The effects of parkinsonism and deep brain stimulation on basal ganglia-thalamocortical circuitry during sleep-wake behavior

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. This project will provide new insight into the pathophysiology of sleep-wake disturbances in PD by characterizing the changes in sleep- related neuronal activity and physiological interactions that occur between subcortical and cortical structures in the basal ganglia thalamocortical (BGTC) circuit during progressively more severe parkinsonian states. We will expand our previous work to include the pedunculopontine nucleus (PPN) given its critical role regulating sleep- wake states and extensive connectivity to the BGTC, exploring the changes in coupling and connectivity that occur within and across the BGTC-PPN network that underlie disordered sleep in PD secondary to dopaminergic loss in the substantia nigra (Aim 1). It will compare how deep brain stimulation (DBS) in the STN, GPi, and GPe modifies subcortical-cortical interactions in the BGTC-PPN circuit to influence sleep-wake behavior and elucidate the fiber pathway activations underlying these changes (Aims 2 and 3). This study will provide data with immediate translational value by identifying whether DBS in one target is more effective than another in normalizing sleep-related neuronal activity and improving sleep-wake behavior. Furthermore, knowledge about how changes in neuronal activity across the BGTC-PPN network correlates with altered sleep from normal, parkinsonian, and parkinsonian+DBS conditions will provide the basis to develop more effective stimulation strategies that utilize target-specific physiological biomarkers and closed-loop DBS control paradigms tailored to individual patient's sleep disturbances. These data will also provide the basis to target specific pathways with DBS to optimize sleep-related outcomes in PD.