Auditory Slow Wave Enhancement in Parkinson Disease and Mild Cognitive Impairment (PDMCI-TS)

Assessing Effects of Auditory Slow Wave Enhancement on Symptoms and Biomarker Levels in Parkinson Disease and Mild Cognitive Impairment: A Randomized, Double-Blind and Placebo- Controlled Crossover Study

The study aims to assess the efficacy of auditory slow-wave sleep (SWS) enhancement in PD patients and patients with amnestic MCI. Patients will be randomized to two groups: Group 1 will first be treated with auditory stimulation for two weeks and then - after a washout period - switched to two weeks of sham stimulation. Group 2 will first receive sham stimulation for two weeks and then - after a washout period - switch to two weeks of auditory stimulation treatment. The washout period in between will be 2-4 weeks.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; Mild Cognitive Impairment
• Intervention / Treatment: Device: TSB Axo

Detailed Description

The study is a randomized, double-blind, sham-controlled cross-over trial to assess the efficacy of auditory slow-wave sleep (SWS) enhancement in PD patients and patients with amnestic MCI. The screening phase includes entry questionnaires about inclusion/exclusion criteria, sleep quality, chronotype, and handedness, and 1-4 screening nights at home with the TSB Axo, to allow for stimulation optimization. One of the screening nights will be extended to screen for sleep apnea and periodic limb movements during sleep using an ambulatory screening device. Upon final inclusion, 24 PD and 24 MCI patients will be enrolled in the study for an overall period of 6-8 weeks (not including screening phase). Patients will receive 2 weeks of auditory SWS enhancement and 2 weeks of sham stimulation (only device application, no tones played) in a counter-balanced cross-over design, with a 2-4 week washout period during cross-over. Study visits will be performed immediately before and after each intervention period, i.e. after 2 weeks of auditory stimulation or sham stimulation, respectively. Study visits will include standardized clinical examinations, symptom questionnaires, blood sampling after intervention and screening for adverse events by a study physician. Study visits will take place at the Department of Neurology, University Hospital Zurich.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jana Horlacher, MD; Phone Number: +41432535022; Email: jana.horlacher@usz.ch
• Study Contact Backup: Name: Angelina Maric, PhD; Phone Number: +41442558615; Email: Angelina.maric@usz.ch

Study Locations

• Switzerland
  • Zurich, Switzerland, 8050
    • Recruiting
    • University Hospital Zurich, Neurology department
    • Contact: Jana Horlacher, MD; Phone Number: +41432535022; Email: jana.horlacher@usz.ch
    • Contact: Angelina Maric, PhD; Phone Number: +41442558615; Email: Angelina.maric@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• PD: Diagnosis of PD along international criteria, with mild to moderate disease severity (Hoehn and Yahr scale, stages ll-lll)
• PD: Ability to apply the intervention for the duration of study
• MCI: Diagnosis of MCI along international criteria, with a predominant amnestic presentation (single- or multi-domain amnestic MCI)
• MCI: Presence of a cohabitant person who could assist with the application
• MCI: Ability to apply the intervention for the duration of study, with assistance of co-habitant if needed

PD and MCI:

• Age above 18 years
• Informed consent as documented by signature
• Stable home situation (e.g. long-term place to live) that allows for reliable application of intervention for the duration of the study
• Sufficient German language comprehension to follow the study procedures and answer all questions related to the study outcomes
• Dosing of dopaminergic, cholinergic, and other PD or MCI medication must have been stable for at least 14 days prior to start of the first intervention
• Negative pregnancy test during screening (except in women who are surgically sterilized/hysterectomized or postmenopausal for longer than 1 year)

Exclusion Criteria:

• PD: Presence of neurologic, psychiatric, or sleep disorders (others than associated with PD)
• PD: Parkinsonism without response to levodopa; Atypical Parkinsonian syndromes
• PD: Cognitive impairment (Montréal Cognitive Assessment [MoCA] <24)
• MCI: Present diagnosis of a neurological (other than MCI) or interfering psychiatric disease or sleep disorder (e.g. sleep apnoea syndrome, restless legs syndrome)

