Adaptive Neurostimulation to Restore Sleep in Parkinson's Disease (Aim 2)

Study Overview
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Brief Summary
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This study is aimed at testing the hypothesis that adaptive stimulation of the Subthalamic Nucleus (STN) drives changes in sleep episode maintenance and improves sleep quality. Investigators will directly test the efficacy of an adaptive stimulation protocol. Study subjects are adults with Parkinson's disease who experience inadequate motor symptom relief, and who have been offered implantation of a deep brain stimulator system targeting STN for the treatment of motor symptoms (standard-of-care). Investigators will implant 20 (n = 10 per clinical site) Parkinson's Disease subjects with the Medtronic RC+S System, enabling the implementation of real-time adaptive stimulation during in-home sleep. Prior to surgery, study subjects will complete clinical sleep questionnaires in an outpatient setting and wear an actigraphy watch for 3 weeks to monitor sleep architecture and sleep fragmentation. Three months after subjects have completed their standard-of-care Deep Brain Stimulation surgery and are optimized in terms of Parkinson's medication and clinical DBS stimulation parameters, we will monitor sleep for an additional 3 weeks, using in-home monitoring. During each week of the in-home monitoring period, subjects will undergo, in a randomized and double-blind fashion, one of three nocturnal stimulation algorithms: Adaptive stimulation, Open-Loop stimulation (standard clinical stimulation therapy) and No stimulation (control). During the 3 weeks of in-home sleep monitoring, we will monitor sleep architecture and sleep fragmentation using an actigraphy watch and subjects will complete a sleep questionnaire. At the end of the 3-week period of sleep-time randomized, blinded stimulation delivery, subjects will return to their standard stimulation therapy.

Detailed Description
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In our previous work, we investigated the use of local field potentials (LFP) recorded from STN-DBS electrodes to identify unique spectral patterns in STN oscillatory activity that correlate with distinct sleep cycles, offering insight into sleep dysregulation and supporting the notion that biomarkers from STN-recorded LFP could be used to identify specific sleep stages. Aim 1 of this study, ClinicalTrials.gov ID: NCT04620551, characterized the relationship between aberrant STN activity (via LFP) and sleep dysregulation in PD by recording and analyzing three consecutive nights of STN-LFP with concurrent PSG. During the third night we collected sleep recordings as we delivered sub-threshold stimulation, to assess how stimulation affects sleep-stage duration and transitions. These data directly informed the development and optimization of an adaptive stimulation algorithm. The current study will assess the efficacy of the adaptive stimulation algorithm and will test the working hypothesis that modulation of STN during nighttime sleep will normalize sleep behavior by offsetting aberrant signaling in the sleep network. Investigators will use subjective assessments, 3-week actigraphy, and nocturnal PSG, in 20 PD subjects 3 months after DBS implantation, a point at which DBS and medication will have been therapeutically optimized for PD motor symptoms. Investigators will compare chronic open-loop stimulation to adaptive stimulation, and to a no-stimulation control group. All subjects will experience each of the 3 conditions (one condition per week; OFF-Stim, ON-Stim-Adaptive, ON-Stim-Open), however the order in which each subject is assigned to a condition will be randomized while preserving a balanced ratio of group assignments. Investigators will monitor sleep architecture and quality in all groups for 3 weeks prior to DBS surgery, and then at 3 months post-DBS surgery, using in-home actigraphy. Subjects will be blinded with respect to group assignment to mitigate subject bias, which will be set by the Research Host PC when a subject initiates the recording sequence. The rationale for this aim is (1) to validate a therapeutic intervention for the burdensome non-motor symptom of sleep dysfunction in PD, and (2) to fill a critical gap in our understanding of the contribution of STN-DBS to ameliorating sleep-wake disturbances in PD. The acquisition of these data will improve the understanding of the role of basal ganglia, specifically STN, in sleep hemostasis in PD. We expect that STN-DBS will improve sleep-wake parameters in both the PSG and actigraphy recordings but that adaptive stimulation, targeted at sleep-stage biomarkers, will further optimize sleep and alleviate this non-motor burden in PD. Specifically, we predict that adaptive more so than chronic open-loop STN-DBS during sleep will decrease nonconsolidated sleep, reduce the frequency of awakenings, increase the percentage time spent in REM sleep, reduce daytime sleepiness, and increase subjective experience of restfulness and sleep quality.

