Wearable Neural Interfacing System for REM Sleep Restoration and Enhancement

This study evaluates the safety, feasibility, and preliminary signals of effect of NEUSleeP, a wearable neural interface for closed-loop modulation of REM sleep using transcranial focused ultrasound (tFUS) targeted to the subthalamic nucleus (STN). The system integrates a flexible ultrasound transducer with bioadhesive hydrogel EEG electrodes in a patch designed for repeated overnight use. REM sleep is implicated in emotional regulation, memory processes, and stress adaptation. Existing noninvasive approaches have focused largely on NREM modulation; this study examines a REM-focused, target-directed approach to determine whether tFUS delivered during sleep can alter REM architecture and related outcomes.

The study comprises four phases:

Phase 1 (device functionality) enrolls four healthy volunteers for repeated bench and on-body checks (EEG signal quality, contact impedance stability, usability) over four weeks, with comparisons to standard clinical electrodes.

Phase 2 (STN stimulation and imaging validation) uses structural MRI and acoustic modeling to configure STN targeting for both a reference research system (BrainSonix Pulsar 1002) and NEUSleeP. In up to 20 healthy volunteers, functional MRI is acquired immediately before and immediately after the same MRI-FUS session to characterize BOLD responses in STN and stress-related networks (e.g., amygdala, insula), using identical imaging protocols across platforms.

Phase 3 (REM modulation in healthy volunteers) enrolls 16 adults for two consecutive overnight recordings: Night 1 baseline (no stimulation) and Night 2 tFUS (closed-loop stimulation time-locked to REM using EEG). Primary sleep outcomes include REM time, REM percentage, number of REM periods, and REM latency; safety and tolerability are recorded throughout.

Phase 4 (REM modulation in participants with non-clinical sleep disturbance) enrolls 12 adults with elevated sleep complaints and perceived stress for the same two-night protocol; exploratory outcomes include self-reported stress measures collected around the FUS night.

Two fMRI paradigms are used across phases. In Phase 2, a same-session MRI-FUS visit includes pre-stimulation and post-stimulation fMRI acquisitions in the same session (healthy imaging-validation subset). In Phases 3 and 4, participants complete morning-before (pre-FUS night) and morning-after (post-FUS night) fMRI sessions to assess changes around the overnight REM-timed stimulation.

Safety procedures include MRI screening where applicable, continuous adverse event capture, stop rules for stimulation, and post-visit follow-up. Ultrasound exposure is controlled within established diagnostic ultrasound limits (e.g., MI <= 1.9 and derated time-averaged intensity within applicable FDA limits), with device-level acoustic verification prior to use. Data monitoring is performed by the study team with predefined criteria for pausing or discontinuation. Findings will inform the feasibility of a wearable EEG-tFUS approach for REM-related modulation and guide parameters for future controlled trials.

Inclusion criteria

for Healthy Volunteers:

• Adults aged 18-50, willing and able to undergo MRI, EEG, and FUS experiments.

Inclusion criteria

for Healthy Volunteers with Non-Clinical Sleep Disturbances:

• Adults aged 18-50, willing and able to undergo EEG and FUS experiments.
• Pittsburgh Sleep Quality Index (PSQI) score between 5 and 10.
• Perceived Stress Scale (PSS) score between 16 and 21.

Exclusion criteria

for Both Groups:

• Current or past history of psychopathology, epilepsy, or other seizure disorders.
• Inability to provide informed consent to undergo EEG recording, FUS stimulation, and MRI.
• Diagnosed sleep disorders (e.g., insomnia, obstructive sleep apnea).
• Contraindications to FUS or MRI, including but not limited to: history of stroke, brain tumors, brain hemorrhages, internal wires, electrodes, pacemakers, implants, irremovable ferromagnetic objects in the head that are unsafe for MRI and/or cause large imaging artifacts, brain surgery, moderate-to-severe head injury, any penetrating head injury, or uncontrolled thyroid disorder.
• Pregnant individuals or those attempting to become pregnant (due to unknown MRI-related risks to fetuses).
• Serious medical illnesses likely to interfere with study participation.
• Current active suicidal or homicidal ideation (or suicide attempt within the past 3 months).
• Current substance use disorder.
• Current or recent (within the past 3 months) psychotic symptoms.
• Currently meeting diagnostic criteria for a manic episode.
• Currently engaged in evidence-based or experimental treatments (e.g., weekly cognitive behavioral therapy, transcranial magnetic stimulation, ketamine/esketamine treatment) other than psychiatric medications that have been on a stable dosage and regimen for at least 3 months (including antidepressants, mood stabilizers, atypical antipsychotics, and sedatives/hypnotics), in order to avoid confounding therapeutic effects.