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
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.
