TITLE: UNCOVERING THE NEUROPHYSIOLOGY OF MOTIVATION IN PARKINSON’S DISEASE WITH IMPLANTED ADAPTIVE BRAIN STIMULATION PROJECT SUMMARY Behavioral symptoms such as apathy and impulsivity represent a prevalent, highly-disabling feature of Parkinson’s disease (PD) and many other neurological conditions, for which treatments are currently very limited. The long-term goal of this award is to understand the neurocircuitry of motivation in order to develop precise and personalized therapies for motor and non-motor symptoms in neurological disorders. The overall objective is to establish the neural structures and signals that underpin motivation in PD. My central hypothesis is that the human motivation system comprises two functionally distinct frontal cortex - basal ganglia (FC- BG) circuits that drive behavior: 1) the prefrontal - basal ganglia circuit evaluates rewards and operates in the theta (3-7Hz) frequency range and 2) the premotor - basal ganglia circuit evaluates action costs, and is mediated by beta (13-30Hz) frequency signals, with both modulated by dopamine. Therefore, the rationale of the project is that understanding the neural structures and signals of the FC-BG reward circuit is critical for the development of effective stimulation therapies for behavioral symptoms in PD. The central hypothesis will be tested by pursuing two Specific Aims: Aim 1) Identify the neurophysiological signatures of reward cost-benefit evaluation in PD. Patients with chronically implanted, sensing-enabled brain stimulators will perform reward cost-benefit evaluation tasks with simultaneous FC-BG recordings, on and off dopamine medication. Additionally, patients will trigger recordings of neural signals at home, with paired self-reports of apathy and impulsivity. Aim 2) Evaluate the causal relationship of frontal cortex-basal ganglia structures & signals to behavior. Spatio-temporally targeted brain stimulation will be delivered to the FC-BG network during reward cost-benefit evaluation to test the causal role of these structures and signals to motivated behavior. The research is innovative because it uses a) chronic invasive brain recordings, in patients, during behavioral tasks that index motivation, b) recordings at home to determine within-subject reproducibility and link to naturalistic motivational states and c) causal interventions to demonstrate mechanistic relationships. It is significant because determining an accurate understanding of the neurocircuitry of reward will enable the future development of precise, spatio-temporally targeted adaptive brain stimulation for apathy and impulsivity in PD, a major unmet need. As such, Dr. Little has assembled a multidisciplinary mentoring group led by Prof. Philip Starr and supported by advisors Profs. Edward Chang, Wendy Mendes and Joshua Berke to develop a comprehensive structured training plan involving 1) cognitive-affective neuroscience 2) electrocorticography 3) machine learning and 4) trial design and statistics. This award will propel Dr. Little towards independence and expertise in the investigation of the neurophysiology, and treatment, of motor and non-motor neurological symptoms. It will also provide the foundation for a future R01 application investigating the relationship between clinical apathy, impulsivity and neurophysiology in a wide cohort of neurological patients.

PROJECT NARRATIVE Personalized, adaptive, brain stimulation has the potential to benefit disabling behavioral symptoms such as apathy and impulsivity across a wide range of neurological conditions, including Parkinson’s disease, but is currently limited by a lack of understanding of how the brain assesses rewards to drive actions. The goal of this project is to determine how rewards are evaluated across the frontal cortex - basal ganglia circuits and to evaluate the mechanistic role of the structures and signals of this network in Parkinson’s disease. This foundational understanding will direct future stimulation therapies to reduce the burden of apathy and impulsivity in Parkinson’s disease and other neurological disorders in a precise and principled manner.