Synthetic Vasomotion for Glymphatic Enhancement

This pilot study will evaluate the feasibility, safety, tolerability, and exploratory physiological effects of a multimodal intervention designed to influence autonomic, cerebrovascular, respiratory, and glymphatic-associated physiology. The study combines guided breathing, intermittent hypercapnia, and noninvasive vagus nerve stimulation (nVNS) with continuous or repeated physiological monitoring and exploratory blood-based biomarker assessment.

The glymphatic system is a brain-wide pathway involved in the exchange of cerebrospinal fluid and interstitial fluid and in the movement of metabolic waste products from brain tissue. Glymphatic-associated fluid transport is influenced by sleep, cerebrovascular pulsatility, vasomotion, respiratory physiology, and autonomic regulation. Parkinson's disease is associated with abnormalities in several of these systems, including autonomic function, sleep, and brainstem noradrenergic signaling. This study therefore examines whether controlled manipulation of respiratory and autonomic physiology produces measurable changes in physiological signals hypothesized to be relevant to glymphatic-associated fluid dynamics.

The study will enroll up to 20 adults, including approximately 10 participants with early-stage Parkinson's disease and 10 age-matched healthy control participants. The target analytic sample is approximately 16 participants after accounting for attrition, incomplete visits, or unusable data. The study is designed as a pilot and is not powered to establish clinical efficacy.

Participants will complete a week-long protocol. Following screening and informed consent, participants will complete an intake and baseline visit that may include health and demographic questionnaires, vital signs, baseline physiological measurements, guided breathing, and training on the Applied Cognition GF Monitor. Participants will then complete overnight at-home monitoring on two baseline nights.

Participants will subsequently complete two in-clinic intervention visits separated by approximately 48 hours. The order of active and sham nVNS will be randomized, and each participant will receive both conditions in a within-participant crossover design. During both intervention visits, nVNS or sham stimulation will be paired with guided breathing and intermittent hypercapnia. For intermittent hypercapnia, participants will breathe through a noninvasive mask connected to a controlled breathing circuit that alternates room air with a gas mixture containing approximately 5% carbon dioxide, 21% oxygen, and balance nitrogen. The hypercapnia procedure consists of three approximately 10-minute exposure blocks according to the study protocol. Respiratory and physiological measures will be monitored throughout the intervention and recovery periods, and participants may pause or discontinue procedures at any time.

Noninvasive vagus nerve stimulation will be delivered with the gammaCore device. In the active condition, stimulation will be applied to the cervical vagus nerve at a participant-tolerated intensity. In the sham condition, participants will undergo an otherwise similar procedure using a sham device that does not deliver the active electrical stimulation.

Physiological measurements may include transcutaneous or end-tidal carbon dioxide, oxygen saturation, respiratory timing and ventilation, heart rate, heart rate variability-related measures, blood pressure, electroencephalography, photoplethysmography, impedance-based physiological measures, and movement. The Applied Cognition GF Monitor will be used during in-clinic and at-home monitoring to collect multimodal physiological signals, including electrical impedance spectroscopy measurements used to estimate changes in brain parenchymal resistance. Overnight monitoring will also be performed after the first intervention visit to explore whether intervention-associated physiological changes persist into subsequent sleep.

Serial blood samples will be collected around the intervention procedures for exploratory measurement of plasma biomarkers associated with neurodegenerative, neuroinflammatory, and glymphatic-related physiological processes. Planned exploratory biomarkers include alpha-synuclein, neurofilament light chain, glial fibrillary acidic protein, amyloid-beta 1-42, amyloid-beta 1-40, and phosphorylated tau 217.

The primary emphasis of the study is feasibility, safety, tolerability, participant adherence, and successful physiological signal acquisition. Exploratory analyses will compare physiological responses during active nVNS plus intermittent hypercapnia with responses during sham nVNS plus intermittent hypercapnia. Additional exploratory analyses will examine relationships among in-clinic physiological responses, overnight monitoring measures, blood-based biomarker changes, and participant group. The results are intended to provide preliminary effect-size and variance estimates, identify practical and physiological response patterns, and inform the design and parameter selection of future hypothesis-driven trials.

This study is non-therapeutic and exploratory. It is not designed to establish clinical benefit or to diagnose, treat, or prevent Parkinson's disease or another medical condition.