PD and MCI:

• Severe medical conditions as renal insufficiency, liver failure or congestive heart failure
• Regular use of the following drugs: Benzodiazepines and other central nervous system (CNS)-depressant substances, melatonin and other sleep inducing substances, approved drugs for Alzheimer-type dementia (acetylcholine-esterase inhibitor, memantine)
• Inability to hear the tones produced by the TSB Axo
• Skin disorders/problems/allergies in face/ear area that could worsen with electrode application
• Known or suspected drug- or medication abuse
• Known or suspected non-compliance
• Participation in another study with investigational drug or investigational medical devices within the 30 days preceding and during the present study
• Previous enrolment in the current study
• Enrolment of the investigator, his/her family members, employees and other dependent persons
• Shift work (work during the night)
• Travelling more than 2 time zones in the last month before intervention starts or during intervention (start of intervention will be adapted to fit with this criteria)
• Substance or alcohol abuse (i.e. > 0.5 l wine or 1 l beer per day)
• High caffeine consumption (> 5 servings/day; including coffee, energy drink)
• Implanted deep brain stimulation electrodes
• Women who are pregnant or breast feeding
• Intention to become pregnant during the course of the study
• Lack of safe contraception, defined as: Female patients of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Verum; The device records EEG and other biosignals throughout the night and scans these signals for slow waves associated with deep Non-Rapid Eye Movement (NREM) sleep. Upon recognition of such slow waves and fulfilment of other criteria, a tone is played via the headphones to stimulate and enhance slow waves without waking up the patient.	Device: TSB Axo; The TSB Axo is a wearable biosignal recording device combined with an auditory stimulation. The device consists of pre-gelled biosignal electrodes, headphones integrated in a headband, and a biosignal processing module.
Sham Comparator: Sham; Playing no tones during NREM sleep but wearing the device and recording the biosignals over a period of 2 weeks, every night.	Device: TSB Axo; The TSB Axo is a wearable biosignal recording device combined with an auditory stimulation. The device consists of pre-gelled biosignal electrodes, headphones integrated in a headband, and a biosignal processing module.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in objective EDS	Difference in objective excessive daytime sleepiness (EDS), measured with Multiple Sleep Latency Test (MSLT; minutes), in Parkinson patients	assessed after each intervention (day 15 of each intervention)
Difference in verbal episodic memory performance	Difference in verbal episodic memory performance, measured with the Hopkins Verbal Learning Test (HVLT; score ranges from 0 to 12, higher scores indicate better performance) delayed recall, in Mild Cognitive Impairment patients	assessed after each intervention (day 15 of each intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective EDS	Change in subjective excessive daytime sleepiness (EDS), measured with the Epworth Sleepiness Scale (ESS; score ranges from 0 to 24, higher scores indicate greater EDS)	assessed before and after each intervention (day 1 and 15 of each intervention)
Sustained attention	Sustained attention, measured with the Sustained Attention to Response Task (SART)	assessed after each intervention (day 15 of each intervention)
Vigilance	Vigilance, measured with the Psychomotor Vigilance Task (PVT)	assessed after each intervention (day 15 of each intervention)
Subjective nocturnal sleep quality	Subjective nocturnal sleep quality, measured with the Parkinson's Disease Sleep Scale -2 (PDSS-2; score ranges from 0 to 60, higher scores indicate worse sleep quality) in PD patients and Pittsburgh Sleep Quality Index (PSQI; score ranges from 0 to 21, higher scores indicate worse sleep quality) in MCI patients	assessed before and after each intervention (day 1 and 15 of each intervention)
Executive Function and attention	Executive function (mental flexibility, verbal fluency, motor programming, sensitivity to interference, working memory, psychomotor processing speed), measured with the Trail Making Test (TMT; in seconds) B/A, the Regensburger Wortflüssigkeitstest (RWT; phonematic and semantic verbal fluency; in word count), the Luria's motor sequence test, the Victoria Stroop Task, the 2-back task, and the TMT A	assessed after each intervention (day 15 of each intervention)
