The overall goal of this project is to provide applicant J. Nicole Bentley, MD appropriate resources and mentorship to develop skills allowing a path to research independence in the field of neuromodulation for cognitive disorders. This proposal focuses on the role of dorsolateral prefrontal cortex (DLPFC) in altered cognition in Parkinson?s disease (PD) patients with simultaneous intracranial cortical and subcortical recordings during awake deep brain stimulation (DBS) surgery. Cognitive impairment is a common non-motor symptom of Parkinson?s disease (PD), affecting one-quarter of newly diagnosed patients, and more than 80% of patients over the course of the disease. Despite its prevalence, very few treatment options exist. Unfortunately, mainstay treatments for motor symptoms of PD such as dopaminergic medications and high- frequency deep brain stimulation (DBS) do not improve and in some instances can even worsen cognitive symptoms. Recent evidence in PD patients suggests that reduced prefrontal theta frequency oscillatory activity is associated with impaired cognition, specifically evident in the domain of inhibitory control. Given its dense connections to basal ganglia and pre-motor areas, neuromodulation of the DLPFC-basal ganglia network could enhance elements of cognitive dysfunction in PD. Our novel preliminary data shows DLPFC and subcortical power modulation and phase-amplitude coupling during an intraoperative Simon task measuring inhibitory control, and that bursting theta-frequency DBS modulates DLPFC theta power. Here we propose studies to (1) simultaneously record DLPFC and globus pallidus interna (GPi) local field potentials (LFPs) in awake PD patients during the Simon task, and (2) contrast continuous and intermittent theta stimulation from the DBS electrode at the GPi to determine the effect on behavioral and electrophysiologic measures. Given the increasing prevalence of cognitive impairment and the dearth of available treatments, there is an urgent need to foster the development of clinician-neuroscientists with this interest. As a neurosurgeon with specialization in neuromodulation, Dr. Bentley is an ideal candidate to serve in this role. She has assembled a multi-disciplinary and multi-institutional team of expert mentors who will provide guidance and support towards the scientific and career development aims of this proposal. She and her mentors have designed a career development plan consisting of cognitive neuroscience, computational neuroscience, and signal processing techniques. These training aims will be combined with the high volume of a tertiary movement disorders functional neurosurgery practice at the University of Alabama, Birmingham. With the institution?s robust resources in research computing, biostatistics, engineering, and neurophysiology, this proposal will ensure that Dr. Bentley is well-prepared for progressing to research independence by the completion of this award.
Cognitive impairment in Parkinson?s disease (PD) is extremely prevalent, affecting more than 80% of patients over the course of their disease, yet few treatment options exist for these disabling symptoms. Dysfunction in prefrontal cortex and subcortical areas likely contributes to PD cognitive impairment, however, very little is known about the activity of and connectivity of these two brain regions. Here, we propose to investigate cognitive networks in PD and to deliver low-frequency deep brain stimulation (DBS), a stimulation pattern with promising early results on cognition, while assessing the effects on a cognitively demanding inhibitory control task and prefrontal-subcortical electrophysiology.
