment for several mental health disorders when conventional therapeutics fail. Its effectiveness, however, depends on correct programming to engage VCVS sub-circuits. VCVS programming is currently an iterative, time-consuming process, with weeks between setting changes and reliance on noisy, subjective self-reports. An objective measure of circuit engagement might allow individual settings to be tested in seconds to minutes, reducing the time to response and increasing patient and clinician confidence in the chosen settings. Here, we present an approach to measuring and optimizing that circuit engagement. ApproachWe leverage prior results showing that effective VCVS DBS engages circuits of cognitive control, that this engagement depends primarily on which contact(s) are activated, and that circuit engagement can be tracked through a state space modeling framework. We combine this framework with an adaptive optimizer to perform a principled exploration of electrode contacts and identify the contacts that maximally improve cognitive control. Main resultsUsing behavioral simulations directly derived from patient data, we show that an Upper Confidence Bound (UCB1) algorithm outperforms other optimizers (roughly 80% probability of convergence to a global optimum). SignificanceWe show that the optimization can converge even with lag between stimulation and effect, and that a complete optimization can be done in a clinically feasible timespan (a few hours). Further, the approach requires no specialized recording or imaging hardware, and thus could be a scalable path to expand the use of DBS in psychiatric and other non-motor applications.

bioengineering↗

Lost in translation: No effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

BACKGROUNDThe orbitofrontal cortex-ventromedial striatum (OFC-VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. METHODS27 male Long-Evans rats implanted with optical-fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC-VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after and one hour after each stimulation, one and two weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC-VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional setshifting. RESULTSOFC-VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the mouse protocol did alter OFC-VMS synaptic weighting. CONCLUSIONSIn sum, although physiological changes were observed in the OFC-VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. If optogenetic effects on behavior do not reliably transfer between rodent species, this may have important implications for designing rodent-to-human translational pipelines.

neuroscience↗