Non-Invasive Bioelectronic Analytics

Autonomic Dysfunction Clinical Trial

— NIBA  

Official title:

A Pilot Study to Quantify the Autonomic Nervous System Balance in Healthy, Able-Bodied Individuals

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04100486
• Other study ID #: 19-0461
• Status: Enrolling by invitation
• Start date: August 29, 2019
• Est. completion date: May 2025

Study information

• Verified date: March 2024
• Source: Northwell Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

The auricular branch of the vagus nerve comes from the vagus and innervates cutaneous areas of the outer ear. Transcutaneous auricular vagus nerve stimulation (taVNS) offers a non-invasive means of stimulating the vagus nerve without surgical intervention. The device consists of a clip that supplies electrical signals to processes of the auricle, and it has been used in previous clinical studies for multiple conditions, including refractory epilepsy, depression, pre-diabetes, tinnitus, memory, stroke, oromotor dysfunction, and rheumatoid arthritis, with additional studies planned for therapy or treatment of stroke, atrial fibrillation, and heart failure. These studies have used a range of electrical stimulation settings and sites; the mechanism of taVNS and responses are not well understood, as well as the effects of changes in stimulation parameters on ANS.

Recently, application of machine learning models and decoding algorithms permits utilizing commonly used clinical measurement of physiological signals to better understand broader phenomena of autonomic function and dysregulation. Research has been focused on developing quantitative standards based on biomarkers to aid with diagnosis, prognosis, and estimates of treatment efficacy. Autonomic data could potentially capture objective measures of disease states, and machine learning techniques can be used to extract relevant features towards building a predictive model of ANS balance. By training such a model on recordings from healthy, able-bodied individuals, the investigators plan to characterize ANS balance, and then apply this model to new data sets and individuals to diagnose or predict disease states.

Modern methods of computational science have been used to decode complex clinical and experimental data by detecting patterns, classifying signals, and extracting information towards new knowledge. Through signal processing techniques, it has been possible to decode autonomic nervous system signals conveyed through the vagus nerve by identifying groups of vagal neurons that fire in response to the administration of specific cytokines. Additionally, machine learning has been used to quantify clinical pain using multimodal autonomic metrics and neuroimaging, and large-scale ambulatory data has been used to monitor physiological signals and develop multi-sensor models to detect stress in daily life.

Additionally, the investigators want to examine how these measurements are affected by the use of non-invasive transcutaneous electrical stimulation of the vagus nerve. Stimulation of the vagus nerve by a surgically implanted stimulator regulates and suppresses pro-inflammatory cytokine release. This has now been used in a successful clinical trial to treat rheumatoid arthritis and Crohn's disease. Non-invasive transcutaneous stimulation of the vagus nerve has also been showing promising early results, indicating that non-invasive methods of activating a specific part of the autonomic nervous system can be used successfully to treat disease. However, real-time biomarkers of efficacy of this treatment are not available.

Here, the study will develop a framework to decode a multitude of noninvasive physiological signals during controlled autonomic testing to form a model that can quantify ANS balance, as well as the effects of taVNS on the system, in healthy and able-bodied individuals. Data derived from this study will enable the ability to detect early and significant deviations from "normal" homeostasis and provide novel non-invasive real-time biomarkers that could be used to assess disease onset or severity, as well as efficacy of a therapy in activating the ANS in a specific way. In the long-term, this will improve current treatment protocols and suggest new therapeutic opportunities.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 48
• Est. completion date: May 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Autonomic Dysfunction
• Autonomic Imbalance
• Autonomic Nervous System Diseases
• Nervous System Diseases
• Primary Dysautonomias
• Vagus Nerve Autonomic Disorder

