Auditory Sleep Stimulation or Sham in People With Parkinson Disease Mild Cognitive Impairment During Cognitive Training

Non-pharmacological Enhancement of Deep Sleep With Auditory Stimulation Versus Sham in People With Parkinson's Disease and Mild Cognitive Impairment Receiving Cognitive Training: A Double-blind Randomized Trial (PD-CogT-Sleep)

People with Parkinson's disease are at higher risk of cognitive decline, and current treatments cannot fully prevent this. This study explores non-drug ways to support brain function.

Intervention: Participants will complete a 5-week cognitive training program at home ("brain fitness"). In addition, they will use a sleep device at night that plays soft sounds to improve deep sleep; Half of the participants will actually receive these sounds (auditory stimulation), while the other half will receive a sham (placebo) version - neither the participants nor the researchers will know the group assignment.

Assessments will take place before and after the intervention, and again three months later, including one overnight stay at University Hospital Zurich per assessment.

The goal is to find out whether improving deep sleep can boost the benefits of cognitive training and help slow cognitive decline in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated not only with motor symptoms (such as tremor, slowness of movement, and rigidity), but also with a broad range of non-motor symptoms. Sleep disturbances are common, and many individuals with PD develop cognitive impairment, ranging from mild cognitive impairment (MCI) to dementia. For early cognitive impairment in PD, pharmacological treatment options are limited, and there are currently no established therapies that reliably prevent further cognitive decline. There is therefore a clear need to develop and evaluate non-pharmacological interventions that can support cognitive functioning in this population.

Cognitive training (CogT) is a structured, exercise-based intervention targeting cognitive domains such as attention, memory, and executive functions (e.g., planning and coordination of actions). Evidence supports the efficacy of CogT in PD and in older adults; however, response to training varies considerably between individuals. Sleep-particularly deep sleep-has been proposed as an important factor influencing learning and cognitive performance. Deep sleep is implicated in processes relevant to memory consolidation and daytime cognition. Because sleep disturbances are frequent in PD, impaired sleep may represent a barrier to achieving optimal benefits from CogT.

This study evaluates whether enhancing deep sleep using phase-targeted auditory stimulation (PTAS) can improve the effectiveness of CogT in people with PD and MCI. PTAS is a non-pharmacological method that delivers soft, non-arousing sounds during sleep with the aim of supporting deep sleep. The intervention is administered using a wearable headband device developed at the University of Zurich and ETH Zurich. The device is designed for home use and can be worn during sleep in the participant's own bed. The technology has been used in previous research in younger and older healthy individuals as well as in people with PD, with no relevant side effects reported, and has demonstrated beneficial effects on measures of deep sleep.

Study Design

This is a double-blind, randomized, sham-controlled trial. After eligibility screening, participants are randomly assigned to one of two groups:

Active auditory stimulation group: Participants complete digital CogT and use the headband during sleep with active PTAS intended to enhance deep sleep.

Sham stimulation group: Participants complete the same digital CogT and use the headband during sleep, but the sounds delivered do not provide targeted deep sleep stimulation (sham condition).

Neither participants nor study staff involved in assessments and trial conduct are aware of group allocation.

Study Procedures The intervention phase lasts 5 weeks and is performed primarily at home. Participants use the headband during sleep as often as possible throughout the 5-week period. Digital CogT is performed at home on a tablet during weeks 2-5 (total of 4 weeks), three sessions per week, approximately 50 minutes per session, with scheduling adapted to individual daily routines.

Participants attend study visits at University Hospital Zurich, including assessments before the intervention, after the 5-week intervention, and at a 3-month follow-up. These visits include approximately half a day of assessments and an overnight stay in the sleep laboratory. Assessments include standardized neuropsychological testing of cognitive performance, questionnaires addressing sleep-related symptoms, non-motor symptoms, and quality of life, and overnight recording of brain activity during sleep using high-density electroencephalography (hdEEG). Blood samples are collected to explore biomarkers that may reflect biological processes related to brain function. In addition, participants wear an actimeter (a watch-like activity monitor) for defined periods to capture activity patterns and sleep-wake behavior.

