Adaptive Neurostimulation to Restore Sleep in Parkinson's Disease: An Investigation of STN LFP Biomarkers in Sleep Dysregulation and Repair

University Of Nebraska Medical Center, Omaha NE

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Abstract

Parkinson’s disease (PD) results from progressive loss of substantia nigra dopaminergic cells and manifests clinically as impaired motor control. Non-motor symptoms are far more disabling for patients, precede the onset of motor symptoms by a decade or more, are more insidious in onset and less effectively treated. Sleep dysfunction is often the most burdensome of non-motor symptoms, is pervasive in PD patients, and includes sleep fragmentation, insomnia, excessive daytime sleepiness, and rapid eye movement (REM) behavior disorder. Changes in sleep macro-architecture are also seen in PD, with less total sleep time, increased wake after sleep onset (WASO), increased non-REM stage 1 (NREM1) sleep, and decreased NREM2, NREM3, and REM. Building on our earlier observations of spectral patterns in subthalamic nucleus local field potentials (STN LFP) that correspond to specific sleep stages, we have used a novel investigational DBS programmable generator (RC+S Summit System; Medtronic) to enable exploration of sleep biomarkers and prototyping of therapeutic closed-loop, stimulation (DBS) algorithms. Specifically, in PD patients undergoing STN DBS, we examined whether STN oscillations correlated with sleep-stage transitions, then constructed and evaluated sensing and adaptive stimulation (aDBS) paradigms that allow ongoing sleep-stage identification, and attempted to induce through aDBS an increase in sleep-stage duration associated with restorative sleep. This work addresses an unmet clinical need—i.e., the significant sleep dysfunction of PD—and enabled evaluation of STN aDBS in PD patients, specifically for the treatment of sleep dysfunction. Our primary hypothesis for UH3NS113768A1 was that STN—a highly interconnected basal ganglia node—affects the regulation and disruption of human sleep behavior and may be modulated for therapeutic advantage. We tested whether dysfunctional PD STN activity correlates with sleep fragmentation, and whether STN aDBS algorithms could be developed that improve sleep-stage maintenance and sleep quality. Results demonstrate that PD sleep disturbance is marked by pronounced fragmentation and under-expression of NREM3 and REM, reinforcing prior reports of disrupted macroarchitecture. Sub-clinical STN DBS did not alter overall sleep-stage expression, though effects on sleep spindle density support microarchitectural benefits. Efforts to implement closed-loop aDBS for sleep in the home environment revealed practical challenges, including wearable limitations and subject compliance, but also highlighted how next-generation DBS devices with enhanced recording and user interface capabilities can empower novel aDBS strategies. While these findings do not yet confirm a definitive approach to restoring sleep in PD, they underscore that STN-LFP signals hold promise as biomarkers for identifying and modulating specific sleep states in real-world settings and set the stage for more targeted, long-term interventions to improve sleep quality and potentially slow disease progression. Progress on study Aims 1 and 2 described above was impeded by the COVID Pandemic, and has gathered steam with navigation past obstacles to patient recruitment and surgeries. Enrollment for Aim 1 and 2 and investigation of Aim 1 subjects are complete, and the 3-week in-home sleep trial for Aim 2 subjects will conclude prior to Year-5 end. We recently developed novel methods for analyzing study data and are requesting additional funding to accomplish this.