Towards circuit-based deep brain stimulation reprogramming for cognition in parkinson's disease

The National Institute of Neurological Disorders and Stroke (NINDS) awarded Brigham & Women's Hospital $230,580 on September 2, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to conduct investigator-initiated research on circuit-based deep brain stimulation (DBS) reprogramming for cognitive impairment in Parkinson's disease patients.

The research addresses cognitive decline that may follow DBS surgery, a common and effective treatment for Parkinson's motor symptoms. Prior studies demonstrated that DBS electrode placement more connected to a cognitive circuit—comprising the anterior cingulate, caudate nucleus, hippocampus, and cognitive regions of the cerebellum—correlates with diminished global cognitive status one year post-surgery. The investigators identified an algorithm to determine the cognitively optimal DBS contact configuration for individual patients by minimizing connectivity to the cognitive circuit while preserving motor benefit. The study will evaluate whether connectivity between the cognitive circuit and the motor-optimal DBS configuration correlates with global and domain-specific cognitive status using the Dementia Rating Scale-2 and neuropsychological test battery. A second aim will assess whether connectivity-based DBS reprogramming improves cognitive task performance while maintaining motor benefits. The research draws on a cohort of 120 Parkinson's disease patients with DBS electrodes localized at Brigham & Women's Hospital in Boston, followed 0.5 to 10 years post-surgery.

The award period runs through July 31, 2031, with place of performance in Boston, Massachusetts.

Abstract

Patients with parkinson's disease (PD) may experience cognitive impairment following deep brain stimulation (DBS), a common and effective treatment for motor symptoms. When detected, the impairment may be reversed by DBS REPROGRAMMING. Predicting which patients will have DBS-induced cognitive impairment and offering treatment will have a personal benefit to a vast number of patients and families, as well as important public health implications for a society that will bear the cost of supporting PD patients. Past studies showed 1) DBS contacts more connected to a cognitive circuit comprising the anterior cingulate, caudate nucleus, hippocampus, and cognitive regions of the cerebellum are associated with diminished global cognitive status 1 year after DBS surgery; 2) higher connectivity between the DBS contacts and cognitive circuit is associated with impairment in working memory; and 3) impairment can be reversed by changing the DBS contacts configuration to reduce the cognitive circuit connectivity (REPROGRAMMING) while maintaining motor benefit. This proposal aims to build on these studies and address their limitations. The PI has localized DBS electrodes in PD patients followed for DBS programming at brigham and women's hospital (BWH, N=120, 0.5-10 years post-surgery), and used an algorithm to determine the cognitively optimal DBS configuration (i.e., the contacts least connected to the cognitive circuit) for each individual. Aim 1 of this study will evaluate whether connectivity between the cognitive circuit and the neurologist-determined/motorically optimal DBS configuration correlates with global and domain-specific cognitive status as measured by dementia rating scale-2 and a neuropsychological test battery. Aim 2 will assess whether connectivity-based DBS REPROGRAMMING improves cognitive task performance while maintaining motor benefits, in a 2-day, double-blinded, crossover REPROGRAMMING clinical trial comparing patients' motorically optimal DBS configuration with the cognitively optimal configuration. Cognition will be measured using a 2-back working memory task and a subset of the aim 1 cognitive battery; motoric status will be assessed with the movement disorder society-unified PD rating scale, part III. This project aligns with ninds priorities to identify biomarkers for non-motor symptoms of PD and provide proof of concept for future trials. The research and training plan will equip the PI to lead an R01- funded trial and advance personalized circuit-based neuromodulation therapy, and her mentors, advisors, and the translational research environment at BWH will ensure her success.