A Pilot Study to Quantify the Autonomic Nervous System Balance in Healthy, Able-Bodied Individuals
Trial Snapshot
- Phase
- Not Applicable
- Status
- Enrolling By Invitation
- Sponsor
- Northwell Health
- Enrollment
- 48
- Locations
- 2
- Primary Endpoint
- Changes in Blood Pressure related to Autonomic Nervous System Perturbations
Study Overview
Brief Summary
Biomarkers can be evaluated to provide information about disease presence or intensity and treatment efficacy. By recording these biomarkers through noninvasive clinical techniques, it is possible to gain information about the autonomic nervous system (ANS), which involuntarily regulates and adapts organ systems in the body. Machine learning and signal processing methods have made it possible to quantify the behavior of the ANS by statistically analyzing recorded signals. This work will aim to systematically measure ANS function by multiple modalities and use decoding algorithms to derive an index that reflects overall ANS function and/or balance in healthy able-bodied individuals. Additionally, this study will determine how transcutaneous auricular vagus nerve stimulation (taVNS), a noninvasive method of stimulating the vagus nerve without surgery, affects the ANS function. Data from this research will enable the possibility of detecting early and significant changes in ANS from "normal" homeostasis to diagnose disease onset and assess severity to improve treatment protocols.
Detailed Description
Biomarkers that reflect disease presence or intensity, or treatment efficacy are central to medical advancements. Recorded biomarkers provide information about physiological processes regulated by the autonomic nervous system (ANS), which include blood pressure, heart rate, sweating, and body temperature. The ANS has two major divisions: sympathetic and parasympathetic systems. Most organs receive reciprocal input from both systems to achieve homeostasis through ANS balance. This regulation occurs without conscious control (i.e., autonomously). Dysregulation of the ANS can occur as the result of disorders or injuries, including diabetes, sepsis, spinal cord injuries (SCI), Parkinson's disease, and many other conditions.
The ANS is the part of the nervous system that regulates and integrates bodily functions that typically run involuntary, particularly internal organs including blood vessels, lungs, pupils, heart, sweat, and salivary glands. Along with immunological systems, it controls and adapts homeostasis of the internal environment based on changes in the external environment. Disturbances in autonomic regulation have been described in a variety of diseases and disorders, including those that directly affect the nervous system, such as spinal cord injuries and stroke, and those that afflict other organ systems, such as sepsis and infection, rheumatoid arthritis, Crohn's disease, diabetes mellitus, and numerous heart conditions. This dysregulation manifests differently for each of these conditions, even inconsistently across patients, and the significance of symptoms due to ANS dysfunction are not well understood.
The ANS can be divided into two major branches: the sympathetic and parasympathetic systems. All internal organs are innervated by one or both component systems through the ANS main conduits, which include the brainstem, spinal cord, and cranial nerves, such as the vagus nerve. The branches typically function opposite and complementary of each other; physiological changes associated with the sympathetic system include accelerating heart rate, dilating pupils, and perspiration, while the parasympathetic system slows the heart, lowers blood pressure, and relaxes muscles. Both systems work in tandem to modulate and maintain blood pressure, vagal tone, heart rate, respiration, and cardiac contractility. While both systems operate to maintain homeostasis, the sympathetic system can be considered a quick response and mobilizing system, while the parasympathetic is a more slowly activated and dampening system.
Instead of measuring the ANS directly from the central or peripheral nervous system through invasive implants, it is possible to record physiological signals through advances in noninvasive clinical testing. Laboratories are able to test autonomic function and rely on batteries of accepted, noninvasive tests. According to the American Academy of Neurology (AAN), standard techniques of autonomic testing include measuring heart rate and blood pressure variability during deep breathing, tilt table, and the Valsalva maneuver to assess cardiovagal (parasympathetic) and sudomotor (sympathetic) function. It is straightforward to add to the limited necessary equipment (blood pressure cuff, electrocardiogram [ECG]) by including electroencephalography (EEG) to measure brain activity, electromyography (EMG) to measure muscle activity, and eye tracking glasses to measure pupillometry during this battery. All noninvasive signals can be measured during controlled perturbations to characterize the ANS. Assessment of ANS function is now used in multiple disciplines, including neurology, cardiology, psychology, psychophysiology, obstetrics, anesthesiology, and psychiatry.
