Synthetic Vasomotion for Glymphatic Enhancement

NCT07814534 | Not Yet Recruiting FDA Device

• 1 other identifier: IRB-2026-0021
• Study Type: interventional
• Target: 20
• Locations: 0 countries
• Sites: N/A

Brief 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 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.

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

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  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

  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

  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

  During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours

• Change in Peripheral Oxygen Saturation During Intervention

  During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours

• Change in Respiratory Rate During Intervention

  During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours

Other Outcomes (10)

• Consensus Sleep Diary Total Sleep Time

  Each morning following scheduled study nights, up to 1 week

• Consensus Sleep Diary Sleep Onset Latency

  Each morning following scheduled study nights, up to 1 week

• Consensus Sleep Diary Wake After Sleep Onset

  Each morning following scheduled study nights, up to 1 week

Study Arms (2)

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.

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.

Device: Active noninvasive vagus nerve stimulation; Device: Sham noninvasive vagus nerve stimulation; Procedure: Active intermittent hypercapnia; Procedure: Sham intermittent hypercapnia; Behavioral: Guided breathing

Interventions

Active noninvasive vagus nerve stimulation DEVICE

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.

Also known as: gammaCore

Sequence A: Sham nVNS First; Sequence B: Active nVNS First

Sham noninvasive vagus nerve stimulation DEVICE

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.

Also known as: sham gammacore

Sequence A: Sham nVNS First; Sequence B: Active nVNS First

Guided breathing BEHAVIORAL

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.

Sequence A: Sham nVNS First; Sequence B: Active nVNS First

Active intermittent hypercapnia PROCEDURE

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.

Also known as: 5% carbon dioxide exposure

Sequence A: Sham nVNS First; Sequence B: Active nVNS First

Sham intermittent hypercapnia PROCEDURE

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.

Also known as: Room air exposure

Sequence A: Sham nVNS First; Sequence B: Active nVNS First

Eligibility Criteria

• Age: 60 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Applied Cognition: collaborator
• Florida Institute for Human and Machine Cognition: lead

Related Publications (8)

• 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.

  PMID: 22896675 BACKGROUND

• van 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.

  PMID: 31810839 BACKGROUND

• Fultz 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.

  PMID: 31672896 BACKGROUND

• Clancy 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.

  PMID: 25164906 BACKGROUND

• Ryman 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.

  PMID: 38817039 BACKGROUND

• Hauglund 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.

  PMID: 39788123 BACKGROUND

• Dagum 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.

  PMID: 40425804 BACKGROUND

• Erhardt 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.

  PMID: 41271795 BACKGROUND

MeSH Terms

Conditions

Parkinson Disease

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• Toshiya Miyatsu, PhD

  Florida Institute for Human & Machine Cognition

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Melissa Do, PhD

CONTACT

850-202-4462; mdo@ihmc.org

Toshiya Miyatsu, PhD

CONTACT

850-202-4462; tmiyatsu@ihmc.org

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants are masked to active versus sham nVNS condition using visually similar active and sham devices. Study personnel administering interventions are not masked.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 28, 2026
• First Posted: September 11, 2026
• Study Start: September 1, 2026
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: September 11, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: During study conduct and analysis, and following completion of data collection as needed for study-related analyses.
• Access Criteria: Access will be limited to authorized study collaborators for analyses consistent with the study objectives and subject to applicable institutional, IRB, confidentiality, and data-use requirements. Shared participant-level data will be de-identified.