Noninvasive Brain Stimulation to Improve Oromotor Function In Neonates With Advanced Neuroimaging to Determine Safety and Target Engagement of taVNS for Neurorehabilitation
Phase: EARLY_PHASE1
Conditions: Poor Feeding, Infant Development, Vagus Nerve Stimulation
Sponsor: Medical University of South Carolina

Protocol Version: 13       
 
 
 
 
 
 
 Date: 1-26-2021 
 
 
 
 
 
PI Name:  Dr. Dorothea Jenkins 
Co-PI: Dr. Mark George  
 
 
Study Title: Noninvasive Brain Stimulation to Improve Oromotor Function In Neonates  
 
Once protocol is complete, save it as a Word document.  Go back to the IRB application and upload the 
protocol.  
 
TABLE OF CONTENTS – Prepare a table of contents based on the following outline, including page 
numbers, and insert here.    
 
Specific Aims………………………………….……………………………………….2 
Background and Significance……………………………………………………… .2 
Preliminary Studies...…………………………………………………………………3 
Research Design and Study Methods………………………………………………4 
Protection of Human Subjects……………………………………………………….8 
References……………………………………………………………………………15 
Facilities.…………………………………………………………………   …………18 
 
 
 
 
 
 
 
 
 
 
Medical University of South Carolina 
Protocol 

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A. SPECIFIC AIMS 
Preterm infants and term infants who suffer hypoxic ischemic encephalopathy (HIE) are at high risk for 
motor problems, which primarily manifest as feeding delays during their neonatal hospital admission. 
Oromotor dyscoordination is very common in both groups of infants, and typically takes 3-6 weeks of 
working on oral feedings in the hospital before the infant may take enough breast milk or formula to 
sustain adequate growth for discharge. Occupational therapy usually works with infants once a day to 
ensure that the feeding particulars, such as nipple choice, frequency of oral feeding, do not tax infant 
physiology too greatly and to guide learning this motor skill. Feeding difficulty is the primary reason for 
delayed discharge of preterm or HIE infants. Many of these infants will not be able to master this motor 
skill before term age (40-42 weeks gestation) and will receive a gastrostomy tube (G-tube) for direct 
gastric feeding, in order that they may finally be discharged from the hospital to home. Over the past 5 
years in our MUSC NICU (2012-2016), we have placed an average of 40 G-tubes per year. This 
procedure requires general anesthesia for both insertion and eventual take down, and leaves scars in 
the epigastric area. The G-tube also reinforces the parental perception that their child is not normal and 
that he or she has a more limited developmental potential than a ‘normal’ child. 
 
Even with significant brain injury, we know that neuroplasticity in infants may lead to improved, and 
even near normal outcomes. This neuroplasticity involves stimulating neurogenesis and reparative 
inter-neuronal connections to improve motor skills in neonatal animal models and in adults after stroke. 
In addition, we know that rehabilitative training may be enhanced by brain stimulation using a variety of 
modalities.  
 
In recent years scientists have discovered that plasticity increases if you pair a stimulus or behavior 
with stimulation of the vagus nerve. We think that the vagus signal likely activates norepinephrine  
fibers coming from the locus ceruleus. This time-dependent signal to the cortex and other parts of the 
brain ‘tells it’ to pay attention to or be alert for other novel signals. By pairing a stimulus or behavior, 
scientists and clinicians can improve processes that involve neuroplasticity, like learning or 
rehabilitating a motor skill. Precisely targeted neural plasticity accomplished through Vagal Nerve 
Stimulation (VNS) and stimulus pairing has so far been shown to improve treatment of neurological 
disorders associated with motor function, tinnitus, and stroke. In motor studies in rats, VNS paired with 
movement led to a doubling in size of the primary motor cortex associated with the paired movement, 
whereas rats receiving identical motor training without VNS pairing did not exhibit motor cortex plasticity 
(1). In stroke, patients who received VNS paired with rehabilitation demonstrated a significant increase 
in their Upper Extremity Fugl–Meyer score compared with patients who received rehabilitation without 
VNS (2). In a different model of tinnitus in noise-exposed rats, VNS paired with auditory tones 
completely eliminated the physiological and behavioral symptoms of tinnitus (3), and the same 
treatment in humans seemed to exert a beneficial effect in nonmedication-taking patients, both with 
regard to perceived sound and distress (4). There are now ongoing FDA-pivotal studies involving 
pairing VNS with rehab to improve stroke rehabilitation (NCT03131960) 
or pairing VNS with sounds to improve tinnitus (NCT01962558). These pivotal studies are funded by a 
small startup company (MicroTransponder) whose patent portfolio involves surgically implanted cervical 
VNS.  
 

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Cervically implanted vagus nerve stimulation (VNS) is an FDA approved treatment for epilepsy and 
major depression, with the first implant in humans in 1988 (5,6). Although cervical VNS is relatively safe 
and effective in seizure prevention (7,8) the risks involved in surgical implantation as well as its high 
cost (about $30-50k) make it less appealing and less available as a treatment modality.  
 
Recently it has been shown that VNS can be administered non-invasively through stimulating the 
auricular branch of the vagus nerve located in the ear (4, 9,10) with a transcutaneous electrical nerve 
stimulation (TENS) device. TENS is a very common, FDA-approved therapy for pain management. 
Researchers in the brain stimulation lab here at MUSC have conducted initial safety and feasibility trials 
of transcranial auricular VNS (taVNS) in healthy adults. In these studies, there were no minor or major 
adverse effects observed throughout the duration of their trial. Their work validates ideal parameters for 
delivering taVNS, suggesting that one-minute taVNS periods at 200% perceptual threshold delivered at 
500μs 10Hz are safe and tolerable and produce regional brain changes consistent with activating the 
vagus nerve related brain regions involved in neuroplasticity (10). 
 
Surgically implanted cervical VNS is expensive, risky, and would not likely be used for transient boosts 
of normal motor development. However, if we can use noninvasive taVNS rather than implanted VNS, 
this promising research modality may be translated to more fragile infants. Such a safe, bedside 
treatment would be ideal for preterm and HIE neonates trying to master motor skills that are reflexive 
for normal near term neonates, but must be learned for those infants born prematurely or relearned for 
those with brain injury. The added benefits of enhancing accomplishment of this primary motor task 
would be earlier discharge, lower hospital costs, improved parental perception of the developmental 
potential of their infant, and finally reduced stress and better bonding with parents, both in and out of 
the hospital.  
 
