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.