Intervention

Other:
• Standing-Squatting-Standing Test
The participant will begin by actively standing for one minute, followed by a transition to a squat for one minute, and one last transition to one minute of standing.
• Deep Breathing Test
The participant will be asked to lay down for seven minutes and take long, controlled breaths at a rate within 4 to 10 breaths per minute.
• Cold Pressor Test
The participant will be asked to immerse their hand into ice water (1- 10°C) for up to three minutes, followed by removal of the hand from the bath and continuation for recording for a further three to five minutes. The participant will be informed that he or she can remove his or her hand at any point if there is discomfort.
• Cold Face Test
The cold stimulus will be applied with refrigerated gel-filled compresses places on the forehead and cheeks of the participant for one minute.
• Valsalva Maneuver
The participant will be asked to inhale deeply, pinch his or her nose, close his or her mouth, and forcibly exhale, while bearing down with tight chest and stomach muscles, for approximately 10 to 15 seconds. The sensors will continue recording as the participant recovers to normal breathing over the next one minute.

Device:
• Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)
The participant will receive electrical stimulation applied to their ear for five minutes. The threshold for stimulation will be determined before the test begins at a level that may elicit sensation (tickling, vibrating, pricking), but no pain. There is a possibility that the participant will receive sham stimulation, or inactive stimulation, for this test.

Locations

Country	Name	City	State
United States	The Feinstein Institutes for Medical Research	Manhasset	New York

Sponsors (1)

Lead Sponsor	Collaborator
Northwell Health

Country where clinical trial is conducted

United States, 

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* Note: There are 41 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Heart Rate (Electrocardiography) related to Autonomic Nervous System Perturbations	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).	4 2-hour sessions over 2 weeks
Primary	Changes in Brain Activity (Electroencephalography) related to Autonomic Nervous System Perturbations	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).	4 2-hour sessions over 2 weeks
Primary	Changes in Respiratory Rate related to Autonomic Nervous System Perturbations	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).	4 2-hour sessions over 2 weeks
Primary	Changes in Sweat Gland Activity (Galvanic Skin Response) related to Autonomic Nervous System Perturbations	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).	4 2-hour sessions over 2 weeks
Primary	Changes in Blood Pressure related to Autonomic Nervous System Perturbations	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).	4 2-hour sessions over 2 weeks
Primary	Changes in Skin Temperature related to Autonomic Nervous System Perturbations	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).	4 2-hour sessions over 2 weeks
Primary	Changes in Pupil Size related to Autonomic Nervous System Perturbations	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).	4 2-hour sessions over 2 weeks
Secondary	Changes in Heart Rate (Electrocardiography) due to taVNS	A secondary objective is to examine how the physiological measurements and the derived ANS index are affected by non-invasive taVNS. The efficacy and specificity of taVNS as it relates to autonomic perturbations will be analyzed while maintaining safety and tolerability in healthy, able-bodied individuals. Heart rates will be assessed as percent change during taVNS, with a comparison to baseline (before and after stimulation).	4 2-hour sessions over 2 weeks
Secondary	Changes in Brain Activity (Electroencephalography) due to taVNS	Power in EEG frequency bands will be assessed as percent change during taVNS, with a comparison to baseline (before and after stimulation).	4 2-hour sessions over 2 weeks
Secondary	Changes in Respiratory Rate due to taVNS	Respiratory rates will be assessed as percent change during taVNS, with a comparison to baseline (before and after stimulation).	4 2-hour sessions over 2 weeks
Secondary	Changes in Sweat Gland Activity (Galvanic Skin Response) due to taVNS	GSR will be assessed as percent change during taVNS, with a comparison to baseline (before and after stimulation).	4 2-hour sessions over 2 weeks
Secondary	Changes in Blood Pressure due to taVNS	Blood pressure will be assessed as percent change during taVNS, with a comparison to baseline (before and after stimulation).	4 2-hour sessions over 2 weeks
Secondary	Changes in Skin Temperature due to taVNS	Skin temperature will be assessed as percent change during taVNS, with a comparison to baseline (before and after stimulation).	4 2-hour sessions over 2 weeks
Secondary	Changes in Pupil Size due to taVNS	Pupil size will be assessed as percent change during taVNS, with a comparison to baseline (before and after stimulation).	4 2-hour sessions over 2 weeks