Feeding in neonates involves a sequence of sucking, swallowing, and breathing that requires 
coordination of the face, head, and neck muscles with the myelinated vagal regulation of the bronchi 
and the heart (11). In preterm neonates, the muscles needed to feed are underdeveloped, resulting in 
the need for OT rehabilitation to ‘learn’ feeding patterns. Preterm neonates’ inability to feed effectively 
is the primary reason for prolonged hospital stays (12). In neonates with HIE, development of cortex 
and basal ganglia is interrupted, and depending on the severity, normal developmental plasticity is 
hindered, further contributing to their inability to feed (13). Both types of feeding difficulties involve 
complex motor learning, which requires integration of sensory and motor pathways. Treating oromotor 
difficulties during the learned task of feeding with noninvasive brain stimulation that promotes plasticity, 
poses a highly novel application of taVNS. Our major premise is that in babies at high risk for motor 
problems, simultaneously delivered brain stimulation via taVNS will boost motor cortical plasticity 
involved in a learned feeding task, leading to better feeding.  
 
This protocol has 2 specific aims that will be investigated: 
 
Specific Aim 1: Improved Motor Learning - We aim to investigate whether pairing taVNS with 
rehabilitation training of feeding behavior in preterm and HIE neonates will enhance and accelerate the 
learning of effective feeding behavior in a dose responsive manner. We call this treatment “taVNS-
paired feeding.” The primary outcome measures of taVNS-paired feeding will be daily oral milk feeding 
volume changes from before to during treatment, and number of infants reaching full oral feeds 

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between once and twice daily taVNS-paired feeding, duration to full feeds, as well as general motor 
functional impairment as measured by Dr Coker-Bolt’s Specific Test of Early infant motor Performance 
(STEP). Our hypothesis is that taVNS-paired feeding for preterm neonates is feasible, safe and 
effective at reducing length of stay solely for feeding reasons, compared to historical controls. As part of 
our safety investigations with separate funding, we may perform taVNS during a clinical modified 
barium swallow study with pediatric speech language pathologists performing the study and compare 
10 swallows with stimulation on and off to determine if taVNS affects swallowing parameters. 
 
Specific Aim 2: Brain Changes - We aim to determine if white matter fiber tracts show improved 
integrity as measured by diffusion imaging (DKI) before, after a 2-week treatment taVNS-paired feeding 
course, and whether treatment improves neuronal energetics in the basal ganglia as measured by 
magnetic resonance spectroscopy (MRS). Unsedated MRS and DKI imaging will last approximately 40 
minutes, and will be done before and after the two-week taVNS-paired rehab treatment session. The 
changes in white matter tract diffusion parameters and N-acetylaspartate (NAA) and glutathione (GSH) 
concentration in the basal ganglia and thalamus will be compared with published changes of these 
parameters over gestational age in preterm infants (14, 15) and with our own MRS data in preterm and 
HIE infants who did not receive taVNS.  
We will perform DKI to determine the effects of taVNS on plasticity, and to identify areas of the brain 
involved in afferent vagal activation. We propose utilizing the concurrent taVNS/fMRI method 
developed by Dr. Badran at MUSC to determine whether taVNS activates the CNS and afferent vagal 
network in a subset of preterm and term infants in the study. 
 
B. BACKGROUND AND SIGNIFICANCE 
 
Traditional cervical VNS involves surgically implanting a stimulator into the left chest wall. Bipolar 
electrodes are then wrapped around the left vagus nerve in the neck with wires connected to these 
electrodes running inside the neck and connecting to the stimulator. Cervical implanted VNS is FDA 
approved in patients with intractable epilepsy (5-8). Serendipitously in initial epilepsy studies, it was 
noticed there were associated mood improvements in implanted patients even in patients who had no 
seizure decrease (16,17). PET studies at the time also showed that VNS caused changes in mood 
regulating regions. These two pieces of evidence led Dr. George to begin exploring VNS as a treatment 
for depression (18, 19) and ultimately being approved for the long-term treatment of chronic or 
recurrent depression. MUSC was the site of the first depressed patient ever implanted with cervical 
VNS.  Aside from the anti-epileptic and positive mood effects in humans, VNS has been studied 
extensively in animal models, with applications ranging from attenuation of inflammatory response (20, 
21), increased survival rate in heart failure (22), reduction of infarct size in cerebral ischemia (23, 24), 
motor rehabilitation after stroke (25, 26, 27) and tinnitus VNS (28, 31). VNS is an emerging area of 
interest in the neuroscience field and has many translatable applications. The ability to pair VNS with 
stimuli and motor behavior and promote learning and plasticity is the most germane aspect of VNS for 
this specific proposal. 
 
The vagus nerve spans from the gut up to the nucleus track solitaris (NTS) of the brainstem. From 
there, projections span to many different regions of the brain, each with its own resulting effect. A small 
branch of the vagus nerve, known as the auricular branch, innervates the ear. This branch also has 
afferent projections to the brain and may elicit similar effects when stimulated as does traditional 

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cervical vagus stimulation in the neck. The concept of transcutaneous auricular vagus nerve stimulation 
(taVNS) as a noninvasive alternative to the conventional implantable VNS is relatively new and was first 
developed in 2000 (2). Since then, there have been several groups that have conducted studies on this 
novel form of neuromodulation (4,9,10). 
 
At MUSC, Dr Bashar Badran and the brain stimulation division have conducted three focused studies 
examining the safety, feasibility, and effectiveness of taVNS in adults. They found that during taVNS, 
participants showed minor but statistically significant immediate heart rate decreases followed by a 
modest sympathetic rebound upon termination of stimulation. The group developed and conducted a 
concurrent taVNS/fMRI trial to determine the neurobiological effect of taVNS. Findings from the 
taVNS/fMRI trial demonstrated that the neurobiological effect of taVNS mimics that of cervically 
implanted VNS and targets several cortical and subcortical vagus afferent pathway targets. It 
additionally suggested that taVNS for short time periods activates the vagus nerve (10-25Hz, average 
1.8mA). The group saw no minor or major adverse events during the treatment sessions and no 
spontaneously reported event following termination of the trial. No rapidly accelerated or sustained 
drops in HR were seen during the one-minute taVNS stimulation periods. Minor, temporary, and light 
redness was seen at the sight of stimulation but disappeared within five minutes of stimulation 
completion. A follow-up study determined that the optimal parameter to modulate the parasympathetic 
response activated via taVNS was 500μs pulse width, 10Hz for 60s duration (10). 
 
VNS has been shown to rescue the brain if stimulation begins immediately after trauma, such as 
immediately after strokes. Rats that received vagal stimulation immediately after focal cerebral 
ischemia had not only significantly better neurological scores compared to non-VNS rats, but these rats 
also had significantly smaller infracts (24). A large group out of Dallas, TX has conducted extensive 
research on the effects of VNS in both animal and human models. In treating tinnitus, the group tested 
VNS, tones, and paired VNS-tones (4, 28). When VNS alone was delivered to the rats in a tinnitus 
model, there was no decrease in tinnitus symptoms. When tones were delivered alone there were no 
reductions. This suggests there is a synergistic effect of VNS when combined with a paired stimulus 
that is directing plastic changes to occur in the cortex. This concept is called “targeted plasticity” (2,3,4) 
or use- or state-dependent plasticity, in which various cortical targets can be selectively changed 
depending on the paired stimulus. This group is exploring VNS induced targeted plasticity as a 
treatment for other neurological disorders in animal models involving cortical reorganization, including 
stroke (25, 26) and have successfully moved into human clinical trials for both these treatments. Most 
notably, this pairing of VNS and rehabilitation paradigms has been shown to restore motor behavior in 
stroke. It is conceivable that these targeted plasticity findings can be seen with taVNS, without the cost 
or risk of surgical implantation. 
 
