Synthetic Vasomotion for Glymphatic Enhancement

This pilot study will evaluate the feasibility, safety, tolerability, and exploratoryphysiological effects of a multimodal intervention designed to influence autonomic,cerebrovascular, respiratory, and glymphatic‐associated physiology. The study combinesguided breathing, intermittent hypercapnia, and noninvasive vagus nerve stimulation(nVNS) with continuous or repeated physiological monitoring and exploratory blood‐basedbiomarker assessment.The glymphatic system is a brain‐wide pathway involved in the exchange of cerebrospinalfluid and interstitial fluid and in the movement of metabolic waste products from braintissue. Glymphatic‐associated fluid transport is influenced by sleep, cerebrovascularpulsatility, vasomotion, respiratory physiology, and autonomic regulation. Parkinson'sdisease is associated with abnormalities in several of these systems, including autonomicfunction, sleep, and brainstem noradrenergic signaling. This study therefore examineswhether controlled manipulation of respiratory and autonomic physiology producesmeasurable changes in physiological signals hypothesized to be relevant toglymphatic‐associated fluid dynamics.The study will enroll up to 20 adults, including approximately 10 participants withearly‐stage Parkinson's disease and 10 age‐matched healthy control participants. Thetarget 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 poweredto establish clinical efficacy.Participants will complete a week‐long protocol. Following screening and informedconsent, participants will complete an intake and baseline visit that may include healthand demographic questionnaires, vital signs, baseline physiological measurements, guidedbreathing, and training on the Applied Cognition GF Monitor. Participants will thencomplete overnight at‐home monitoring on two baseline nights.Participants will subsequently complete two in‐clinic intervention visits separated byapproximately 48 hours. The order of active and sham nVNS will be randomized, and eachparticipant will receive both conditions in a within‐participant crossover design. Duringboth intervention visits, nVNS or sham stimulation will be paired with guided breathingand intermittent hypercapnia. For intermittent hypercapnia, participants will breathethrough a noninvasive mask connected to a controlled breathing circuit that alternatesroom air with a gas mixture containing approximately 5% carbon dioxide, 21% oxygen, andbalance nitrogen. The hypercapnia procedure consists of three approximately 10‐minuteexposure blocks according to the study protocol. Respiratory and physiological measureswill be monitored throughout the intervention and recovery periods, and participants maypause or discontinue procedures at any time.Noninvasive vagus nerve stimulation will be delivered with the gammaCore device. In theactive condition, stimulation will be applied to the cervical vagus nerve at aparticipant‐tolerated intensity. In the sham condition, participants will undergo anotherwise similar procedure using a sham device that does not deliver the activeelectrical stimulation.Physiological measurements may include transcutaneous or end‐tidal carbon dioxide, oxygensaturation, respiratory timing and ventilation, heart rate, heart ratevariability‐related measures, blood pressure, electroencephalography,photoplethysmography, impedance‐based physiological measures, and movement. The AppliedCognition GF Monitor will be used during in‐clinic and at‐home monitoring to collectmultimodal physiological signals, including electrical impedance spectroscopymeasurements used to estimate changes in brain parenchymal resistance. Overnightmonitoring will also be performed after the first intervention visit to explore whetherintervention‐associated physiological changes persist into subsequent sleep.Serial blood samples will be collected around the intervention procedures for exploratorymeasurement of plasma biomarkers associated with neurodegenerative, neuroinflammatory,and glymphatic‐related physiological processes. Planned exploratory biomarkers includealpha‐synuclein, neurofilament light chain, glial fibrillary acidic protein, amyloid‐beta1‐42, amyloid‐beta 1‐40, and phosphorylated tau 217.The primary emphasis of the study is feasibility, safety, tolerability, participantadherence, and successful physiological signal acquisition. Exploratory analyses willcompare physiological responses during active nVNS plus intermittent hypercapnia withresponses during sham nVNS plus intermittent hypercapnia. Additional exploratory analyseswill examine relationships among in‐clinic physiological responses, overnight monitoringmeasures, blood‐based biomarker changes, and participant group. The results are intendedto provide preliminary effect‐size and variance estimates, identify practical andphysiological response patterns, and inform the design and parameter selection of futurehypothesis‐driven trials.This study is non‐therapeutic and exploratory. It is not designed to establish clinicalbenefit or to diagnose, treat, or prevent Parkinson's disease or another medicalcondition.