An interventional study of Active noninvasive vagus nerve stimulation and Sham noninvasive vagus nerve stimulation in Parkinson Disease (PD), sponsored by Florida Institute for Human and Machine Cognition. Not yet recruiting. Open to participants aged 60 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-09-11.
Sponsored by Florida Institute for Human and Machine Cognition · Not applicable, Interventional, and Basic science
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:
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:
This is an exploratory pilot study. It is not intended to diagnose, treat, or prevent Parkinson's disease or any other medical condition.
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.
4,576 studies on the registry are indexed under Parkinson Disease; 1,087 are open to participants now.
This study's planned enrollment of 20 is below the median of 40 across 3,355 interventional studies indexed under Parkinson Disease.
Browse Parkinson Disease studies →Florida Institute for Human and Machine Cognition is the lead sponsor of 9 studies on the registry; 6 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
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 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 (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 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 .
(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.
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
COPD
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
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
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
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
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
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.
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.
Time frame: 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.
Time frame: 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.
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
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.
Time frame: From baseline through completion of scheduled intervention, recovery, and overnight monitoring periods, up to 1 week
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.
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
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.
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
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.
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
Peripheral oxygen saturation (SpO2) will be monitored during baseline, intervention, and recovery periods to characterize respiratory responses and support participant safety monitoring.
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
Respiratory rate will be measured during baseline, guided breathing, intermittent hypercapnia, and recovery periods to characterize intervention-associated respiratory responses.
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
Tidal volume will be measured when available using respiratory monitoring equipment during baseline, intervention, and recovery periods.
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
Minute ventilation will be measured when available during baseline, guided breathing, intermittent hypercapnia, and recovery periods to characterize intervention-associated respiratory responses.
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
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.
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
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.
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
Systolic and diastolic blood pressure will be assessed at predefined timepoints during study procedures to characterize cardiovascular responses and support participant safety monitoring.
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
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.
Time frame: Approximately t=0, t=45 minutes, and t=60 minutes relative to the intervention period during each intervention visit
Consensus Sleep Diary Total Sleep Time
Total sleep time will be derived from the Consensus Sleep Diary based on participant-reported sleep and wake times for the previous night.
Time frame: Each morning following scheduled study nights, up to 1 week
Consensus Sleep Diary Sleep Onset Latency
Sleep onset latency will be derived from the Consensus Sleep Diary as the participant-reported time from attempting to fall asleep to sleep onset.
Time frame: Each morning following scheduled study nights, up to 1 week
Consensus Sleep Diary Wake After Sleep Onset
Wake after sleep onset will be derived from the Consensus Sleep Diary based on participant-reported nighttime awakenings after initial sleep onset.
Time frame: Each morning following scheduled study nights, up to 1 week
Consensus Sleep Diary Sleep Efficiency
Sleep efficiency will be derived from the Consensus Sleep Diary as the percentage of time in bed spent asleep.
Time frame: Each morning following scheduled study nights, up to 1 week
Groningen Sleep Quality Scale Score
Subjective sleep quality will be assessed using the Groningen Sleep Quality Scale (GSQS). Higher scores indicate poorer perceived sleep quality.
Time frame: Following scheduled overnight study periods during the approximately 1-week protocol
Karolinska Sleepiness Scale Score
Momentary subjective sleepiness will be assessed using the Karolinska Sleepiness Scale, ranging from 1 (extremely alert) to 9 (very sleepy, fighting sleep).
Time frame: At predefined study assessment timepoints during the approximately 1-week protocol
System Usability Scale Score
Usability of study devices and procedures will be assessed using the 10-item System Usability Scale (SUS), which provides an overall measure of perceived system usability.
Time frame: At completion of study device use, within the approximately 1-week protocol
Participant-Reported Applied Cognition Device Tolerability
Participants will report discomfort, irritation, technical difficulties, and other issues associated with use of the Applied Cognition GF Monitor and other study devices.
Time frame: During device use and at completion of scheduled monitoring periods, within approximately 1 week
Composite Autonomic Symptom Score-31
Autonomic symptom burden may be characterized using the Composite Autonomic Symptom Score-31 (COMPASS-31), including orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor domains.
Time frame: During the study intake/baseline assessment
Subjective Overnight Sleep Parameters
Consensus Sleep Diary measures may include total sleep time, sleep onset latency, wake after sleep onset, number and duration of awakenings, sleep efficiency, and perceived sleep quality.
Time frame: Each morning following scheduled study nights during the approximately 1-week protocol
No study locations are listed for this record.
Plan to share: 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.
Supporting information: 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.
Start is estimated for Sep 2026; primary completion for Nov 2026, 2 months later.
Of 1,293 non-industry interventional studies with no phase under Parkinson Disease, half reached primary completion within 24 months of starting (the median), counting those still running; a quarter within 11 and three quarters within 44. This study's planned 2 months is below that.
Counting every sponsor, half of 1,369 studies reached it within 25 months; a quarter within 12 and three quarters within 44.
How these figures are worked out, and which studies are left out of them.
This study is not yet recruiting, as verified in Sep 2026. You cannot join it, but the record below documents what was studied.
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Florida Institute for Human and Machine Cognition