Project Summary Parkinson’s disease (PD) is a neurodegenerative disorder that leads to both motor and non-motor symptoms. While there is as yet no cure for PD, medical and surgical therapies have been developed that effectively target the motor symptoms of PD. Non-motor symptoms are far more disabling for patients, precede the onset of motor symptoms by a decade, are more insidious in onset, have been less apparent to clinicians, and are less effectively treated. Sleep dysfunction is oftentimes the most burdensome of the non-motor symptoms—both to patients and to their caregivers—is pervasive in patients with PD, and includes sleep fragmentation, insomnia, excessive daytime sleepiness, REM behavioral disorder, and restless leg syndrome. There are limited options for treating sleep dysfunction in PD, and the mainstay of therapy is the use of agents that mask the sleep disturbance—such as the sedative-hypnotic drugs—without addressing the underlying mechanisms. Although much attention has been devoted to PD motor symptoms, sleep dysfunction in PD has largely been ignored. Sleep is vital to homeostasis, cognition, and nervous system repair, and the dysfunctional sleep accompanying PD adversely affects both motor and non-motor symptoms, resulting in diminished quality of life, impairments in mood and behavior, and increased morbidity and mortality. Patients with PD who demonstrate significant motor fluctuations and dyskinesia are considered for subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. Although STN-DBS is routinely used to treat PD motor symptoms, several studies have reported that STN-DBS also provides benefit for sleep dysregulation through normalization of sleep architecture. Additionally, local field potentials recorded from STN DBS electrodes implanted for the treatment of PD, have led to the identification of unique spectral patterns in STN oscillatory activity that correlate with distinct sleep cycles, offering insight into sleep dysregulation. Building on this work, and in response to RFA-NS- 18-023, this proposal will leverage novel investigational DBS battery technology (RC+S Summit System; Medtronic) that allows the exploration of sleep biomarkers and prototyping of closed-loop stimulation algorithms, to test the hypothesis that STN—a highly interconnected node within the basal ganglia—contributes to the regulation and disruption of human sleep behavior and can be manipulated for therapeutic advantage. Specifically, in PD patients undergoing STN-DBS, we will determine whether STN oscillations correlate with sleep stage transitions, then construct and evaluate sensing and adaptive stimulation paradigms that allow ongoing sleep-stage identification, and induce through adaptive stimulation an increase in duration of sleep stages associated with restorative sleep. This work will lead to findings that address a currently unmet clinical need, and relevant to the mission of NINDS and the BRAIN Initiative, will evaluate the use of adaptive stimulation of the STN in PD patients for the treatment of sleep dysfunction.

Project Narrative With this study, we will gain a better understanding of how the basal ganglia contribute to pathological sleep behavior in humans. This information will be used to understand better how the brain regulates sleep and how we can intervene therapeutically in sleep regulation in order to develop new therapies for sleep disorders both for patients with Parkinson’s disease and for other populations suffering from dysfunctional sleep. In addition, we will use these results to improve the accuracy of sleep dysfunction diagnoses, enabling the application of existing therapies more appropriately, and the development of novel therapies.