Neural reflexes control responses in the cardiovascular, pulmonary, gastrointestinal, renal, hepatic, and endocrine systems. The vagus nerve-based inflammatory reflex is of particularly interest at the Feinstein Institute for Medical Research and has been shown to regulate immune function. The nervous system interacts with the immune system by this pathway; molecular mediators of innate immunity activate afferent signals in the vagus nerve to the brainstem, which sends efferent signals down the vagus nerve to regulate inflammation and cytokine release. Vagus nerve stimulation (VNS) has been shown to decrease production and release of pro-inflammatory cytokines; bioelectronic devices have been used in preclinical and pilot clinical trials to reduce inflammation in patients with rheumatoid arthritis and Crohn's disease.
Study Design
- Study Type
- Observational
- Observational Model
- Other
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 18 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Individuals between 18-60 years of age (to avoid changes in ANS with age)
- •Individuals that are considered English Proficient due to the study requirements to follow verbal commands
- •Able-bodied persons with no known health conditions
- •BMI < 30.0, based on height and weight (to limit known effects of high BMI on ANS activity [Costa et al., 2019])
- •Able and willing to give written informed consent and comply with the requirements of the study protocol
Exclusion Criteria
- •History of any of the following: cardiac arrhythmia, coronary artery disease, autoimmune disease, chronic inflammatory disease, anemia, malignancy, depression, neurologic disease, diabetes mellitus, renal disease, dementia, psychiatric illness including active psychosis, or any other chronic medical condition
- •Evidence of active infection
- •Family history of inflammatory disease
- •Treatment with an anti-cholinergic medication, including over-the-counter medications for allergy and sleep-aid within the past 1 week, including all drugs with Amitriptyline, Atropine, Benztropine, Chlorpheniramine, Chlorpromazine, Clomipramine, Clozapine, Cyclobenzaprine, Cyproheptadine, Desipramine, Dexchlorpheniramine, Dicyclomine, Diphenhydramine (Benadryl), Doxepin, Fesoterodine, Hydroxyzine, Hyoscyamine, Imipramine, Meclizine, Nortriptyline, Olanzapine, Orphenadrine, Oxybutynin, Paroxetine, Perphenazine, Prochlorperazine, Promethazine, Protriptyline, Pseudoephedrine, Scopolamine, Thioridazine, Tolterodine, Trifluoperazine, and Trimipramine
- •Implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants, deep brain stimulators, or vagus nerve stimulators
- •Current tobacco or nicotine use (to limit any potentially confounding effects of exposure to nicotine), which includes any use within the past 1 week
- •Chronic inflammatory disorders
- •Pre-existing neurological disease, which indicates any significant neurological condition, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's Disease, or stroke
- •Pregnancy or lactation (determined by self-report), as early pregnancy may potentially impact ANS measurements
- •Active ear infection (otitis media or externa) or any other afflictions of the ear
- •Any condition that, in the investigator's opinion, would jeopardize the participant's safety following exposure to a study intervention
- •Inability to comply with study procedures and methods
- •Prisoners
Outcomes
Primary Outcomes
Changes in Blood Pressure related to Autonomic Nervous System Perturbations
Time Frame: 4 2-hour sessions over 2 weeks
Changes in blood pressure will be measured by an inflatable cuff on one finger while purposefully activating the sympathetic (e.g. cold pressor test) or parasympathetic nervous systems (e.g. deep breathing) with safe, established tests to measure responses to changes in ANS function in healthy, able-bodied individuals. A wrist device is placed with a Velcro strap on the wrist to provide air and power for the finger cuff to inflate and deflate with changes in blood pressure. Blood pressure will be assessed as percent change during tasks, with a comparison to baseline (before and after each autonomic test).
Changes in Skin Temperature related to Autonomic Nervous System Perturbations
Time Frame: 4 2-hour sessions over 2 weeks
Changes in skin temperature will be measured by a circular probe (smaller than a dime) placed on the skin while purposefully activating the sympathetic (e.g. cold pressor test) or parasympathetic nervous systems (e.g. deep breathing) with safe, established tests to measure responses to changes in ANS function in healthy, able-bodied individuals. Temperature will be assessed as percent change during tasks, with a comparison to baseline (before and after each autonomic test).