If we can use taVNS rather than implanted VNS, the prior wealth of promising research can potentially 
be translated to more fragile patients noninvasively. While surgical implantation VNS has produced a 
large body of positive results, it would be far more cost effective and easier to conduct VNS 
noninvasively. In looking to the future of VNS, noninvasive taVNS poses significant applications in 
populations such as preterm neonates, who are too unstable to undergo surgery and might benefit from 
VNS for a specific motor task of feeding. This population represents an ideal group for testing this novel 
use of taVNS.  To ingest milk properly and efficiently, neonates must have the neural integration to 
coordinate the complex sequence of sucking, swallowing, and breathing. This sensorimotor sequence 

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requires coordination of the face, head, and neck muscles with the myelinated vagal regulation of the 
bronchi and the heart. Since the structures involved in feeding are linked to the myelinated vagus, the 
ability to feed may provide an early indicator of the functional status of a neuromuscular system that will 
later be involved in social engagement behaviors. Prematurity and illness affect the developmental 
trajectory of many neural circuits, including the vagal circuit. Abnormal development of the vagus is 
reflected in myelination of the vagus, interneuronal connections in the brainstem that form the face-
heart connection, and/or corticobulbar regulation of the brainstem circuits regulating both vagal activity 
and the striated muscles of the face, head, and neck. The consequences in typical neural maturation 
seen frequently in older preterm infants would be expressed as RSA (Respiratory sinus arrhythmia) due 
to lower vagal tone and brainstem immaturity (11). RSA has been associated with poor behavioral state 
regulation common in preterm or HIE infants, and too little or too much autonomic reactivity (37). Such 
reactivity and neural immaturity make coordinating and learning a complex motor task even more 
difficult, explaining why the feeding mechanism must be taught through OT rehabilitation, when it 
should be a normal reflex. Interestingly, the RSA also associates with behavioral reactivity problems in 
older children, conditions for which both preterm and HIE infants are at increased risk, and vagal 
regulation deficits are reported in adult psychiatric disorders (38).  
 
Although postnatally the developing brain is more plastic than the adult brain, and thus would be 
expected to have better recovery mechanisms following injury, the immature or injured neonatal brain 
has some of the worst developmental outcomes following significant insult. Injury, oftentimes occurring 
in the difficult labor associated with preterm birth and conditions associated with HIE, trigger excessive 
stimulation of particular inflammatory pathways normally involved in shaping the developing brain 
circuitry. In the immature brain outgrowth of neural projections resulting from injury actually generate 
abnormal connections and circuitry as well as a paucity of myelinating cells and inter-neurons that 
subsequently lead to motor and cognitive impairment. Around the time of birth, the cortex and basal 
ganglia undergo significant integrative connectivity associated with shaping of central motor pathways. 
A HI or other injury event around this time interrupts these processes and can affect normal 
developmental plasticity through altering neurotransmission and changes in cellular signaling leading to 
abnormal connectivity (13).  
 
The data in both animals and adult humans is convincing that VNS paired with motor training improves 
motor functioning (2,3,4). A multisite, FDA-pivotal, industry-sponsored trial of implantable cervical VNS 
to treat upper motor hemiplegia after stroke in adults is currently underway, built on this promising data. 
Activity dependent plasticity that is enhanced by electrical stimulation, has become a common tenant of 
neuromodulatory research, but has not yet been translated to infants or neonates after global brain 
injury of prematurity or HIE. The justice of holding back investigational drugs and therapies from 
children and infants who may benefit simply because they are children, has come into question the past 
years, as we clinicians have to acknowledge that virtually NONE of the treatments we use in infants 
have actually undergone testing or are FDA approved in the childhood populations routinely used. We 
have an obligation as pediatric clinical researchers to remedy this extreme discrepancy in innovative 
research in children.  
 
The data and safety supporting the study of non-invasive TENS in neonates and young infants is 
represented in studies that investigated TENS for specific purposes such as pain reduction or treatment 
of torticollis or brachial plexus injuries (39-42). There were no adverse effects reported at various HZ 

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from 2-10 and for 0.5 – 5 mA. Moreover, the safe use of TENs for the iontophoresis necessary for the 
sweat test in neonates to confirm cystic fibrosis, supports its minimal risk designation in neonates (43). 
The investigators in these neonatal and infant studies as well as research conducted by Drs. Badran 
and George in adults at this institution, used the same frequency and intensity (10Hz, 0.5-5mA), and no 
painful or ill effects have been observed. Not only is TENS safe in all populations and is FDA cleared, in 
the case of VNS, we already have substantial evidence of dose response in adults (Badran, George) as 
well as efficacy and safety. The dosing parameters chosen in this study were found to be safe and have 
positive brain imaging results. 
 
The purpose of this study is primarily to determine feasibility of the proposed taVNS dose and duration 
with a paired feeding, that has minimal negative effects and confers positive functional and CNS 
structural benefits. As this is a pilot study, we do not know the exact intensity of the stimulus that our 
infants will perceive. We have built in a dose determination during rest and during feeding for 
perceptual threshold. We also have an immediate reduction built in for safety if it causes discomfort, 
and we have planned for a gradual increase in the duration of treatment over the first feeding sessions 
to determine the tolerability. We have included the protocol for the perceptual threshold determination 
for clarification.  
 
We hope to verify that the protocol for delivering taVNS-paired feeding will effectively align with regular, 
pre-existing OT rehabilitation performed in nearly all pre-term neonates, and that taVNS-paired feeding 
improves their ability to feed. We anticipate that taVNS-paired feeding treatments can be conducted in 
a feasible, time and cost effective manner. Our secondary purpose is to understand with brain imaging 
how taVNS may improve the CNS circuitry and metabolism, which correlates with the specific early 
motor task of learning to feed. As long term developmental data is always important in studies of 
infants, we will also look at preliminary data to see if this effect can be linked to long-term functional 
ability.  
 