Prior to final enrollment, participants complete a familiarization phase at home (typically 1-5 nights) to assess tolerability of sleeping with the headband. Depending on prior clinical information, a one-night home sleep assessment may be performed to screen for relevant sleep disorders such as sleep apnea.

Outcome and Objectives - Overview The primary objective is to determine whether enhancement of deep sleep via PTAS increases the benefit of CogT on cognitive performance in people with PD and MCI. Secondary objectives include evaluating the effects of the combined intervention on sleep physiology (as assessed by hdEEG) and exploratory blood-based biomarkers.

The study is conducted in Switzerland in accordance with applicable legal and ethical requirements for research involving humans, including data protection regulations, and has been reviewed and authorized by the responsible ethics committee and Swissmedic. The study is planned as a national trial in Switzerland with approximately 50 participants. Participant data and samples are coded to protect confidentiality, and participation is voluntary; participants may withdraw at any time without consequences for their ongoing medical care.

Inclusion Criteria:

• clinical diagnosis of PD along the MDS criteria (Postuma et al., 2015)
• MCI according to the MDS criteria, level I (Litvan et al., 2012):
• - cognitive decline: Gradual decline, in the context of established PD, in cognitive ability reported by either the patient or informant, or observed by the clinician, AND
• - MoCA ≤ 26 and ≥ 18 (Hoops et al., 2009)
• stable home situation (e.g. long-term place to live) that allows for reliable application of intervention for the duration of the study
• ability to apply the sleep intervention for the duration of study, either alone or with assistance of a co-habitant if needed
• ability to apply the CogT intervention for the duration of study
• sufficient German language comprehension to follow the study procedures and answer all questions related to the study outcomes
• dosing of dopaminergic and other PD treatment must have been stable for at least 14 days prior to the intervention period and will be expected to remain stable until the end of the study.

Exclusion Criteria:

Diagnosis/Comorbidities:

• clinical diagnosis of dementia (cognitive impairment sufficient to interfere with independence in everyday activities, i.e. "major neurocognitive disorder", DSM-5)
• known presence of neurologic (other than PD) or psychiatric disorder
• Parkinsonism without response to levodopa; atypical Parkinsonian syndromes as assessed from medical history and clinical examination
• severe medical conditions (for example, renal insufficiency, liver failure, or congestive heart failure) as assessed in the semi-structured screening interview
• regular use of benzodiazepines and other central nervous system (CNS)-depressant substances as assessed in the semi-structured screening interview
• known or suspected drug- or medication abuse as assessed in the semi-structured screening interview
• substance or alcohol abuse (i.e. > 0.5 l wine or 1 l beer per day) as assessed in the semi-structured screening interview

Sleep disorders that could interfere with the sleep intervention:

• obstructive sleep apnea with apnea-hypopnea index (AHI)>15, apnea-related NREM sleep fragmentation, and indication for treatment (in turn, primarily REM-related sleep apnea, not requiring specific treatment may be considered eligible); or use of continuous positive airway pressure (CPAP)
• Restless Legs Syndrome
• frequent (i.e. weekly) Non-REM sleep parasomnia (Sleep disorders typically associated with PD will not lead to exclusion, i.e. REM sleep behavior disorder, insomnia, nocturnal PD symptoms.)

PTAS:

• inability to hear the tones produced by the sleep headband (TOSOO Axora device)
• non-responder to PTAS during screening (PTAS does not evoke a discernable auditory evoked potential AEP)
• skin disorders/problems/allergies in face/ear area that could worsen with electrode application
• known or suspected non-compliance

Cognition & informed consent:

• inability to follow the procedures of the study, e.g. due to language problems, cognitive deficits
• failure to give informed consent

Other studies:

• participation in another study with investigational interventions within 30 days (PTAS) or 1 year (CogT) 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

Special events / behavior with impact on circadian rhythm, sleep, or cognition:

• 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)
• planned medical intervention of substantial relevance, e.g. surgery, during intervention (routine assessments, e.g. check-ups will be allowed)

Pregnancy:

• women who are pregnant or breastfeeding,
• intention to become pregnant during the course of the study,
• lack of safe contraception, defined as: Female participants 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. Please note that female participants who are surgically sterilized/hysterectomized or post-menopausal for longer than 1 year are not considered as being of child bearing potential.