Home-Based Closed-Loop Auditory Stimulation to Enhance Slow-Wave Activity in MCI Due to Alzheimer's Disease: A Proof-of-Concept Study

N/AEnrolling By InvitationNCT07672977

Bitbrain30 enrolled

Overview

This proof-of-concept study explores whether long-term home-based closed-loop auditory stimulation during sleep enhances slow-wave activity (SWA) and yields preliminary efficacy signals in patients with amnestic mild cognitive impairment due to Alzheimer's disease (MCI-AD), confirmed by cerebrospinal fluid (CSF) biomarkers or positron emission tomography (PET). The intervention is self-administered at participants' homes over an initial treatment period of 3 months, followed by a 1-month off-treatment (washout) period. Participants may then enter an optional extension phase consisting of 3 additional months of treatment followed by a second 1-month washout period, for a total study duration of up to 8 months. Participants who complete the Nana-Lab Study (NCT07402590) may be invited to provide informed consent for screening and potential enrollment in this study. All enrolled participants receive nightly active treatment during intervention periods. This study does not include randomization or a sham control group.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and is preceded by a prodromal stage known as amnestic mild cognitive impairment due to AD (MCI-AD), in which early neurophysiological alterations are detectable. Among these, disruptions in sleep architecture-particularly reductions in slow-wave activity (SWA; \~0.5-4 Hz) and sleep spindle activity (\~11-16 Hz)-have been associated with impaired memory consolidation and the progression of AD-related pathophysiological processes. Closed-loop auditory stimulation during sleep (CLAS) is a non-invasive neuromodulation approach that delivers precisely timed auditory stimuli phase-locked to endogenous slow oscillations, with the aim of enhancing slow-wave activity and associated thalamocortical spindle dynamics. This targeted entrainment of sleep oscillations may improve sleep-dependent neural processes and represents a potential therapeutic strategy in the early stages of AD. The present study is an open-label, single-arm investigation designed to evaluate the effects of home-based CLAS in patients with biomarker-confirmed amnestic mild cognitive impairment due to Alzheimer's disease (MCI-AD). The intervention is self-administered in the participants' home environment. All participants complete an initial treatment period of 3 months followed by a one-month off-treatment (washout) period to assess persistence of effects. Participants who elect to continue may then enter an optional extension phase consisting of 3 additional months of treatment, followed by a second one-month off-treatment period. The total study duration is approximately 4 months for participants completing the initial phase only, or approximately 8 months for those completing the extension phase. The primary objective is to assess target engagement, defined as the modulation of NREM sleep electrophysiological activity, with particular focus on slow-wave sleep. More precisely, sustained increases in slow-wave activity across the intervention period will be quantified using the study EEG device during intervention nights. Secondary objectives include evaluation of adherence to the intervention, usability of the device in the home environment, and safety and tolerability. Exploratory objectives include evaluation of the intervention's effects on clinical, functional, cognitive, and sleep-related outcomes, as well as blood-based biomarkers. Clinical, functional, and cognitive variables will be assessed at three time points: before intervention (baseline, Month 0), at the end of the initial treatment period (Month 3), and, for participants entering the extension phase, at the end of the extended treatment period (Month 7). Blood biomarkers will be obtained at the following time points: baseline (Month 0), end of the initial treatment period (Month 3), and end of the first washout period (Month 4). Participants entering the extension phase will have two additional blood draws: at the end of the extended treatment period (Month 7) and at the end of the second washout period (Month 8). Sleep metrics, derived from EEG recordings or subjective responses to digitized questionnaires, will be acquired daily using the home-based study device. This study does not include randomization or a sham control group; all participants receive active treatment during intervention periods. The results are expected to provide evidence on neurophysiological target engagement, feasibility, safety, and the clinical and biological effects of home-based CLAS as a therapeutic strategy in early-stage AD.

Interventions

Closed-Loop Auditory StimulationDEVICE

The system delivers brief auditory stimuli (pink noise bursts) that are time-locked to the up-phase of endogenous slow oscillations during non-rapid eye movement (NREM) sleep, as detected in real time using electroencephalography (EEG). Stimulation is withheld in approximately half of detected slow oscillations (Sham) to serve as a within-session control condition for the acute effects of stimulation. The other half of the slow oscillations are stimulated at a volume between 30-60 dB (Stim), which is personalized to the patient and adapts during the night to improve response while reducing awakenings. The objective of the stimulation is to enhance slow-wave activity (SWA) during deep sleep through phase-specific entrainment of endogenous slow-wave activity. The intervention is self-administered using a portable system adapted for use in patients with MCI. Participants are instructed to use the device for as many nights as possible throughout the study period.