Diffusion MRI (dMRI) may determine effects of taVNS on plasticity. 
Rapid changes in diffusion have been noted with electrical stimulation accompanied by a 20-45% 
increase in extracellular water in animals and human volunteers(3-5). On a cellular level, the diffusion 
changes are believed to indicate increased Na+/K+ATPase activity(6), and ionic and water movement 
through neuronal and glial membranes(5). These diffusion changes in white matter (WM) tracts have 
been proposed as an alternative to BOLD  fMRI(3), and may be particularly applicable to measuring 
direct changes after taVNS in this neonatal and infant population after global HI brain injury. In addition, 
we will use DKI which is more sensitive in neonates and infants, who generally have lower FA and 
higher kurtosis values. This is a novel application of DKI as an indication of vagal-mediated central 
effects induced by taVNS paired feeding. 
 
This research proposal will further develop a noninvasive vagus nerve stimulation as an assistive tool in 
the rehabilitation of neonates born with feeding deficits. We will confirm the safety of this new technique 
using fluoroscopic imaging as well as its effect on brain plasticity using advanced structural and 
functional neuroimaging. 
We hypothesize, based on the paired VNS studies in animals and humans to date as well as human 
noninvasive VNS studies conducted here at MUSC, that taVNS-paired feeding in pre-term neonates will 
feasible, safe and not worsen swallowing problems and perhaps improve them. Additionally, we 
hypothesize that ta-VNS-paired feeding will accelerate pre-term neonates’ ability to learn feeding 

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sensorimotor skills, which will be apparent in increased volume of milk consumed and longer oral 
feeding durations. If feeding behavior is improved, then we further expect decreased levels of functional 
impairment as compared to baseline STEP tests after receiving taVNS-paired feeding. These 
hypotheses regarding neonatal health and improvement, while vital in understanding the impact of 
taVNS-paired rehab in pre-term neonates, come second to the primary hypothesis that this novel 
treatment is safe and feasible.  
 
C. PRELIMINARY STUDIES 
 
The principal investigator, Dr. Jenkins, is a neonatologist. Her clinical research focuses on the 
management and treatment of hypoxic ischemic and neuroinflammatory diseases in neonates. She 
conducted a phase II multicenter randomized controlled trial of hypothermia to treat hypoxic-ischemic 
encephalopathy (HIE) in neonates. She developed other neuroprotective treatments in animal models, 
which she is currently translating to critically ill neonates with HIE undergoing hypothermia treatment in 
conjunction with N-acetylcysteine (NAC) and Vitamin D. In this IRB approved study (HR#31254), she is 
using magnetic resonance spectroscopy (MRS) to quantify participants’ GSH levels before and after 
NAC and Vitamin D, using glutathione as a biomarker for oxidative stress and NAC pharmacodynamic 
CNS effect. The hope is that improving oxidative stress in neonates with HIE will improve neuronal 
growth and development. She has also safely performed other cutting edge studies using NAC 
maternal chorioamnionitis to cross the placenta and protect the fetal brain before delivery (HR#16708). 
She is well suited to conduct these studies safely in infants. 
 
Dr. Mark George, MD, is a neurologist and psychiatrist and is an expert in brain imaging in mood 
disorders and is a pioneer in using brain stimulation, particularly TMS and VNS, for treating depression. 
In his earlier research at MUSC, he and his group were the first to use VNS to treat depression, and 
also were the first group to perform VNS within an fMRI scanner. He is currently chair of the DSMB for 
a multisite, FDA-pivotal, industry-sponsored trial of implantable cervical VNS to treat upper motor 
hemiplegia after stroke in adults, which is built on promising data in both animal and humans that VNS 
paired with motor activity improves motor learning. He is also the editor in chief of the major journal in 
the field of brain stimulation (Brain Stimulation). In the past 7 years he has become more interested in 
how and when to use brain stimulation devices to improve stroke rehabilitation and is a part of the 
MUSC COBRE involving brain stimulation and stroke recovery.  
 
Dr. Bashar Badran, Ph.D, obtained his doctorate under Dr. George, and has extensive experience and 
background in clinical TMS and taVNS, especially in the development of novel protocols for 
neurological disorders.  His thesis work involves systematic elucidation of the dose response of taVNS 
on heart rate, use of heart rate as a biomarker of taVNS effect, and the use of taVNS with fMRI in 
determining pathways and regions affected by taVNS in adults. He determined that the ‘on’ pulse heart 
rate change was a mean of -3 beats per minute (bpm) while the ‘off’ pulse heart rate change was +6 
bpm. Although these are statistically significant and measurable changes, they are physiologically 
insignificant. Nevertheless, this will be an important biomarker for infants, but is not expected to result 
in safety concerns. Dr Badran’s careful and thorough studies lay the safety and efficacy groundwork for 
the current proposal.  
 
 

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D. RESEARCH DESIGN AND METHODS (including data analysis)  
Due to the novelty of these studies, Dr. Dorothea Jenkins will be present for each taVNS-paired feeding 
session conducted in the first participants, and as needed thereafter. Dr George and or Dr Badran will 
monitor taVNS effects. If any adverse events are noticed which are not described in the consent or are 
serious, we will inform the IRB before continuing with the next enrolled subject. Importantly, all of these 
methods have been done before, and published by our and other groups in adults, and we believe 
these extra precautions will assure the safety and well-being of any participants enrolled.  
 
taVNS-paired feeding to enhance feeding behavior in neonates  
 
Screening 
 
Prospective participants will be identified by the PI (Jenkins) at the MUSC neonatal intensive care units 
(Level II and III), and checked for potential inclusion (please see the uploaded taVNS screening form). 
Paige Merrill, and other clinical OTs based in the nursery may also mention the study to parents and 
refer them to Dr. Jenkins if they are interested in participating.  
 
Participants  
Inclusion criteria:  
Infants must be clinically stable, on minimal respiratory support (nasal cannula, or room air), in 
discussions about Gtube placement for poor po feeding and are currently greater than or equal to 
39weeks post-menstrual age and  
1) If born premature have been working on oral feeding for 30days;  
or  
2) If term Infant with significant medical issues that have precluded oral feeding, such as hypoxic 
ischemic encephalopathy (HIE), have been working on oral feeding for 14days. 
 
Exclusion criteria:  
1) Unstable infants or those requiring respiratory support involving positive pressure.  
2) Major unrepaired congenital anomalies 
3) Anomalies/conditions that limit feeding volumes  
4) Cardiomyopathy  
5) Repeated episodes of autonomic instability (apnea or bradycardia) which are not self-resolving * 
 
*Preterm infants commonly have short periods of shallow or absent breathing or lower heart rate 
termed apnea and bradycardia, respectively, and most are being treated for these physiologic 
manifestations of prematurity with caffeine, an effective central stimulant. Infants are on 
cardiorespiratory monitors through the nursery stay to capture events, many of which are self-resolving. 
Infants who require repeated episodes of tactile stimulation to come out of these events are defined as 
unstable. 
 
Neonates who are beginning oral feeds after medical treatment for critical illnesses, such as HIE brain 
injury, will be included as these neonates represent a population in which taVNS-paired feeding could 
present the largest success in overcoming impaired brain development. Congenital syndromes may be 
included if the infants do not have major, unrepaired anomalies or anomalies that limit feeding volumes.  

