Clinical trial NCT05070013: Adaptive Neurostimulation to Restore Sleep in Parkinson's Disease (Aim 2)
Official title: Adaptive Neurostimulation to Restore Sleep in Parkinson's Disease: An Investigation of STN LFP Biomarkers in Sleep Dysregulation and Repair
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Parkinson's Disease
Sleep Fragmentation
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2021-10-06
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: All participants will experience all 3 DBS stimulation interventions (one condition per week, 3 consecutive weeks): adaptive stimulation, open-loop stimulation (standard clinical stimulation therapy) and no stimulation (control). The order of stimulation conditions is randomly assigned.
Primary purpose: TREATMENT

Brief summary: Parkinson's Disease (PD) is the second most common of the age-related neurodegenerative disorders, affecting over 1,900 adults per 100,000 over the age of 80 in the US. The prevalence of sleep dysfunction in PD is estimated at nearly 80-90% which includes sleep fragmentation, insomnia, rapid eye movement (REM or dream sleep) Sleep Behavior Disorder (RBD), Restless legs syndrome (RLS), periodic limb movement, excessive daytime sleepiness, and sleep apnea. Sleep is vital to homeostasis, cognition, and nervous system repair. The dysfunctional sleep accompanying PD adversely affects both motor and non-motor symptoms, resulting in diminished quality of life for both patients and caregivers, including impairments in mood and behavior, and increased morbidity and mortality. Knowledge of sleep phenomenology and pathology in humans has largely been informed by analysis of non-invasive scalp electroencephalogram (EEG), and despite the profound importance of sleep, the underlying neural circuits important for controlling sleep and wakefulness in humans remain poorly understood.

This study assesses whether adaptive stimulation of the Subthalamic Nucleus (STN) drives changes in sleep episode maintenance and improves sleep quality. Participants are adults with PD 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). Prior to surgery, participant sleep patterns will be assessed with questionnaires and monitored with a non-invasive watch-like device. Approximately four months after implantation surgery, participants will each receive 2 1-week deep brain stimulation (DBS) treatments and 1 1-week control session with no DBS in random order. Sleep patterns will again be monitored during the treatments and compared to the patterns before surgery.

Detailed description: IIn previous studies, investigators examined the use of local field potentials (LFP) recorded from Subthalamic Nucleus (STN) - Deep brain stimulation (DBS) electrodes to identify unique spectral patterns in STN oscillatory activity that correlate with distinct sleep cycles. This offered insight into sleep dysregulation and supported the idea that biomarkers from STN-recorded LFP could be used to identify specific sleep stages. Data from this study 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 polysomnogram (PSG), in 20 Parkinson's Disease (PD) participants for 3-weeks prior to surgery and again 4-months after DBS implantation during the interventions. The time between surgery and the start of interventions allows DBS and medication to be therapeutically optimized for PD motor symptoms. Investigators will compare chronic open-loop stimulation to adaptive stimulation, and to a no-stimulation control group. All participants will experience each of the 3 interventions in random order and be blinded to the type of intervention received.

The study hopes to validate a therapeutic intervention for the burdensome non-motor symptom of sleep dysfunction in PD, and 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 homeostasis in PD. It is expected 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, investigators predict that adaptive more so than chronic open-loop STN-DBS during sleep will decrease non-consolidated 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.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent
* Diagnosis of Idiopathic Parkinson's disease (PD) with motor symptoms present for a minimum of 4 years
* Severe motor symptoms (e.g., motor fluctuations, dyskinesia, tremor, bradykinesia, rigidity) despite optimized medical therapy, that warrant surgical implantation of deep brain stimulation (DBS), according to standard clinical criteria
* Unified Parkinson's Disease Rating Scale (UPDRS-III) score off medication 20 to 80, and improvement of at least 30% in UPDRS-III score on medications, or 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 resulting in inadequate relief of motor symptoms as determined by a movement disorders neurologist, and stable dose of anti-PD medications for 30 days prior to study enrollment
* Requested and approved for subthalamic nucleus deep brain stimulation surgery (STN DBS) by study site Multi-Disciplinary Movement Disorders Patient Care Conference
* Absence of abnormalities on brain magnetic resonance imaging (MRI) scan suggestive of an alternate diagnosis or serving as a contraindication to surgery
* Absence of significant cognitive deficits or significant depression (Beck Depression Inventory-II, BDI-II, score \> 20) on formal Neuropsychological Testing
* Age 18 to 80 years (19 to 80 years in Nebraska)
* Able to conduct follow up neurological care exclusively at study site for duration of the RC+S INS neurostimulator device lifespan (9 years)

Exclusion Criteria:

* Any medical condition considered to elevate risk for surgical complications, such as coagulopathy,, uncontrolled hypertension, history of seizures, heart disease, inability to undergo general anesthesia, or anticoagulant medications that cannot be safely discontinued for perioperative period
* Pregnancy (women of child-bearing potential must have a negative urine pregnancy test prior to surgical procedures)
* Significant untreated depression (Beck Depression Inventory-II, BDI-II \> 20 or Geriatric Depression Scale, GDS, score \> 8)
* Personality or mood disorder symptoms that investigators believe will interfere with study requirements
* Required ongoing treatment with electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or diathermy
* Pre-existing implanted stimulation system (e.g., cochlear implant, cardiac pacemaker, defibrillator, neuro-stimulator for indication other than Parkinson's disease), or ferromagnetic metallic implant
* Prior intracranial surgery
* History or active, drug or alcohol abuse
* Meets criteria for Parkinson's disease (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
* Restless Leg Syndrome
* Obstructive Sleep Apnea
* Inability to perform the recharge process necessary to use the RC+S brain stimulation system

Primary outcomes:
measure: Sleep Efficiency - Frequency
timeFrame: Baseline (days 1 - 21 before surgery) and intervention (approximately days 144 - 172)
measure: Sleep Efficiency - Duration
timeFrame: Baseline (days 1 - 21 before surgery) and intervention (approximately days 144 - 172)
measure: Subjective Sleep Quality
timeFrame: Baseline (days 1 - 21 before surgery) and intervention (approximately days 144 - 172)
Secondary outcomes:
measure: Duration of REM Sleep Stage
timeFrame: During intervention (approximately days 144 - 172)
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
Study officials:
affiliation: University of Nebraska
name: Aviva Abosch, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: