Parkinson Disease (PD)NCT07814534
Synthetic Vasomotion for Glymphatic Enhancement
A study testing Active noninvasive vagus nerve stimulation, Active intermittent hypercapnia and Guided breathing in people with Parkinson Disease (PD), run by Florida Institute for Human and Machine Cognition.
Trial summary
The goal of this pilot clinical trial is to learn whether a week-long study combining controlled breathing procedures, intermittent exposure to a low-concentration carbon dioxide gas mixture, and noninvasive vagus nerve stimulation can be carried out safely and comfortably in adults with early-stage Parkinson's… Read more about this study
- Who is it for?
- Ages 60 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Parkinson Disease (PD)
- What is being tested?
- Active noninvasive vagus nerve stimulation, Active intermittent hypercapnia and Guided breathing
- Type of treatment
- Medical device, Surgery or procedure, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- No sites listed yet
- Study dates
- Sep 2026to Nov 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Show all 10Show fewer
- 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.
Who cannot join
- 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.
Show all 16Show fewer
- 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.
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
Official title: Synthetic Vasomotion for Glymphatic Enhancement: A Pilot Study of Intermittent Hypercapniaand Noninvasive Vagus Nerve Stimulation With Continuous Parenchymal Resistance Monitoring inParkinson's Disease and Healthy Older Adults
The goal of this pilot clinical trial is to learn whether a week-long study combining controlled breathing procedures, intermittent exposure to a low-concentration carbon dioxide gas mixture, and noninvasive vagus nerve stimulation can be carried out safely and comfortably in adults with early-stage Parkinson's disease and age-matched healthy adults. The study will also explore how these procedures affect physiological signals related to breathing, cardiovascular and autonomic function, brain activity, and physiological processes thought to be related to fluid movement in and around the brain.
The main questions the study aims to answer are:
Read more
- Can participants safely and comfortably complete the study procedures and at-home monitoring?
- Do physiological responses differ when intermittent hypercapnia is paired with active noninvasive vagus nerve stimulation compared with sham stimulation?
- Are changes measured during the intervention visits related to overnight physiological measurements and changes in blood-based biomarkers?
Researchers will compare active and sham noninvasive vagus nerve stimulation within the same participants. Both conditions will be paired with guided breathing and intermittent hypercapnia, in which participants briefly breathe a controlled gas mixture containing 5% carbon dioxide.
Participants will:
- Complete an intake and baseline visit and several nights of at-home physiological monitoring.
- Complete two intervention visits in randomized order, one using active vagus nerve stimulation and one using sham stimulation.
- Complete guided breathing and intermittent hypercapnia procedures while respiratory, cardiovascular, and other physiological signals are monitored.
- Provide blood samples before and after intervention procedures for exploratory biomarker measurements.
This is an exploratory pilot study. It is not intended to diagnose, treat, or prevent Parkinson's disease or any other medical condition.
Read the detailed description
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.
- Conditions
- Parkinson Disease (PD)
- Being tested
- Active noninvasive vagus nerve stimulation, Sham noninvasive vagus nerve stimulation, Active intermittent hypercapnia, Sham intermittent hypercapnia, Guided breathing
- Keywords
- Intermittent hypercapnia, Noninvasive vagus nerve stimulation, Glymphatic clearance, Glymphatic system, Brain parenchymal resistance, Electrical impedance spectroscopy, Cerebrovascular physiology, Autonomic regulation
- Medical subject headings
- Parkinson Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Active noninvasive vagus nerve stimulationDevice
Also called gammaCore
Active cervical noninvasive vagus nerve stimulation (nVNS) will be delivered using the gammaCore device. Participants will receive two consecutive 2-minute stimulation applications, one on each side of the neck. Stimulation intensity will be adjusted by the participant to a perceptible but comfortable level. The device delivers 1-ms pulses of 5-kHz sine waves at 25 Hz.
Sham noninvasive vagus nerve stimulationDevice
Also called sham gammacore
Participants will undergo the same application procedure and duration as active nVNS using a sham device. The sham device is similar in appearance to the active device and produces vibration and audible feedback but does not deliver active electrical stimulation.
Active intermittent hypercapniaProcedure or surgery
Also called 5% carbon dioxide exposure
Participants will intermittently breathe a controlled hypercapnic gas mixture containing approximately 5% carbon dioxide, 21% oxygen, and balance nitrogen through a noninvasive mask. The intervention consists of three approximately 10-minute hypercapnia blocks according to the study protocol, with respiratory and physiological monitoring throughout.
Sham intermittent hypercapniaProcedure or surgery
Also called Room air exposure
Participants will undergo the same mask-based breathing procedures used for the intermittent hypercapnia condition but will breathe room air rather than the hypercapnic gas mixture. This condition serves as the baseline/sham hypercapnia condition.
Guided breathingBehavioural
Participants will complete approximately 10 minutes of guided breathing during study visits. Breathing will be standardized using verbal instruction from study personnel and/or visual or auditory pacing cues, which may include commercially available applications such as Elite HRV or study-specific pacing aids. The guided breathing procedure is intended to standardize breathing timing and pacing during physiological monitoring and intervention procedures and is not used for diagnosis, treatment, or medical decision-making.
| Study group | Role | What they receive |
|---|---|---|
| Sequence A: Sham nVNS First | Experimental | Participants complete the common baseline condition with sham nVNS and sham intermittent hypercapnia, followed by sham nVNS + active intermittent hypercapnia and then active nVNS + active intermittent hypercapnia. Receives: Device: Active noninvasive vagus nerve stimulation; Device: Sham noninvasive vagus nerve stimulation; Procedure: Active intermittent hypercapnia; Procedure: Sham intermittent hypercapnia; Behavioral: Guided breathing |
| Sequence B: Active nVNS First | Experimental | Participants complete the common baseline condition with sham nVNS and sham intermittent hypercapnia, followed by active nVNS + active intermittent hypercapnia and then sham nVNS + active intermittent hypercapnia. Receives: Device: Active noninvasive vagus nerve stimulation; Device: Sham noninvasive vagus nerve stimulation; Procedure: Active intermittent hypercapnia; Procedure: Sham intermittent hypercapnia; Behavioral: Guided breathing |
What is being measured
The primary outcome is the main question the study is designed to answer.
Feasibility of Completing the Multimodal Study Protocol
Feasibility will be assessed as the number and proportion of enrolled participants who complete the planned in-clinic visits, intervention procedures, and scheduled at-home Applied Cognition GF Monitor recordings. Reasons for incomplete procedures or study withdrawal will also be documented.
Measured: From enrollment through completion of the approximately 1-week study protocol
Incidence of Study-Related Adverse Events
Safety will be assessed by the number and proportion of participants experiencing adverse events during or following study procedures. Adverse events will be documented with respect to type, severity, timing, and relationship to intermittent hypercapnia, guided breathing, nVNS, physiological monitoring, or blood collection.
Measured: From initiation of study procedures through completion of the approximately 1-week protocol
Change in Participant-Reported Tolerability During Intervention Procedures
Participants will rate dizziness, stress/anxiety, and overall discomfort on 1-to-10 numeric rating scales before and after each 10-minute intermittent hypercapnia block and following completion of the overall hypercapnia protocol. Additional symptoms and tolerability concerns will also be recorded.
Measured: During intervention visits on Days 3 and 5, before and after each 10-minute hypercapnia block and immediately after the overall hypercapnia protocol, up to 1 week
Proportion of Planned Physiological Recordings With Usable Data
The proportion of planned physiological recording sessions that yield usable data will be assessed across the Applied Cognition GF Monitor and respiratory, cardiovascular, and autonomic monitoring systems. Device failures, incomplete recordings, and technical problems resulting in unavailable or unusable data will be documented.
Measured: From baseline through completion of scheduled intervention, recovery, and overnight monitoring periods, up to 1 week
Secondary outcomes (11)
Change in EIS-Derived Brain Parenchymal Resistance During Intervention
Electrical impedance spectroscopy (EIS) obtained with the Applied Cognition GF Monitor will be used to quantify changes in brain parenchymal resistance across baseline, intervention, and recovery periods. Within-participant responses will be compared across the study intervention conditions.
Measured: During each intervention visit, from pre-intervention baseline through the post-intervention recovery period, approximately 1.5-2 hours
Change in Overnight EIS-Derived Brain Parenchymal Resistance Following Intervention
Overnight EIS-derived brain parenchymal resistance measured following the first intervention visit will be compared with measurements obtained during the baseline overnight monitoring nights to explore intervention-associated changes in overnight physiology.
Measured: Baseline Nights 1 and 2 compared with the overnight recording following the first intervention visit, within approximately 3 days
Change in Carbon Dioxide Levels During Intervention
Transcutaneous carbon dioxide and/or end-tidal carbon dioxide will be measured continuously or repeatedly during baseline, intermittent hypercapnia, and recovery to characterize the physiological response to controlled carbon dioxide exposure.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Peripheral Oxygen Saturation During Intervention
Peripheral oxygen saturation (SpO2) will be monitored during baseline, intervention, and recovery periods to characterize respiratory responses and support participant safety monitoring.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Respiratory Rate During Intervention
Respiratory rate will be measured during baseline, guided breathing, intermittent hypercapnia, and recovery periods to characterize intervention-associated respiratory responses.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Tidal Volume During Intervention
Tidal volume will be measured when available using respiratory monitoring equipment during baseline, intervention, and recovery periods.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Minute Ventilation During Intervention
Minute ventilation will be measured when available during baseline, guided breathing, intermittent hypercapnia, and recovery periods to characterize intervention-associated respiratory responses.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Heart Rate During Intervention
Heart rate will be measured continuously or repeatedly during baseline, guided breathing, nVNS, intermittent hypercapnia, and recovery periods to characterize intervention-associated cardiovascular and autonomic responses.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Heart Rate Variability During Intervention
Heart rate variability-related measures derived from ECG or heart-rate monitoring will be evaluated across baseline, guided breathing, nVNS, intermittent hypercapnia, and recovery periods to characterize autonomic responses.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Blood Pressure During Intervention
Systolic and diastolic blood pressure will be assessed at predefined timepoints during study procedures to characterize cardiovascular responses and support participant safety monitoring.
Measured: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Plasma Neurodegenerative and Glymphatic-Associated Biomarkers
Serial blood samples will be analyzed for plasma alpha-synuclein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta 1-42 (Aβ1-42), amyloid-beta 1-40 (Aβ1-40), and phosphorylated tau 217 (pTau217). Changes in biomarker concentrations across sampling timepoints will be evaluated within participants and across intervention conditions.
Measured: Approximately t=0, t=45 minutes, and t=60 minutes relative to the intervention period during each intervention visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Sep 2026
- Study startSep 2026 (estimated)
- Primary completionNov 2026 (estimated)
- Study completionNov 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Parkinson Disease (PD)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Participants will complete a within-participant design comprising three experimental conditions: (1) a baseline condition with sham noninvasive vagus nerve stimulation (nVNS) and sham intermittent hypercapnia, followed by two randomized crossover intervention conditions: (2) sham nVNS + active intermittent hypercapnia and (3) active nVNS + active intermittent hypercapnia. The order of the two active-hypercapnia intervention conditions will be randomized. Participants include adults with early-stage Parkinson's disease and age-matched healthy controls.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Florida Institute for Human and Machine Cognition
- Sponsor type
- University, hospital or other
- Collaborators
- Applied Cognition
- Responsible party
- Sponsor
- Investigators
- Toshiya Miyatsu, PhD, Principal investigator, Florida Institute for Human & Machine Cognition
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07814534
- Sponsor's protocol ID
- IRB-2026-0021
- Status last verified
- Sep 2026
- First submitted
- 28 Aug 2026
- Last updated
- 11 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- Yes: De-identified individual participant data may be shared with study collaborators, including Applied Cognition, Inc., for device-related processing, feature extraction, and analyses related to the study objectives. Applied Cognition will receive physiological data generated by the GF Monitor for processing of electrical impedance spectroscopy (EIS) and related measures. Additional de-identified physiological, demographic, clinical, or intervention-related data may be shared when necessary to support prespecified or collaborative analyses. Direct participant identifiers will not be shared.
Publications
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012 Aug 15;4(147):147ra111. doi: 10.1126/scitranslmed.3003748.
PubMed 22896675van Veluw SJ, Hou SS, Calvo-Rodriguez M, Arbel-Ornath M, Snyder AC, Frosch MP, Greenberg SM, Bacskai BJ. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain. Neuron. 2020 Feb 5;105(3):549-561.e5. doi: 10.1016/j.neuron.2019.10.033. Epub 2019 Dec 3.
PubMed 31810839Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019 Nov 1;366(6465):628-631. doi: 10.1126/science.aax5440.
PubMed 31672896Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014 Nov-Dec;7(6):871-7. doi: 10.1016/j.brs.2014.07.031. Epub 2014 Jul 16.
PubMed 25164906Ryman SG, Vakhtin AA, Mayer AR, van der Horn HJ, Shaff NA, Nitschke SR, Julio KR, Tarawneh RM, Rosenberg GA, Diaz SV, Pirio Richardson SE, Lin HC. Abnormal Cerebrovascular Activity, Perfusion, and Glymphatic Clearance in Lewy Body Diseases. Mov Disord. 2024 Aug;39(8):1258-1268. doi: 10.1002/mds.29867. Epub 2024 May 30.
PubMed 38817039Hauglund NL, Andersen M, Tokarska K, Radovanovic T, Kjaerby C, Sorensen FL, Bojarowska Z, Untiet V, Ballestero SB, Kolmos MG, Weikop P, Hirase H, Nedergaard M. Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep. Cell. 2025 Feb 6;188(3):606-622.e17. doi: 10.1016/j.cell.2024.11.027. Epub 2025 Jan 8.
PubMed 39788123Dagum P, Giovangrandi L, Levendovszky SR, Winebaum JJ, Singh T, Cho Y, Kaplan RM, Jaffee MS, Lim MM, Vandeweerd C, Iliff JJ. A wireless device for continuous measurement of brain parenchymal resistance tracks glymphatic function in humans. Nat Biomed Eng. 2025 Oct;9(10):1656-1676. doi: 10.1038/s41551-025-01394-9. Epub 2025 May 27.
PubMed 40425804Erhardt EB, Mayer AR, Lin HC, Pirio Richardson SE, Shaff NA, Vakhtin AA, Caprihan A, van der Horn HJ, Hoffman N, Phillips JP, Grigg-Damberger M, Wang CH, Gough J, Hobson S, Deligtisch A, Suarez Cedeno G, Sugar D, Ryman SG. The influence of intermittent hypercapnia on cerebrospinal fluid flow and clearance in Parkinson's disease and healthy older adults. NPJ Parkinsons Dis. 2025 Nov 21;11(1):334. doi: 10.1038/s41531-025-01179-6.
PubMed 41271795
Study at a glance
From the registry record, last updated by the sponsor on 11 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Synthetic Vasomotion for Glymphatic Enhancement: A Pilot Study of Intermittent Hypercapniaand Noninvasive Vagus Nerve Stimulation With Continuous Parenchymal Resistance Monitoring inParkinson's Disease and Healthy Older Adults
- ClinicalTrials.gov ID
- NCT07814534
- Acronym / sponsor ID
- IRB-2026-0021
- Conditions
- Parkinson Disease (PD)
- Keywords
- Intermittent hypercapnia, Noninvasive vagus nerve stimulation, Glymphatic clearance, Glymphatic system, Brain parenchymal resistance, Electrical impedance spectroscopy, Cerebrovascular physiology, Autonomic regulation
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Florida Institute for Human and Machine CognitionUniversity, hospital or other
- Collaborators
- Applied Cognition
- Study start
- Sep 2026 (estimated)
- Primary completion
- Nov 2026 (estimated)
- Study completion
- Nov 2026 (estimated)
- First posted
- 11 Sep 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this pilot clinical trial is to learn whether a week-long study combining controlled breathing procedures, intermittent exposure to a low-concentration carbon dioxide gas mixture, and noninvasive vagus nerve stimulation can be carried out safely and comfortably in adults with early-stage Parkinson's disease and age-matched healthy adults. The study will also explore how these procedures affect physiological signals related to breathing, cardiovascular and autonomic function, brain activity, and physiological processes thought to be related to fluid movement in and around the brain.
The main questions the study aims to answer are:
- Can participants safely and comfortably complete the study procedures and at-home monitoring?
- Do physiological responses differ when intermittent hypercapnia is paired with active noninvasive vagus nerve stimulation compared with sham stimulation?
- Are changes measured during the intervention visits related to overnight physiological measurements and changes in blood-based biomarkers?
Researchers will compare active and sham noninvasive vagus nerve stimulation within the same participants. Both conditions will be paired with guided breathing and intermittent hypercapnia, in which participants briefly breathe a controlled gas mixture containing 5% carbon dioxide.
Participants will:
- Complete an intake and baseline visit and several nights of at-home physiological monitoring.
- Complete two intervention visits in randomized order, one using active vagus nerve stimulation and one using sham stimulation.
- Complete guided breathing and intermittent hypercapnia procedures while respiratory, cardiovascular, and other physiological signals are monitored.
- Provide blood samples before and after intervention procedures for exploratory biomarker measurements.
This is an exploratory pilot study. It is not intended to diagnose, treat, or prevent Parkinson's disease or any other medical condition.
Detailed description
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Participants will complete a within-participant design comprising three experimental conditions: (1) a baseline condition with sham noninvasive vagus nerve stimulation (nVNS) and sham intermittent hypercapnia, followed by two randomized crossover intervention conditions: (2) sham nVNS + active intermittent hypercapnia and (3) active nVNS + active intermittent hypercapnia. The order of the two active-hypercapnia intervention conditions will be randomized. Participants include adults with early-stage Parkinson's disease and age-matched healthy controls.
| Arm | Type | Receives |
|---|---|---|
| Sequence A: Sham nVNS First | Experimental | Device: Active noninvasive vagus nerve stimulation, Device: Sham noninvasive vagus nerve stimulation, Procedure: Active intermittent hypercapnia, Procedure: Sham intermittent hypercapnia, Behavioral: Guided breathingParticipants complete the common baseline condition with sham nVNS and sham intermittent hypercapnia, followed by sham nVNS + active intermittent hypercapnia and then active nVNS + active intermittent hypercapnia. |
| Sequence B: Active nVNS First | Experimental | Device: Active noninvasive vagus nerve stimulation, Device: Sham noninvasive vagus nerve stimulation, Procedure: Active intermittent hypercapnia, Procedure: Sham intermittent hypercapnia, Behavioral: Guided breathingParticipants complete the common baseline condition with sham nVNS and sham intermittent hypercapnia, followed by active nVNS + active intermittent hypercapnia and then sham nVNS + active intermittent hypercapnia. |
Who may qualify
- Ages
- 60 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Active noninvasive vagus nerve stimulationAlso: gammaCoreActive cervical noninvasive vagus nerve stimulation (nVNS) will be delivered using the gammaCore device. Participants will receive two consecutive 2-minute stimulation applications, one on each side of the neck. Stimulation intensity will be adjusted by the participant to a perceptible but comfortable level. The device delivers 1-ms pulses of 5-kHz sine waves at 25 Hz. | Device | Sequence A: Sham nVNS First, Sequence B: Active nVNS First |
| Sham noninvasive vagus nerve stimulationAlso: sham gammacoreParticipants will undergo the same application procedure and duration as active nVNS using a sham device. The sham device is similar in appearance to the active device and produces vibration and audible feedback but does not deliver active electrical stimulation. | Device | Sequence A: Sham nVNS First, Sequence B: Active nVNS First |
| Active intermittent hypercapniaAlso: 5% carbon dioxide exposureParticipants will intermittently breathe a controlled hypercapnic gas mixture containing approximately 5% carbon dioxide, 21% oxygen, and balance nitrogen through a noninvasive mask. The intervention consists of three approximately 10-minute hypercapnia blocks according to the study protocol, with respiratory and physiological monitoring throughout. | Procedure or surgery | Sequence A: Sham nVNS First, Sequence B: Active nVNS First |
| Sham intermittent hypercapniaAlso: Room air exposureParticipants will undergo the same mask-based breathing procedures used for the intermittent hypercapnia condition but will breathe room air rather than the hypercapnic gas mixture. This condition serves as the baseline/sham hypercapnia condition. | Procedure or surgery | Sequence A: Sham nVNS First, Sequence B: Active nVNS First |
| Guided breathingParticipants will complete approximately 10 minutes of guided breathing during study visits. Breathing will be standardized using verbal instruction from study personnel and/or visual or auditory pacing cues, which may include commercially available applications such as Elite HRV or study-specific pacing aids. The guided breathing procedure is intended to standardize breathing timing and pacing during physiological monitoring and intervention procedures and is not used for diagnosis, treatment, or medical decision-making. | Behavioural | Sequence A: Sham nVNS First, Sequence B: Active nVNS First |
Primary outcome
Feasibility of Completing the Multimodal Study Protocol
Time frame: From enrollment through completion of the approximately 1-week study protocol
Feasibility will be assessed as the number and proportion of enrolled participants who complete the planned in-clinic visits, intervention procedures, and scheduled at-home Applied Cognition GF Monitor recordings. Reasons for incomplete procedures or study withdrawal will also be documented.
Incidence of Study-Related Adverse Events
Time frame: From initiation of study procedures through completion of the approximately 1-week protocol
Safety will be assessed by the number and proportion of participants experiencing adverse events during or following study procedures. Adverse events will be documented with respect to type, severity, timing, and relationship to intermittent hypercapnia, guided breathing, nVNS, physiological monitoring, or blood collection.
Change in Participant-Reported Tolerability During Intervention Procedures
Time frame: During intervention visits on Days 3 and 5, before and after each 10-minute hypercapnia block and immediately after the overall hypercapnia protocol, up to 1 week
Participants will rate dizziness, stress/anxiety, and overall discomfort on 1-to-10 numeric rating scales before and after each 10-minute intermittent hypercapnia block and following completion of the overall hypercapnia protocol. Additional symptoms and tolerability concerns will also be recorded.
Proportion of Planned Physiological Recordings With Usable Data
Time frame: From baseline through completion of scheduled intervention, recovery, and overnight monitoring periods, up to 1 week
The proportion of planned physiological recording sessions that yield usable data will be assessed across the Applied Cognition GF Monitor and respiratory, cardiovascular, and autonomic monitoring systems. Device failures, incomplete recordings, and technical problems resulting in unavailable or unusable data will be documented.
11 secondary outcomes
Change in EIS-Derived Brain Parenchymal Resistance During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through the post-intervention recovery period, approximately 1.5-2 hours
Change in Overnight EIS-Derived Brain Parenchymal Resistance Following Intervention
Time frame: Baseline Nights 1 and 2 compared with the overnight recording following the first intervention visit, within approximately 3 days
Change in Carbon Dioxide Levels During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Peripheral Oxygen Saturation During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Respiratory Rate During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Tidal Volume During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Minute Ventilation During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Heart Rate During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Heart Rate Variability During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Blood Pressure During Intervention
Time frame: During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours
Change in Plasma Neurodegenerative and Glymphatic-Associated Biomarkers
Time frame: Approximately t=0, t=45 minutes, and t=60 minutes relative to the intervention period during each intervention visit
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Sep 2026.