Page 10 of 23 
 
 
 
 
Written informed consent will be obtained from the mother if available and if she has custody or 
decision making authority for the participant, otherwise a parent or legal guardian, prior to participation 
in the experimental paradigm. Department of Social services may have custody of infant but require the 
parent or foster parent to consent for all medical procedures. 
 
Electronic Consent will be used for situations when the parent (or Legally Authorized Representative) is 
at another hospital and cannot travel to MUSC to provide consent in person. We will use the approved 
REDcap system to obtain consent. Dr. Jenkins or other approved study personnel will go over the 
entire consent document on the phone with the parent to ensure comprehension and to confirm identity. 
Parent will be given a copy of the completed, signed consent form in person or by email or fax. 
 
Study Design 
 
Up to 40 preterm/HIE neonates will be enrolled in this prospective, open-label safety and feasibility trial, 
with a dose response. The experimental paradigm consists of 2 to 3 weeks of once or twice daily 
taVNS-paired feeding.  
 
Our control group was investigated by Drs. Allison Chapman and Rita Ryan at MUSC, who have 
researched all infants failing feeding and getting Gastrostomy tubes in our nurseries over the past 5 
years. We can compare our data to this historical group at our own institution. 
 
All consented participants will receive the active stimulation condition.   
 
taVNS Stimulation (in Detail) 
 
After obtaining consent and describing this procedure to the parents and all members of the baby’s 
care team, we will first, with a 500μs, 25Hz pulse, gradually increase the intensity of the TENS unit until 
the baby can first feel something in their ear. We will use the facial expression change and fidgety 
movements to determine when the infants feel the stimulation. This intensity will be recorded as the 
perceptual sensory threshold. The stimulation intensity we will use for this study on taVNS-paired 
feeding is a small decrement from the perceptual sensory threshold for each infant (-0.1mA), a point at 
which they should not react to the stimulation. We will retest the sensory threshold before every 
session.  
 
Determination of Perceptual Threshold 
1. Electrode clip will be placed on the left tragus in an enrolled infant at rest. Starting at 0.2mA at 
25Hz, we will deliver 5 seconds of pulses, and increase by 0.1mA until the perceptual threshold 
is achieved by observation of the infant’s facial expression, fidgety movements, or NIPPS score. 
This will be termed the perceptual threshold. 
2. We will then deliver this level of microcurrent while the infant is feeding on the first day to 
determine if the perceptual threshold changes with feeding. Current will then be held constant 
while pulse width and frequency will be set at 500us and 25Hz, respectively.  

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3. Finally, we will decrease the microcurrent by 0.1mA below the perceptual threshold and 
administer this taVNS treatment during the feeding and deliver this only while the infant is 
actively sucking from the bottle.  
4. The total duration of this ‘on-and-off’ taVNS stimulation treatment will continue for 30 minutes or 
the duration of the feed.  
5. We may manually trigger the taVNS stimulation or place a gel EMG electrode over the 
temporomandibular joint area to trigger the taVNS impulse. 
 
Once the daily taVNS intensity has been determined, the treatment will continue to be administered in 
conjunction with the daily OT feeding once or twice daily. 
 
As the baby begins to suck from the bottle or breast, stimulation will be triggered and a timer will be 
started. Sometimes the infant has non-nutritive sucking and it is difficult for the operator to discern 
between these lip motions and real suck/swallow. We wish to stimulate during sucking motions that 
include swallowing but may occasionally pair with ineffective and incomplete lip sucking, characteristic 
of more immature patterns. We may use manual triggering by a research assistant or triggering by the 
EMG at the buccinator muscle to ensure accurate delivery of impulses and pairing of impulse with 
sucking/swallowing. 
 
The stimulation will continue until the baby stops sucking, at which point the stimulation will be stopped 
and the timer will stop, until the baby begins to suck again. The typical feeding OT session lasts up to 
30 minutes. Physiological data will be monitored continuously as measured by the echocardiogram 
(ECG). Neonatal Infant Pain Scale (NIPS) data will be collected at beginning, middle and the end of 
treatment session. The NIPS rating scale currently in use in the nursery is included in this submission. 
These studies will be conducted in both level II and III Neonatal Intensive Care Units (NICUs), 
depending on the location and of the enrolled participants.  
 
taVNS Device  
 
tVNS will be delivered to the left ear only using an active (tragus) location for the taVNS clip using 
either the Digitimer Type DS7AH (Digitimer Ltd, Hertfordshire, England) or Soterix 0125-LTE stimulator 
customized for our infant trials. Both are TENS units and are cleared by the FDA for electrical nerve 
stimulation in research trials (See uploaded documents from Soterix). We also recently received FDA 
Breakthrough device designation for our BabySTrong taVNS infant feeding system, based on a 
customized 0125-LTE Soterix taVNS unit. TENS units are widely used in children with overactive 
bladder and dysfunctional voiding and stooling (44-45) and for analgesia in children, and as a treatment 
for chronic pain, including cancer (46). A custom electrode, embedded within a carbon matrix will be 
used to stimulate the auricular branch of the vagal nerve at the tragus. We will then trigger the  taVNS 
unit to deliver the microcurrent or to stop the microcurrent when the infant is actively sucking and 
swallowing.  
 
Safety Monitoring   
 
Prior to determination of the daily sensory threshold of the infant, an initial pain level will be recorded 
using the NIPS. Previous studies using pain as a marker for safety in neonates check for pain halfway 
through the respective treatment (39-40). TENS treatments in studies examined in creating our protocol 

Page 12 of 23 
 
 
 
typically lasted 30 minutes (41-43). Because the duration of the taVNS-paired feeding varies daily and 
will ultimately exceed 10 minutes, we will record pain levels before, at the end of treatment, and 
additionally at 5 and 10 minutes for longer sessions. This is shown in more detail in the In Session Form 
included.  
 
In an effort to standardize delivery of taVNS-paired feeding treatment, the taVNS device will placed in 
the left ear as default. Skin redness at the site of taVNS attachment to the ear is possible after treatment, 
but is expected to be transient. In order to prevent injury to the skin in contact with the device, each day 
the left ear will be first examined for redness prior to attaching the taVNS device However, if there is skin 
redness at the site attachment to the ear prior to each day’s treatment, we will switch the stimulation that 
day to the right ear.  If these symptoms are persistent, we will decrease the stimulation.   
 
ECG will be monitored during each treatment session. The HR measures will provide valuable data for 
safety analysis as well as immediate markers for physiological safety during taVNS-paired feeding. 
Bradycardia will be defined by NICU standards of <80bpm for 5 seconds. 
 
In all sessions of taVNS-paired feeding, Dr. Jenkins or research staff trained in taVNS will be present. At 
any point during taVNS-paired feeding, the research staff will decrease stimulation intensity, if they feel 
the participant is in mild distress.  
 
Developmental follow-up 
Developmental follow-up is routine in all preterm and HIE infants, with clinical visits occurring every 3 
months at Neonatal High-risk clinic. If parents do not bring their infants back for standard of care 
developmental testing, and if more convenient for parents, the developmental testing will be performed 
by Drs. Coker-bolt and/or Aljuhani in the home or other location of the parent's choosing. Developmental 
testing in the home will be free of charge, and test information will be discussed with parents during the 
testing session and then uploaded into EPIC for other care providers. 
 
Payment 
 
No payment will be provided in this trial. 
 
Data Analysis 
 
For safety we will compare HR changes from baseline to during taVNS within subjects. We will 
compare treatment before and after the taVNS-paired feeding treatment for the rate of feeding volume 
increase, and days to full po feeds. We will use repeated measures ANOVA to analyze repeated 
measures such as HR over 5 minutes and mean daily feeding volumes in 7-10 day epochs. We will 
analyze the number of infants who reach full feeds vs requiring G-tube during taVNS-paired feeding, 
between once and twice daily stimulation by Chi-squared. We will assess differences in kurtosis 
parameters from pre-to post taVNS scans by paired t-test, and between those that reach full oral feeds 
vs those that require a Gtube by unpaired t-test. 
 
Estimated Difficulties, Limitations and Time Frames 
 

Page 13 of 23 
 
 
 
Estimated Difficulties. Many of the initial parameters for taVNS in humans, such as frequency and pulse 
width, were accomplished in trials at MUSC by Badran et al. that were approved by the IRB. In one 
sense, we will be shrinking many of the components into miniature form to deliver stimulation to 
neonates and infants. In spite of the clear differences in size and skin between the neonatal and adult 
ear, the custom electrodes have been fitted to several different weights of infants (2.5-4.0 kg).  
 
Limitations. We will not be delivering a SHAM stimulation paradigm (electrodes and Digitizer with 
appearance of taVNs treatment without actual current). Our goal is to determine safety and feasibility of 
active treatment with a dose response in order to investigate whether this should be administered in a 
larger randomized control trial. In this respect, the comparison we lose in not having a SHAM 
stimulation is offset by the validation we will receive in the safety and feasibility of active treatment. We 
will compare our overall results with characteristics of infants who required a Gtube from Dr Chapman 
and Ryan’s publications. 
 
Estimated Time Frames. The duration of the study will likely be ~4 years, with 2 years of active 
enrollment and 18 months of follow-up. 
 
E. PROTECTION OF HUMAN SUBJECTS 
 
1.  RISKS TO THE SUBJECTS  
 
The human subjects involved in this research will be preterm neonates or infants with critical illnesses 
that preclude oral feeding, such as HIE. Inclusion criteria involves 2 main groups. The first is comprised 
of typical pre-term, high risk neonates who are in the convalescent near and post-term period and 
learning to po feed. The second is comprised of neonates that present after severe medical illnesses or 
brain injury. In both cases, the infants can only be enrolled if they are stable, not making progress with 
OT training, and are in discussion for Gtube placement. Participants will be excluded if they have major 
unrepaired congenital abnormalities that limit volume of feeds, cardiomyopathy, significant autonomic 
instability, such as repetitive, unresolved bradycardia or apnea, or use a continuous positive airway 
pressure (CPAP) device or other form of high respiratory support preventing them from breathing 
without assistance.  
 
Targeted/Planned Enrollment Table 
 
Total Planned Enrollment: 40 babies (active)  
 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects receiving active 
taVNS 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
   4 
   5 
     9 
Not Hispanic or Latino 
  15 
 16 
     31 
Ethnic Category: Total of All Subjects* 
 

Page 14 of 23 
 
 
 
Racial Categories 
 
American Indian/Alaska Native 
 
 
 
Asian 
 
 
 
Native Hawaiian or Other Pacific Islander 
 
 
 
Black or African American 
8 
7 
15 
White 
12 
13 
25 
Racial Categories: Total of All Subjects* 
20 
20 
40 
 
 
 
 
*The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All 
Subjects”.  
 
Volunteers of all ethnicities and racial categories will be accepted into this study protocol. No 
preference will be given based on race, gender or ethnicity. No vulnerable populations or special 
classes of subjects will be considered for participation.  
 
b.  Sources of Materials  
 
Participants will be screened for eligibility in person by the PI (Jenkins). All participants enrolling in the 
study will be given an alphanumerical code that will be used to identify them. This code will be used to 
link participants to any identifying demographic information that is collected. Only the principal 
investigator and appropriate study staff will have access to the documents linking identifying information 
with alphanumerical codes. Infant data on medical conditions, significant clinical events including birth 
history, and postnatal course, as well as medications, and surgeries will be collected from EPIC.   
 
c.  Potential Risks  
 
taVNS has been conducted in individuals under the age of 18. Moreover, TENS has been used in 
several studies in neonates and young infants as detailed below.  A summary of potential risks in 
infants include the risk of skin irritation, discomfort, slightly decreased heart rate, and loss of 
confidentiality. The potential risks have been clearly outlined in the informed consent document. 
There are no alternative treatments, except the standard infant feeding with OT, speech or nurses. 
 
Potential Risks of taVNS 
taVNS is transcutaneous electrical nerve stimulation (TENS) of the auricular branch of the vagus nerve 
(ABVN) that innervates the ear. Although this novel therapeutic modality is still in the development and 
optimization process, risks are a combination of those to be expected by both the peripheral TENS and 
implantable cervical VNS. 
TENS devices are FDA approved for pain relief and are available over the counter. The main risks 
associated with TENS are electrical hazards that may result in user discomfort or injury. The unit used 

Page 15 of 23 
 
 
 
