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

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.

Grant Number: 3UH3NS113769-05S1
NIH Institute/Center: NIH
Principal Investigator: AVIVA ABOSCH