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.

Inclusion criteria

Parkinson's Disease Group

Adults aged 60-80 years at the time of enrollment. Clinical diagnosis of early-stage Parkinson's disease and not currently receiving levodopa or other dopaminergic medication.

Hoehn and Yahr stage I. English-speaking and able to provide informed consent and complete study procedures and questionnaires administered in English.

Cognitively able to participate in study procedures, as determined by investigator assessment and/or optional cognitive screening measures, when administered.

Willing and able to comply with all study visits and procedures. Able to tolerate wearing the Applied Cognition GF Monitor, physiological monitoring equipment, face mask, and noninvasive vagus nerve stimulation (nVNS) device for the duration of study procedures.

Age-Matched Healthy Control Group

Adults aged 60-80 years at the time of enrollment. No known diagnosis of Parkinson's disease or other major neurodegenerative disorder.

English-speaking and able to provide informed consent and complete study procedures and questionnaires administered in English.

Cognitively able to participate in study procedures, as determined by investigator assessment and/or optional cognitive screening measures, when administered.

Willing and able to comply with all study visits and procedures. Able to tolerate wearing the Applied Cognition GF Monitor, physiological monitoring equipment, face mask, and noninvasive vagus nerve stimulation (nVNS) device for the duration of study procedures.

Exclusion criteria

Diagnosis of moderate-to-severe neurocognitive impairment or dementia. Significant pulmonary disease, including chronic obstructive pulmonary disease (COPD), severe asthma requiring daily rescue therapy, restrictive lung disease, or resting oxygen saturation <92%.

Untreated or poorly controlled hypertension, defined as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening.

Symptomatic hypotension, orthostatic hypotension associated with syncope, or clinically significant autonomic dysfunction.

Peripheral vascular disease, significant upper-extremity injury, or other conditions that may interfere with peripheral perfusion or physiological monitoring measurements.

Uncontrolled diabetes mellitus or diabetes-associated complications that may significantly affect autonomic or vascular physiology.

History of significant cardiac disease, including clinically significant arrhythmia, congestive heart failure, unstable angina, myocardial infarction within the prior 12 months, or other conditions judged unsafe for intermittent hypercapnia exposure.

Active implanted electrical or neurostimulation devices, including cardiac pacemakers, implantable cardioverter-defibrillators (ICDs), deep brain stimulators, cochlear implants, or implanted vagus nerve stimulators.

Active carotid artery disease, carotid bruits, history of carotid endarterectomy, or other clinically significant cervical vascular abnormalities that may increase risk during cervical nVNS application.

History of moderate or severe traumatic brain injury, defined as loss of consciousness >30 minutes or post-traumatic amnesia >24 hours.

Active psychiatric condition requiring hospitalization within the prior 12 months.

Current use of medications known to substantially alter cerebrovascular reactivity or carbon dioxide sensitivity, such as acetazolamide or other carbonic anhydrase inhibitors.

Claustrophobia or inability to tolerate mask-based breathing procedures. Pregnancy, suspected pregnancy, or lactation in participants of childbearing potential.

Body mass index (BMI) >40 kg/m² due to potential effects on respiratory physiology, mask fit, and CO₂ tolerance.

Known allergy or sensitivity to latex, adhesives, electrode gels, medical tapes, or study device materials that may interfere with safe participation.

Current acute respiratory infection or other acute illness at the time of study participation.

Any other medical, neurological, psychiatric, or safety-related condition that, in the opinion of the Principal Investigator, would compromise participant safety, interfere with study procedures, or affect data integrity.