in these studies (Digitimer DS7AH) is a 510(k) cleared electrical stimulator that meets the rigorous 
electrical standards of the FDA. The Soterix© taVNS unit has been customized for our infants with a 
maximum current delivery of 2 mA and automatic shut-off after 120 seconds (See uploaded documents 
and letter from Soterix). The customized Soterix unit will be used in our BabyStrong device which has 
received Breakthrough Device designation from the FDA 12/8/2020. Skin irritation, redness, or 
inflammation may occur under the stimulating electrodes if TENS current is delivered for a prolonged 
period of time.  
Two studies have used TENS on neonates to try to prevent or mitigate painful procedures (39-40). The 
TENS was administered at acupuncture sites with increasing current from 1-3.5 mA, and Hz from 2-10 
in 30 healthy infants <3 days old. (39)  In a subsequent study, this investigative team randomized 162 
term neonates to TENS (3.5mA, 10Hz) or usual care to prevent pain from lancet heelsticks for blood 
sampling (40). These TENS parameters were safe and did not cause discomfort in the neonates.  
TENs has also been used with passive stretching in neonatal torticollis at 8Hz, 0.2mA for 30 minutes 
continuously (41) and in brachial plexus nerve injuries starting at 6 weeks of age to improve motor 
function of the hand, in conjunction with constraint induced movement therapy (42). Neither study 
reported adverse effects of electrical stimulation. TENS has also been used in peroneal and sacral 
nerve stimulation for dysfunctional voiding and stooling (44-45). Finally, the routine sweat test 
employed in newborns and infants to confirm the diagnosis of cystic fibrosis uses transcutaneous 
electrical stimulation to deliver pilocarpine via iontophoresis (43). From the product brochure of the 
Nanoduct™ Neonatal Sweat Analysis System (Discovery Diagnostics, Canada), the nominal current is 
0.5 (± 0.02) mA up to 5 mA for 2.5 minutes (± 0.2 Sec.). 
Implantable cervical VNS is FDA approved for the treatment of treatment resistant depression and 
intractable epilepsy in children as young as 8 months (47-49). Cervical VNS has risks associated with 
the procedure of implanting the nerve, and the surgery. None of those apply here. VNS does have 
some minimal risks that are due to the actual stimulation of the nerve within the neck such as skin 
irritation. tVNS also has associated risks that may arise from the direct brain effects stimulating the 
vagus nerve. These theoretical risks associated with neuromodulation of the parasympathetic nervous 
system would also be applicable in the administration of noninvasive tVNS. They are the following: 
reduction of heart rate, blood pressure, and vasovagal syncope. 
There have been dozens of studies in which tVNS has been used on humans, none of them reporting 
adverse events. A simple PubMed search for “transcutaneous vagus nerve stimulation” shows 24 peer-
reviewed articles, 15 of which have been published within the past 3 years. See below table for 10 most 
recent publications on PubMed involving tVNS on the auricular branch of the vagus in humans: 
Author, Year 
Aim (subject number) 
Side effects/Risks/AEs 
Aihua et al. 2014 
Epilepsy (n= 60) 
Dizziness, drowsiness 
Capone et al, 2014 
Cortical excitability 
(n=10) 
No modification of instantaneous HR, systolic 
BP, diastolic BP, and mean BP   
Kreuzer et al, 2014 
Tinnitus (n=50) 
Twitching and pressure at electrode site 
Rong et al, 2014 
Epilepsy (n=144) 
None reported 

Page 16 of 23 
 
 
 
Kraus et al, 2013 
tVNS/fMRI (n=16) 
A bright, prickling sensation, twinge or stabbing 
pain 
Rong et al, 2012 
Depression (n=120) 
None Reported – trial still under progress 
Kreuzer et al, 2012 
Safety Study (n=24) 
In those subjects with no known pre-existing 
cardiac pathology, preliminary data do not 
indicate arrhythmic effects of tVNS 
Busch et al, 2013 
Pain (n=48) 
No relevant alterations of cardiac or breathing 
activity or clinical relevant side effects were 
observed during t-VNS 
Stefan et al, 2012 
Epilepsy (n=10) 
Hoarseness, headache, or constipation 
Polak et al, 2009 
Far field potentials 
(n=20) 
Slight pain at electrode site 
An extremely through review of all tVNS literature has been performed and no harm or adverse events 
have been observed and any side effects were resolved by decreasing current intensity. There also is 
currently a commercial tVNS device available for purchase on the European market (Cerbomed - 
Nemos device; www.cerbomed.com) that is marketed as a take-home treatment for epilepsy.  
Not only does the current literature show a lack of harm done by tVNS, implantable cervical VNS also 
has a good safety record. According to Cyberonics, the company that supplies the cervical VNS 
implantable devices, there has been over 100,000 implanted patients being monitored by over 3,000 
providing physicians. Most side effects range from alteration of voice, coughing, pharyngitis, 
hoarseness, headache, and nausea. Cardiac evaluations have been made on hundreds of VNS 
patients with no changes in cardiac function (Handforth et al, 1998; Sackeim et al, 2001b; Morris and 
Mueller, 1999) with long-term safety confirmed in recent large sample retrospective studies (Menascu 
et al, 2013; Ryvlin et al, 2014; Choi et al, 2013).  
Bradycardia: Dr. Badran’s own safety studies in adults and this pilot study in infants designate a small, 
measurable change in heart rate which is not clinically significant (-3 and+6 bpm). Given the minimal 
risk of both of these already FDA approved methods, we intend to show that taVNS will continue to be 
a very safe procedure in neonates.  
 
2.  ADEQUACY OF PROTECTION AGAINST RISKS  
 
a.  Recruitment and Informed Consent 
 
This information is listed on the eIRB website.  
 
b.  Protection against Risk 
 
The following risks are present with this study: Risk of skin irritation, risk of discomfort, risk of slightly 
decreased heart rate, and risk of loss of confidentiality. 

Page 17 of 23 
 
 
 
Risk of skin irritation: we will monitor the skin on the inner aspect of the left ear before and after each 
session, and will switch to the right ear if redness is present, and decrease the stimulation if redness 
persists. 
 
Risk of discomfort: We expect to be able to use the pain ratings scales to identify the perception of 
tingling versus pain with taVNS in these infants. We will use facial expression change, fidgety 
movements and infant behavioral discomfort using our standard neonatal pain scale (NIPS) with the 
bedside nurse at the start and after 5 minutes of taVNS, at 10 minutes and at the end of treatment. We 
will protect against the risk of discomfort by close monitoring and by the determination of perceptual 
threshold using the protocol outlined above.  
 
We will hold the treatment for a NIPS score of >3, until discomfort subsides, and resume at a lower 
stimulus level if this level of discomfort recurs. We do not expect the infant to cry at this level, but show 
discomfort in brow furrowing, grimace, etc.  Feeding is generally comforting for infants, and we expect 
to see minimal pain response to treatment. Infants are fed sidelying in the nursery. We will position the 
baby so that the left ear is facing up, and we can monitor the site and pain without disturbing the 
feeding process unduly.  
 
Risk of slightly decreased heart rate: we will monitor HR, respiratory rate and oxygen saturation 
continually during the feeding to monitor these physiologic responses to taVNS-paired feeding. The 
infants’ vital signs are constantly monitored as standard of care while in the nursery. We will print out 
values at baseline, and changes with feeding and taVNS-paired feeding. Normal heart rate is 120-170 
beats per minute in preterm infants feeding, and 110-140 bpm in term HIE infants. As HR usually 
accelerates with motor activity of feeding, we do not expect significant bradycardic HR changes during 
the ‘on’ pulse. However, if the HR decreases to <100bpm during ‘on’ pulse, or if HR rebound is > 
190bpm during ‘off’ pulse, we will hold treatment and start again at a lower stimulation level.  
 