- Background: PubMed 22896675Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012 Aug 15;4(147):147ra111. doi: 10.1126/scitranslmed.3003748.
- Background: PubMed 31810839van Veluw SJ, Hou SS, Calvo-Rodriguez M, Arbel-Ornath M, Snyder AC, Frosch MP, Greenberg SM, Bacskai BJ. Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain. Neuron. 2020 Feb 5;105(3):549-561.e5. doi: 10.1016/j.neuron.2019.10.033. Epub 2019 Dec 3.
- Background: PubMed 31672896Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019 Nov 1;366(6465):628-631. doi: 10.1126/science.aax5440.
- Background: PubMed 25164906Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014 Nov-Dec;7(6):871-7. doi: 10.1016/j.brs.2014.07.031. Epub 2014 Jul 16.
- Background: PubMed 38817039Ryman SG, Vakhtin AA, Mayer AR, van der Horn HJ, Shaff NA, Nitschke SR, Julio KR, Tarawneh RM, Rosenberg GA, Diaz SV, Pirio Richardson SE, Lin HC. Abnormal Cerebrovascular Activity, Perfusion, and Glymphatic Clearance in Lewy Body Diseases. Mov Disord. 2024 Aug;39(8):1258-1268. doi: 10.1002/mds.29867. Epub 2024 May 30.
- Background: PubMed 39788123Hauglund NL, Andersen M, Tokarska K, Radovanovic T, Kjaerby C, Sorensen FL, Bojarowska Z, Untiet V, Ballestero SB, Kolmos MG, Weikop P, Hirase H, Nedergaard M. Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep. Cell. 2025 Feb 6;188(3):606-622.e17. doi: 10.1016/j.cell.2024.11.027. Epub 2025 Jan 8.
- Background: PubMed 40425804Dagum P, Giovangrandi L, Levendovszky SR, Winebaum JJ, Singh T, Cho Y, Kaplan RM, Jaffee MS, Lim MM, Vandeweerd C, Iliff JJ. A wireless device for continuous measurement of brain parenchymal resistance tracks glymphatic function in humans. Nat Biomed Eng. 2025 Oct;9(10):1656-1676. doi: 10.1038/s41551-025-01394-9. Epub 2025 May 27.
- Background: PubMed 41271795Erhardt EB, Mayer AR, Lin HC, Pirio Richardson SE, Shaff NA, Vakhtin AA, Caprihan A, van der Horn HJ, Hoffman N, Phillips JP, Grigg-Damberger M, Wang CH, Gough J, Hobson S, Deligtisch A, Suarez Cedeno G, Sugar D, Ryman SG. The influence of intermittent hypercapnia on cerebrospinal fluid flow and clearance in Parkinson's disease and healthy older adults. NPJ Parkinsons Dis. 2025 Nov 21;11(1):334. doi: 10.1038/s41531-025-01179-6.
- Individual participant dataSharing planned: Yes. De-identified individual participant data may be shared with study collaborators, including Applied Cognition, Inc., for device-related processing, feature extraction, and analyses related to the study objectives. Applied Cognition will receive physiological data generated by the GF Monitor for processing of electrical impedance spectroscopy (EIS) and related measures. Additional de-identified physiological, demographic, clinical, or intervention-related data may be shared when necessary to support prespecified or collaborative analyses. Direct participant identifiers will not be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Toshiya Miyatsu, PhD principal investigator
Florida Institute for Human & Machine Cognition
Questions about this trial
What is this clinical trial studying?
A study testing Active noninvasive vagus nerve stimulation, Active intermittent hypercapnia and Guided breathing in people with Parkinson Disease (PD), run by Florida Institute for Human and Machine Cognition.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 11 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Melissa Do, PhD (850-202-4462, mdo@ihmc.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility of Completing the Multimodal Study Protocol (time frame: From enrollment through completion of the approximately 1-week study protocol). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07814534, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2026.