Identifying the neural mechanisms of goal-directed decision-making in Parkinson's disease using closed-loop deep brain stimulation

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TITLE: IDENTIFYING THE NEURAL MECHANISMS OF GOAL-DIRECTED DECISION-MAKING IN PARKINSON’S DISEASE USING CLOSED-LOOP DEEP BRAIN STIMULATION PROJECT SUMMARY People with Parkinson’s disease commonly suffer from non-motor symptoms, including motivation deficits, that impact quality of life more than classical motor symptoms and are exacerbated by current treatments like dopaminergic drugs and deep brain stimulation. The long-term goal of this research is to understand the neural basis of motivated decision-making to develop new therapies that can re-tune reward networks and address this therapy gap. The overall objective of this proposal is to identify the neural signals that implement top-down, goal-directed control of choices and their causal role in decision-making. My central hypothesis is that theta frequency activity in the basal ganglia is required for implementing top-down control over decisions, and that inhibiting the basal ganglia with closed-loop neurostimulation based on theta activity will reduce goal-directed decision-making. Therefore, the rationale of the project is that identifying the neural signals underlying goal- directed decision-making and causally manipulating them in a reward learning paradigm will reveal biomarkers that can be used to re-tune these circuits and treat behavioral disorders. The central hypothesis will be tested by pursuing two Specific Aims: Aim 1) Identify spatially and spectrally specific neural network signals for goal- directed decision-making. We will record chronic frontal cortical and basal ganglia activity using electrocorticography and sensing-enabled deep brain stimulation devices implanted in patients with Parkinson’s disease while they perform a reward learning task. We will quantify choice strategies using reinforcement learning models and relate goal-directed decision-making to neural signals, both ON and OFF dopaminergic medications. Aim 2) Test the causal role of theta in goal-directed decision-making using closed- loop brain stimulation. We will trigger inhibitory deep brain stimulation in the basal ganglia when theta power is high to disrupt goal-directed decisions, thereby establishing the causal role of theta in top-down control of decision-making. The research is innovative because it will be the first to use chronic, multi-site, invasive electrophysiology and closed-loop brain stimulation to establish causal relationships between specific neural signals and goal-directed decision-making in humans. It is significant because it will lead to biomarkers to guide diagnosis and treatment of motivation deficits in patients with Parkinson’s disease and other neuropsychiatric conditions. Dr. Hoy has assembled an interdisciplinary team of mentors led by Dr. Simon Little and supported by Drs. Philip Starr, Wouter Kool, and Winston Chiong. Together, they have designed a comprehensive training plan involving (1) closed-loop deep brain stimulation and subcortical neurophysiology, (2) reinforcement learning computational modeling, (3) neuroethics, and (4) professional development. This fellowship will facilitate Dr. Hoy’s evolution into a leader in reward neuroscience and invasive human neurotechnology. It will also prepare him to develop a K award grant application as a means to transition into an independent academic researcher.