Risk of loss of confidentiality: We will assign study numbers to each participant, keep CRF and consent 
forms in locked cabinets in locked offices. Database files with names and contact information will be 
password protected and stored on the MUSC Pediatric server. All other data files related to this study 
will be identified by participant number only, without link to standard identifiers. We will publish the 
aggregate data only. MRI files are stored by participant study number and date of scan.  
 
3.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS  
 
taVNS paired with oromotor feeding training may enhance feeding skills, and enable the infants to learn 
this task more quickly and be discharged from hospital sooner. The treatment could potentially help 
avoid placement of a G-tube, but we will not be able to determine this from this dose-finding study. The 
treatment may also help with development of other motor skills, which we will assess by 
neurodevelopmental tests. We may also discover that taVNS-paired feed improves swallowing function, 
but even if we do not show any change in swallowing function, this data will support the safety of taVNS 
in neonates and infants.  However, there may be no direct benefit to the participant, but we will gain 
knowledge about taVNS in infants, and strategies to improve oromotor skill training. 
 
4.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED  

Page 18 of 23 
 
 
 
 
This trial could demonstrate the concept of “targeted plasticity” that could be used to enhance deficient 
networks in the preterm neonatal central nervous system. Behaviors integral to development such as 
feeding are impaired in this cohort, and if we can accelerate the learning of this behavior, we would 
greatly impact the recovery times and growth abilities of preterm or injured neonates. A positive 
connection between taVNS and learned motor function at such a critical time of development would 
contribute significantly to the field of neuronal plasticity and learned behaviors in neonates. 
If taVNS is shown to improve swallowing function, then this research may open up an entirely new 
treatment modality for these and other patients, such as post-stroke patients, who have swallowing 
problems. 
 
5.  SUBJECT SAFETY AND MINIMIZING RISKS (Data and Safety Monitoring Plan) 
 
Introduction 
The participants who receive active taVNS involved with this proposal will be neonates whose 
participation is agreed to by their guardians in written consent. The principal investigator will be 
responsible for monitoring the safety of the proposed experiments. She will also execute the Data Safety 
Management (DSM) plan and provide any necessary progress reports to the IRB, including but not limited 
to subject demographics, recruitment rates, retention rates, quality assurance issues, and adverse events 
or significant adverse events.  
Data and Safety Monitoring Plan 
Dr. Jenkins or her designee, should she be unavailable, will be responsible for reporting all unanticipated 
problems or AEs to the IRB. The PI will be present for each patient and record AE's real time.  Dr. George 
will be responsible for reporting any unanticipated device-related AE's to FDA. All screening data will be 
kept in a binder in the locked office in Dr Jenkins office. Screening data collected from participants who 
do not qualify for the study will be securely destroyed.  
Dr. Mark George, who is a board certified neurologist and psychiatrist, and Dr Badran will oversee the 
use of taVNS. Dr. Jenkins will also personally attend the sessions to monitor safety and adverse 
events. 
An independent Safety Monitoring Committee (SMC) will be formed to advise the study investigators. 
The SMC will review and evaluate accumulated study data to ensure safety. They also will make 
recommendations concerning continuation, modification, or termination of any of the taVNS studies. It 
will be composed of Dr. David Annibale, neonatologist; Dr. Jeff Borckardt, MUSC associate professor 
and assistant provost with extensive VNS, TMS, and tDCS experience. Patty Coker-Bolt, OT PhD, 
infant feeding expert, will be available to discuss subjective and objective measures of infant response 
during the taVNS experiments. Paige Merrill, clinical OT and infant feeding expert, is not involved with 
the study, but will be giving many of the feeds during the tVNS sessions, and may also be called upon 
for impressions of safety and infant response, if the safety committee requires it. 
Data will be discussed after the first five infants, and then again after 10 infants. The SMC will be 
notified immediately of any and all SAE's. We will report to the IRB the number of treatments held for 

Page 19 of 23 
 
 
 
HR or redness, discomfort. 
Dr. Jenkins will obtain informed consent, during which participants’ guardians are fully advised on the 
research procedures to be used, the amount of time required of them, the possible risks and benefits of 
the procedures, their right to refuse their infant’s participation in the study without prejudice, their right 
to terminate participation of their infant at any moment without prejudice, and the name and telephone 
number of the principal investigator.  
Electronic Consent will be used for situations when the parent (or Legally Authorized Representative) is 
at another hospital and cannot travel to MUSC to provide consent in person. We will use the approved 
REDcap system to obtain consent. Dr. Jenkins or other approved study personnel will go over the 
entire consent document on the phone with the parent to ensure comprehension and to confirm identity. 
Parent will be given a copy of the completed, signed consent form in person or by email or fax. 
Legal guardians will give informed consent. However, the Department of Social services may have 
custody of infant, but require the parent or foster parent to consent for all medical procedures. 
Regarding confidentiality, subjects’ guardians are informed that the information they provide, as well as 
participation in the study, will be kept strictly confidential, with access limited to the research staff. All 
paper records (consents, CRFs, study tools) will be kept in Dr Jenkins’ locked office, in a locked 
cabinet. The identity of subjects in databases will be protected with alphanumeric codes. All data will be 
kept in locked file cabinets or on secure servers designed for use and access by Brain Stimulation and 
Neonatology Lab members only.  
*Clinical Trials 
Unless required by a funding agency, this study will not be registered on clinicaltrials.gov, as it will be 
considered a Phase 0 trial, used for assuring safety and feasibility of the taVNS-paired feeding 
treatment. The potential for intellectual property development and patent application by MUSC will 
preclude disclosure of this invention. 
 
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G.CONSULTANTS___________________________________________________________________ 
N/A 
 
H. FACILITES AVAILABILITY  
These studies will be conducted in the NICUs, clinical units on the 5th floor of Shawn Jenkins 
Children’s Hospital. The portable taVNS devise will be brought to the nursery room for each taVNS 
session. The Brain Stimulation Lab (BSL) is a series of labs and offices (>3000 square feet) primarily 
located on the 5th floor of the Institute of Psychiatry (IOP). BSL studies use electromagnetic 
approaches as either research tools investigating neuroscience questions or as investigational or 
FDA approved treatments for brain diseases. Techniques actively being used by BSL researchers and 

Page 23 of 23 
 
 
 
their collaborators include: transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), 
transcranial direct current stimulation (tDCS), electroconvulsive therapy (ECT), deep brain stimulation 
(DBS) and epidural cortical stimulation (epCS). ECT, VNS and TMS are clinical services offered within 
the BSL. BSL researchers at MUSC were the first in the world (in 1998) to implant VNS devices in 
patients with major depression who had not adequately responded to traditional antidepressants.  
 
I. INVESTIGATOR BROCHURE ____________________________________________________ 
N/A 
 
J.APPENDIX_______________________________________________________________________ 
N/A