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
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 20
- 主要终点
- Feasibility of Completing the Multimodal Study Protocol
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
盲法说明
Participants are masked to active versus sham nVNS condition using visually similar active and sham devices. Study personnel administering interventions are not masked.
入排标准
- 年龄范围
- 60 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Sequence A: Sham nVNS First
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.
干预措施: Active noninvasive vagus nerve stimulation (Device)
Sequence A: Sham nVNS First
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.
干预措施: Sham noninvasive vagus nerve stimulation (Device)
Sequence A: Sham nVNS First
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.
干预措施: Active intermittent hypercapnia (Procedure)
Sequence A: Sham nVNS First
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.
干预措施: Sham intermittent hypercapnia (Procedure)
Sequence A: Sham nVNS First
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.
干预措施: Guided breathing (Behavioral)
Sequence B: Active nVNS First
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.
干预措施: Active noninvasive vagus nerve stimulation (Device)
Sequence B: Active nVNS First
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.
干预措施: Sham noninvasive vagus nerve stimulation (Device)
Sequence B: Active nVNS First
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.
干预措施: Active intermittent hypercapnia (Procedure)
Sequence B: Active nVNS First
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.
干预措施: Sham intermittent hypercapnia (Procedure)
Sequence B: Active nVNS First
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.
干预措施: Guided breathing (Behavioral)
结局指标
主要结局
Feasibility of Completing the Multimodal Study Protocol
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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)
- Change in Tidal Volume During Intervention(During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours)
- Change in Minute Ventilation During Intervention(During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours)
- Change in Heart Rate During Intervention(During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours)
- Change in Heart Rate Variability During Intervention(During each intervention visit, from pre-intervention baseline through post-intervention recovery, approximately 1.5-2 hours)
- Change in Blood Pressure During Intervention(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(Approximately t=0, t=45 minutes, and t=60 minutes relative to the intervention period during each intervention visit)