Plasma biomarkers	Plasma levels of protein accumulation (aSyn, beta-amyloid 40 and 42 [Aß40, Aß40], tau, phosphorylated tau [p-tau]), neurodegeneration (neurofilament light chain; NFL), and synaptic and inflammatory markers	assessed after each intervention (day 15 of each intervention)
Subjective sleep quality	Subjective sleep quality measured with a Visual Analog Scale (VAS) on a scale from very poor to very good	assessed every morning during the intervention period (days 1-15 of each intervention)
Subjective mood	Subjective mood during daytime measured with a Visual Analog Scale (VAS) on a scale from very poor to very good	assessed every evening during the intervention period (days 1-14 of each intervention)
Subjective momentary sleepiness	Subjective momentary sleepiness measured with Karolinska Sleepiness Scale (KSS; score ranges from 1 to 9, higher scores indicate greater momentary sleepiness)	assessed every evening during the intervention period (days 1-14 of each intervention)
Digital biomarkers	tapping behavior on tablet	assessed every day during the intervention (days 1-15 of each intervention)
Sleep intensity	Sleep intensity, represented by Slow Wave Activity/ Slow Wave Energy (SWA/SWE), calculated from EEG recordings obtained every night at home with a frontal EEG electrode of the TSB Axo	assessed continuously during the intervention period (days 1-15 of each intervention)
Depressive symptoms	Depressive symptoms, indicated by the Hospital Anxiety and Depression Scale (HADS; score ranges from 0 to 21, higher scores indicate more depressive symptoms), in MCI patients	assessed before and after each intervention (day 1 and 15 of each intervention)
Verbal episodic and visuospatial memory function	Verbal episodic and visuospatial memory function, measured with the Hopkins Verbal Learning Test (HVLT; score ranges from 0 to 12, higher scores indicate better performance), and Brief Visuospatial Memory Test (BVMT; score ranges from 0 to 12, higher scores indicate better performance), in MCI patients	assessed after each intervention (day 15 of each intervention)
Quality of life (VAS)	Quality of life, measured with a Visual Analog Scale (VAS) on a scale from very poor to very good, in Parkinson patients	assessed before and after each intervention (day 1 and 14, day 29 and 42)
Motor symptoms	Motor symptoms, assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) lll remote version (on tablet; score ranges from 0 to 104, higher scores indicate worse motor symptoms), in Parkinson patients	assessed before and after each intervention, in the morning prior to dopaminergic medication intake (day 1 and 14 of each intervention)
Focused motor assessment	Assessment of hand/finger movements, in Parkinson patients	assessed on day 4 of each intervention
Overnight memory consolidation	Overnight memory consolidation, assessed with a word-pair task and finger tapping sequence test in PD and MCI patients	assessed in the evening of day 13 and in the morning of day 14
Overnight restoration inhibitory control	Overnight restoration of inhibitory control, assessed with the Go/NoGo Task (GNG) in PD and MCI patients	assessed in the evening of day 13 and in the morning of day 14
Overnight restoration working memory	Overnight restoration of the working memory, assessed by the 2-back task in PD and MCI patients	assessed in the evening of day 13 and in the morning of day 14
Overnight restoration vigilance	Overnight restoration of vigilance, assessed by the Psychomotor Vigilance Test (PVT) in PD and MCI patients	assessed in the evening of day 13 and in the morning of day 14

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Angelina Maric, PhD, University of Zurich

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2021
• Primary Completion (Anticipated): March 31, 2024
• Study Completion (Anticipated): March 31, 2024

Study Registration Dates

• First Submitted: January 25, 2021
• First Submitted That Met QC Criteria: January 29, 2021
• First Posted (Actual): February 3, 2021

Study Record Updates

• Last Update Posted (Actual): November 15, 2022
• Last Update Submitted That Met QC Criteria: November 14, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Mild Cognitive Impairment; Sleep; Neurodegeneration; Cognition; Parkinson Disease; Excessive Daytime Sleepiness; Slow wave sleep; Auditory enhancement
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Cognition Disorders; Parkinson Disease; Cognitive Dysfunction
• Other Study ID Numbers: PDMCI-TS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No