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

Conditions
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Parkinson's Disease, Sleep Fragmentation

Intervention / Treatment
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* Device: Deep Brain Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide informed consent for this study. Signed informed consent. Diagnosis of Idiopathic Parkinsons disease with motor symptoms that have been present for a minimum of 4 years. Motor symptoms (e.g., motor fluctuations, dyskinesia, tremor, bradykinesia, rigidity) that are severe enough, despite optimized medical therapy, to warrant surgical implantation of DBS, according to standard clinical criteria. UPDRS-III score off medication between 20 and 80, and an improvement in UPDRS-III score on medications of at least 30%, or patients with tremor-dominant PD (score >/= 2 on UPDRS-III tremor sub-score) or tremor in addition to other motor symptoms that are treatment-resistant and result in significant functional disability. Appropriate trials of oral PD medications have resulted in inadequate relief of motor symptoms as determined by a movement disorders neurologist, and anti-PD medications have been at stable doses for 30 days prior to study enrollment. Patient has requested DBS surgery, and has been approved by the site (UNMC or University of Pennsylvania) Multi-Disciplinary Movement Disorders Patient Care Conference for STN DBS Absence of abnormalities on brain MRI suggestive of an alternate diagnosis or serving as a contraindication to surgery. Absence of significant cognitive deficits or significant depression (BDI-II score > 20) on formal Neuropsychological Testing. Age 18 to 80 years (19 years for Nebraska) Ability to conduct follow up neurological care exclusively at the study site for the duration of the RC+S INS lifespan (9 years). Exclusion Criteria: Coagulopathy, anticoagulant medications that cannot be discontinued safely for perioperative period, uncontrolled hypertension, history of seizures, heart disease, inability to undergo general anesthesia, or other medical conditions considered to place the patient at elevated risk for surgical complications. Pregnancy: All women of child-bearing age will have a negative urine pregnancy test prior to undergoing surgical procedures. Significant untreated depression (BDI-II score > 20 or GDS score > 8). Personality or mood disorder symptoms that Study Personnel believe will interfere with study requirements Patients requiring ongoing treatment with ECT, rTMS, or diathermy. Pre-existing implanted stimulation system (e.g., cochlear implant, cardiac pacemaker, defibrillator, neuro-stimulator for indication other than Parkinsons disease) or ferromagnetic metallic implant. Prior intracranial surgery. History of, or active, drug or alcohol abuse. Meets criteria for PD with Mild Cognitive Impairment (PD-MCI), as defined by Performance > 2 standard deviations below appropriate norms on tests from 2 or more of the following cognitive domains: Attention, Executive Function, Language, Memory, and Visuospatial Ability. Patients with Restless Leg Syndrome. Patients with Obstructive Sleep Apnea. Inability to perform the recharge process necessary for use of the RC+S system.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: All subjects will experience all 3 DBS stimulation conditions (one condition per week, 3 consecutive weeks): adaptive stimulation, open-loop stimulation (standard clinical stimulation therapy) and no stimulation (control). The order in which each subject is assigned to a condition will be randomized.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adaptive DBS stimulation<br>Subjects experience adaptive stimulation during one week of at-home night sleep. | Device: Deep Brain Stimulation<br>* All subjects will undergo three 1-week conditions of stimulation during nighttime sleep over the course of three consecutive weeks of in-home sleep: adaptive stimulation, open-loop stimulation and no stimulation.<br>|
| Active Comparator: Open-loop DBS stimulation<br>Subjects experience open-loop stimulation (standard clinical stimulation therapy based on DBS programming for the treatment of motor symptoms) during one week of at-home night sleep. | Device: Deep Brain Stimulation<br>* All subjects will undergo three 1-week conditions of stimulation during nighttime sleep over the course of three consecutive weeks of in-home sleep: adaptive stimulation, open-loop stimulation and no stimulation.<br>|
| No Intervention: No DBS Stimulation<br>DBS stimulation is turned off (control) during one week of at-home night sleep. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep efficiency | Sleep fragmentation frequency and duration will be measured using FDA-approved wrist-based Actigraphy (ActiWatch Spectrum Pro). | Years 1-3 | 
| Subjective Sleep Quality | Change in subjective sleep quality will be measured between the 3 stimulation conditions. The measure will be captured using the Pittsburgh Sleep Diary. | Years 1-3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of REM sleep stage | Change in the duration of REM stage sleep will be measured between the 3 stimulation conditions. We will use the artificial neural network to identify sleep stage and assess whether the duration changes as a function of stimulation protocol. | Years 1-3 |