PROJECT SUMMARY/ABSTRACT Over 75% of people with Parkinson's disease (PD) have significant sleep-wake disturbances that are major contributors to decreased quality of life and can be more disabling and resistant to treatment than the motor symptoms of PD. Currently, the mechanisms contributing to disordered sleep in people with PD are poorly understood and there is a critical need for therapeutic inventions to improve sleep quality. Deep brain stimulation (DBS) has been shown to improve sleep in PD however effects are highly variable across patients. A better understanding of the neuronal mechanisms underlying sleep dysfunction in PD, how DBS affects sleep quality, and the neurophysiological changes and patterns of pathway activation with DBS that underlie these changes would provide the rationale for development of circuit-based DBS approaches to the treatment of sleep disorders in PD. The goal of this proposal is to: (1) characterize the changes in oscillatory activity and connectivity in the basal ganglia-thalamocortical network during disturbances in sleep in PD patients; (2) examine the relative effects of DBS in the STN or GPi on these changes; (3) identify the neural pathways that are preferentially activated (or avoided) in patients with improved or impaired sleep after STN or GPi DBS. We will leverage the well-established infrastructure at the University of Minnesota to externalize DBS leads and perform electrophysiology recordings and stimulation studies in PD patients prior to pulse generator placement (Specific Aims 1 and 2). We will also use high-resolution 7 Tesla (T) MRI, diffusion tractography, and subject-specific computational biophysical modeling to associate pathway activation patterns with quantitative and qualitative measures of sleep outcomes in the year following DBS surgery (Specific Aim 3). This project will increase our understanding of the role of BG-cortical activity patterns on sleep and provide new insights into the mechanisms by which DBS impacts sleep. It will inform the development of more effective stimulation strategies to normalize sleep activity that utilize physiological biomarkers and closed-loop control paradigms tailored to individual patient's sleep-wake cycle. These data will provide the basis to target specific pathways with DBS to optimize sleep-related outcomes in PD.

PROJECT NARRATIVE Sleep-wake disturbances are a major factor associated with reduced quality of life of individuals with Parkinson's disease (PD), a progressive neurological disorder affecting millions of people in the U.S and worldwide. The brain mechanisms underlying these sleep disorders, and the effects of therapeutic interventions such as deep brain stimulation on sleep-related neuronal activity and sleep behavior, are not well understood. Results from this study will provide a better understanding of the brain circuitry involved in disordered sleep in PD and inform the development of targeted therapeutic interventions to treat sleep disorders in people with neurodegenerative disease.