Parkinson Disease (PD)
Conditions
Keywords
Intermittent hypercapnia, Noninvasive vagus nerve stimulation, Glymphatic clearance, Glymphatic system, Brain parenchymal resistance, Electrical impedance spectroscopy, Cerebrovascular physiology, Autonomic regulation
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.
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.
Interventions
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.
DEVICESham noninvasive vagus nerve stimulation
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.
PROCEDUREActive intermittent hypercapnia
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.
PROCEDURESham intermittent hypercapnia
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.
BEHAVIORALGuided breathing
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.
Sponsors
Florida Institute for Human and Machine Cognition
Applied Cognition
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
Participants are masked to active versus sham nVNS condition using visually similar active and sham devices. Study personnel administering interventions are not masked.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
60 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
Parkinson's Disease Group Adults aged 60-80 years at the time of enrollment. Clinical diagnosis of early-stage Parkinson's disease and not currently receiving levodopa or other dopaminergic medication. Hoehn and Yahr stage I. English-speaking and able to provide informed consent and complete study procedures and questionnaires administered in English. Cognitively able to participate in study procedures, as determined by investigator assessment and/or optional cognitive screening measures, when administered. Willing and able to comply with all study visits and procedures. Able to tolerate wearing the Applied Cognition GF Monitor, physiological monitoring equipment, face mask, and noninvasive vagus nerve stimulation (nVNS) device for the duration of study procedures. Age-Matched Healthy Control Group Adults aged 60-80 years at the time of enrollment. No known diagnosis of Parkinson's disease or other major neurodegenerative disorder. English-speaking and able to provide informed consent and complete study procedures and questionnaires administered in English. Cognitively able to participate in study procedures, as determined by investigator assessment and/or optional cognitive screening measures, when administered. Willing and able to comply with all study visits and procedures. Able to tolerate wearing the Applied Cognition GF Monitor, physiological monitoring equipment, face mask, and noninvasive vagus nerve stimulation (nVNS) device for the duration of study procedures.
Exclusion criteria
Diagnosis of moderate-to-severe neurocognitive impairment or dementia. Significant pulmonary disease, including chronic obstructive pulmonary disease (COPD), severe asthma requiring daily rescue therapy, restrictive lung disease, or resting oxygen saturation \<92%. Untreated or poorly controlled hypertension, defined as systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg at screening. Symptomatic hypotension, orthostatic hypotension associated with syncope, or clinically significant autonomic dysfunction. Peripheral vascular disease, significant upper-extremity injury, or other conditions that may interfere with peripheral perfusion or physiological monitoring measurements. Uncontrolled diabetes mellitus or diabetes-associated complications that may significantly affect autonomic or vascular physiology. History of significant cardiac disease, including clinically significant arrhythmia, congestive heart failure, unstable angina, myocardial infarction within the prior 12 months, or other conditions judged unsafe for intermittent hypercapnia exposure. Active implanted electrical or neurostimulation devices, including cardiac pacemakers, implantable cardioverter-defibrillators (ICDs), deep brain stimulators, cochlear implants, or implanted vagus nerve stimulators. Active carotid artery disease, carotid bruits, history of carotid endarterectomy, or other clinically significant cervical vascular abnormalities that may increase risk during cervical nVNS application. History of moderate or severe traumatic brain injury, defined as loss of consciousness \>30 minutes or post-traumatic amnesia \>24 hours. Active psychiatric condition requiring hospitalization within the prior 12 months. Current use of medications known to substantially alter cerebrovascular reactivity or carbon dioxide sensitivity, such as acetazolamide or other carbonic anhydrase inhibitors. Claustrophobia or inability to tolerate mask-based breathing procedures. Pregnancy, suspected pregnancy, or lactation in participants of childbearing potential. Body mass index (BMI) \>40 kg/m² due to potential effects on respiratory physiology, mask fit, and CO₂ tolerance. Known allergy or sensitivity to latex, adhesives, electrode gels, medical tapes, or study device materials that may interfere with safe participation. Current acute respiratory infection or other acute illness at the time of study participation. Any other medical, neurological, psychiatric, or safety-related condition that, in the opinion of the Principal Investigator, would compromise participant safety, interfere with study procedures, or affect data integrity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Completing the Multimodal Study Protocol | 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 | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| 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 | 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. |
| Change in Carbon Dioxide Levels During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | 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. |
| Change in Peripheral Oxygen Saturation During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | Peripheral oxygen saturation (SpO2) will be monitored during baseline, intervention, and recovery periods to characterize respiratory responses and support participant safety monitoring. |
| Change in Respiratory Rate During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | Respiratory rate will be measured during baseline, guided breathing, intermittent hypercapnia, and recovery periods to characterize intervention-associated respiratory responses. |
| Change in Tidal Volume During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | Tidal volume will be measured when available using respiratory monitoring equipment during baseline, intervention, and recovery periods. |
| Change in Minute Ventilation During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | Minute ventilation will be measured when available during baseline, guided breathing, intermittent hypercapnia, and recovery periods to characterize intervention-associated respiratory responses. |
| Change in Heart Rate During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | 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. |
| Change in Heart Rate Variability During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | 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. |
| Change in Blood Pressure During Intervention | During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours | Systolic and diastolic blood pressure will be assessed at predefined timepoints during study procedures to characterize cardiovascular responses and support participant safety monitoring. |
| Change in Plasma Neurodegenerative and Glymphatic-Associated Biomarkers | Approximately t=0, t=45 minutes, and t=60 minutes relative to the intervention period during each intervention visit | 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. |
Contacts
CONTACTMelissa Do, PhD
CONTACTToshiya Miyatsu, PhD
PRINCIPAL_INVESTIGATORToshiya Miyatsu, PhD
Florida Institute for Human & Machine Cognition
Outcome results
None listed