Changes in Respiratory Rate related to Autonomic Nervous System Perturbations
Time Frame: 4 2-hour sessions over 2 weeks
Changes in respiratory rate will be measured by a belt while purposefully activating the sympathetic (e.g. cold pressor test) or parasympathetic nervous systems (e.g. deep breathing) with safe, established tests to measure responses to changes in ANS function in healthy, able-bodied individuals. The belt stretches and relaxes during inspiration (inhalation) and expiration (exhalation), respectively, to infer respiration rate. Respiration changes will be assessed as percent change during tasks, with a comparison to baseline (before and after each autonomic test).
Changes in Pupil Size related to Autonomic Nervous System Perturbations
Time Frame: 4 2-hour sessions over 2 weeks
Changes in pupil size will be measured by eye tracking glasses while purposefully activating the sympathetic (e.g. cold pressor test) or parasympathetic nervous systems (e.g. deep breathing) with safe, established tests to measure responses to changes in ANS function in healthy, able-bodied individuals. The glasses are easily wearable and mobile glasses with multiple small cameras to track gaze and pupil size. Pupil sizes will be assessed as percent change during tasks, with a comparison to baseline (before and after each autonomic test).
Changes in Heart Rate (Electrocardiography) related to Autonomic Nervous System Perturbations
Time Frame: 4 2-hour sessions over 2 weeks
The primary objective is to measure changes in ANS balance in healthy able-bodied individuals by discovering a multi-modal index to quantify the activation status of the sympathetic and parasympathetic nervous systems during a battery of clinically relevant tasks. Changes in electrocardiography (EKG) signals will be measured to measure heart rates while purposefully activating the sympathetic (e.g. cold pressor test) or parasympathetic nervous systems (e.g. deep breathing) with safe, established tests to measure responses to changes in ANS function in healthy, able-bodied individuals. Heart rates will be assessed as percent change during tasks, with a comparison to baseline (before and after each autonomic test).
Changes in Brain Activity (Electroencephalography) related to Autonomic Nervous System Perturbations
Time Frame: 4 2-hour sessions over 2 weeks
Changes in electroencephalography (EEG) signals by a dry and noninvasive electrode cap will be measured to measure brain activity while purposefully activating the sympathetic (e.g. cold pressor test) or parasympathetic nervous systems (e.g. deep breathing) with safe, established tests to measure responses to changes in ANS function in healthy, able-bodied individuals. EEG activity will be analyzed by measuring changes in power in specific frequency bands (delta, theta, alpha, beta, and gamma). Brain activity will be assessed as percent change during tasks, with a comparison to baseline (before and after each autonomic test).
Changes in Sweat Gland Activity (Galvanic Skin Response) related to Autonomic Nervous System Perturbations
Time Frame: 4 2-hour sessions over 2 weeks
Changes in sweat gland activity will be measured by dry metal electrodes on two fingers while purposefully activating the sympathetic (e.g. cold pressor test) or parasympathetic nervous systems (e.g. deep breathing) with safe, established tests to measure responses to changes in ANS function in healthy, able-bodied individuals. The electrodes measure the galvanic skin response (GSR), a measure of electrical activity that changes depends on the sweat response. Sweat responses will be assessed as percent change during tasks, with a comparison to baseline (before and after each autonomic test).
Secondary Outcomes
- Changes in Respiratory Rate due to taVNS(4 2-hour sessions over 2 weeks)
- Changes in Heart Rate (Electrocardiography) due to taVNS(4 2-hour sessions over 2 weeks)
- Changes in Blood Pressure due to taVNS(4 2-hour sessions over 2 weeks)
- Changes in Sweat Gland Activity (Galvanic Skin Response) due to taVNS(4 2-hour sessions over 2 weeks)
- Changes in Brain Activity (Electroencephalography) due to taVNS(4 2-hour sessions over 2 weeks)
- Changes in Skin Temperature due to taVNS(4 2-hour sessions over 2 weeks)
- Changes in Pupil Size due to taVNS(4 2-hour sessions over 2 weeks)
Investigators
Theodoros Zanos
Assistant Professor, Neural and Data Science Laboratory
Northwell Health