Eligibility

Sex: ALLMin age: 50 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion criteria: * Age between 50 and 75 years (inclusive). * Spanish as native language. * Diagnosis of amnestic mild cognitive impairment due to Alzheimer's disease, confirmed by cerebrospinal fluid biomarkers or amyloid PET. * Normal or corrected-to-normal color vision (required for completion of visual-analog study assessments). * Adequate hearing to perceive the auditory stimuli used in the intervention, defined as a hearing threshold of 50 dB or below, assessed during the screening session. Exclusion criteria: * Severe systemic or complex chronic disease that, in the investigator's judgment, would compromise participant safety or data quality, including but not limited to: advanced heart disease; advanced chronic kidney disease (stage 4 or 5); severe pulmonary disease (e.g., COPD GOLD stage III-IV); metastatic or terminal cancer; severe hematological disorders; or active or uncontrolled chronic infectious disease (e.g., untreated HIV). * Evidence on neuroimaging of strategic infarcts or other findings that may account for secondary cognitive impairment. * Alcohol or psychotropic substance abuse. * Diagnosis of depression or any severe psychiatric disorder within the 5 years prior to evaluation. * Changes in benzodiazepine or antidepressant treatment within the 6 months prior to baseline evaluation. * Current treatment with neuroleptics. * Epilepsy with active treatment within the last 5 years, or any neurological comorbidity that may cause cognitive impairment or structural brain damage. * Unable to read and write in Spanish. * Inability to use the study device effectively, as determined during the screening session. This includes, but is not limited to, anatomical or dermatological factors preventing adequate electrode placement, or excessive EEG signal artifacts that prevent reliable detection of sleep oscillations.

Outcomes

Primary Outcomes

Target Engagement: Sustained Increase in Slow-Wave Activity During N2-N3 Sleep

Within-subject difference in mean slow-wave activity during N2-N3 sleep between stimulation and sham conditions, computed nightly and aggregated across the intervention period. The sustained effect will be evaluated as the consistency of the stimulation-induced increase in slow-wave activity across nights throughout the intervention period.

Time frame: Assessed at each intervention night, from baseline through the end of the intervention period (3 months, or up to 7 months for participants entering the extension phase).

Secondary Outcomes

Sustained Increase in Spindle Activity During N2-N3 Sleep

Within-subject difference in spindle activity (spindle occurrence during N2-N3 sleep) between stimulation and sham conditions, computed nightly and aggregated across the intervention period. The sustained effect will be evaluated as the consistency of the stimulation-induced increase in spindle activity across nights throughout the intervention period.

Time frame: Assessed at each intervention night, from baseline through the end of the intervention period (3 months, or up to 7 months for participants entering the extension phase).

Adherence to the Intervention

Average number of intervention nights attempted per week. An intervention night is defined as a night during which the participant initiates use of the technology. Adherence will also be summarized as the proportion of participants achieving an average of at least 4 nights per week.

Time frame: Computed as a summary measure over each participant's full intervention period (3 months, or up to 7 months for participants entering the extension phase).

Usability of the Closed-Loop Auditory Stimulation System

Percentage of successful sessions among all attempted sessions. A successful session is defined as one in which the participant correctly sets up the device, the system initializes, and usable physiological data are recorded. Sessions may be unsuccessful due to patient-side factors (e.g., electrode placement errors), device-side factors (e.g., technical malfunction), or both.

Time frame: Computed as a summary measure over each participant's full intervention period (3 months, or up to 7 months for participants entering the extension phase).

Safety and Tolerability

Incidence, severity, and relatedness of adverse events associated with the intervention, including sleep disturbance, discomfort related to auditory stimulation, and any device-related adverse effects. Safety will be assessed continuously and summarized at interim and final analyses.

Time frame: Continuously monitored from enrollment through the end of participation, with summary analyses at 3 months and, for participants entering the extension phase, at 7 months.