Pilot Study--The Effects of Non-invasive Vagal Neurostimulation (nVNS) in Adolescents With Postural Orthostatic Tachycardia Syndrome (POTS)
Phase: NA
Conditions: Postural Tachycardia Syndrome, Autonomic Dysfunction, Postural Orthostatic Tachycardia Syndrome, POTS - Postural Orthostatic Tachycardia Syndrome
Sponsor: Mayo Clinic

 
 
Pilot Study--The Effects of Non-invasive Vagal 
Neurostimulation (nVNS) in Adolescents with 
Postural Orthostatic Tachycardia Syndrome 
(POTS) 
  
 
NCT06268288 
 
9March2023 

Lytitia Shea, MD 
March 9, 2023 
Non-invasive Vagal Neurostimulation in Adolescents with  
Postural Orthostatic Tachycardia Syndrome (POTS)  
Title of project:  Pilot Study --The Effects of Non-invasive Vagal Neurostimulation (nVNS) in Adolescents 
with Postural Orthostatic Tachycardia Syndrome (POTS). 
Principle Investigator:  Lytitia Shea, MD, Division of General Pediatric and Adolescent Medicine, 
Department of Pediatric and Adolescent Medicine 
Co-principle investigators:  Shelley Ahrens, APRN, CNP, DNP; Kelsey Klaas, MD; Alexander Gurfinkel, 
MD; Amie Jones, MD 
Project summary: Excessive sympathetic stimulation and reduced vagal modulation is found in patients 
with postural orthostatic tachycardia syndrome, hyperadrenergic subtype. The use of non-invasive vagal 
neurostimulation (nVNS) in adolescents as treatment for many POTS- associated diagnoses including 
irritable bowel syndrome, depression, and chronic abdominal pain has resulted in statistically significant 
symptom improvement [1-3]. Dana Shiffler’s study in 2021 showed that use of transcutaneous VNS for 
14 days in 16 adults with hyperadrenergic POTS resulted in an increase in vagal stimulation, a decrease 
in sympathetic discharge, and improvement in dysautonomia symptoms [4].  
Two types of non-invasive vagal neurostimulation devices exist including auricular and neck stimulated 
devices. Numerous research studies utilizing the device gammaCore [5], a non-invasive handheld 
medical device that is applied to the side of the neck and sends gentle patented mild electrical 
stimulation through the skin to activate the vagus nerve, have been conducted to decrease symptoms 
such as nausea, headache, abdominal pain, tinnitus, and Parkinson symptoms.  
Currently the multifaceted mode of management for POTS patients at Mayo Clinic General Pediatric and 
Adolescent Medicine department (i.e. recovery STEPS) [6], including increasing fluid and salt intake, 
slowly increasing duration and intensity of exercise, utilizing prescription medications, and 
implementing biobehavioral modalities can be overwhelming and discouraging for adolescent patients 
suffering from POTS. Use of GammaCore neurostimulation as an additional treatment modality in 
addition to the recovery STEPS for POTS may serve to improve cardiac autonomic profile and decrease 
symptom intensity. It may also help young adults exercise more on a weekly basis and decrease 
headache frequency.  
Specific aims:  
Specific Aim 1: To determine if nVNS will decrease autonomic symptom intensity (COMPASS-31 total 
score) in comparison to standard recovery STEPS management. 
Hypothesis:  Use of VNS will decrease autonomic symptom intensity compared to control group 
(decrease the COMPASS score). 
Specific Aim 2:  To determine if nVNS with result in improvement in functioning (Child Functional 
Disability Inventory, cFDI, total score). 
Hypothesis:  Use of nVNS will improve the child function (decrease in the cFDI score) 

Specific Aim 3:  To determine if nVNS with result in less heart rate variability with tilt table testing.  
Hypothesis:  HR variability will show less of an increase in treatment group compared to control group.  
Secondary aims: 
Secondary Aim 1:  To determine if utilization of nVNS influences headache frequency.  
Hypothesis:  Headache frequency will decrease in treatment group more than in the control group. 
Secondary Aim 2:  To determine if utilization of nVNS will influence weekly duration of aerobic exercise.  
Hypothesis:  Weekly exercise duration will increase more in the treatment group than in the control. 
Background and significance: 
The incidence of Postural Orthostatic Tachycardia syndrome in the United States is estimated to be 
500,000 to 2 million people [7]. Despite being first described in 1993 [7], this syndrome continues to be 
underdiagnosed. In addition, institutions with programs designed to help adolescents with POTS by 
providing education, physical therapy, psychological therapies, and biobehavioral programs are severely 
limited in number in the United States. 
Vagal nerve stimulation has been used since the 1990s for treatment of intractable epilepsy. Auricular 
neurostimulation therapy to the auricular branch of the vagal nerve utilizes a noninvasive device that 
delivers transcutaneous electrical nerve stimulation [8]. It has been used in multiple studies to decrease 
sympathetic nerve activity and augment vagal stimulation [9] in the treatment of conditions such as 
irritable bowel syndrome, depression, and chronic migraines. [1,10-11]. Other non-invasive vagal 
stimulation devices, such as gammaCore, have been shown in clinical studies to decrease symptoms 
such as depression, abdominal pain, tinnitus, and others. 
This study is clinically important because it may improve the symptoms of patients suffering from POTS 
minimizing both physical and psychological burdens. By improving symptoms, the adolescent patient 
can start to feel better and be able to function more fully in normal activities. Use of this device may 
help “jumpstart” improvement and decrease symptoms allowing the adolescent patient to be able to 
engage earlier in more physical activity. Physical activity which also improves the sympathetic/vagal 
modulation pathway [12] can then act synergistically to evoke a successful recovery program. A 
subanalysis looking at total weekly duration of aerobic exercise will also be conducted.  
Currently, the pediatric subspecialty groups at Mayo Clinic evaluate these same patients with autonomic 
dysfunction for a variety of related problems including headaches, migraines, abdominal pain, irritable 
bowel syndrome, constipation, pelvic pain, back pain, generalized musculoskeletal pain, arthralgias, 
difficulty concentrating, tremors, temperature dysregulation, dermatological conditions, and syncope. 
Often treatment modalities and medications provided are limited or are not successful in managing 
symptoms. The results of this study may also result in interesting subanalysis cohorts looking at specific 
symptom resolution such as frequency of headaches. 
The COMPASS-31 is a questionnaire of autonomic symptoms severity in 6 domains [13]. The scoring 
system yields individual autonomic domain symptom burden and a total score expressed as a 
percentage from 0-100 . A higher score indicates greater symptom intensity. The child Functional 
Disability Inventory (cFDI) evaluates activities of daily living such as walking, going to school, ability to do 

homework, etc [14]. Higher scores represent more difficulty. Pre-study, mid-study, and  post-study 
COMPASS-31 and cFDI questionnaires will assess change. Forms to chart daily headache frequency and 
aerobic exercise will be provided to each participant and evaluated for change over the two months of 
study duration.  
In the independent article “Safety and tolerability of transcutaneous vagus nerve stimulation in humans:  
a systematic review” by Redgrave et. al 1 , they review the safety of these devices in 51 studies.  Of the 51 
studies, 18 were transcutaneous vagus nerve stimulator devices utilized in the neck. Four studies did not 
report their side effect rate. The side effects are documented in this review article as percent 
participants with any side effects (%SE) and side effect rate per 100 hours of tVNS (%SE/100 h).  
In summary, of the 14 studies, eight had no side effects and 2 had side effect rates less than 1%.  Four 
studies had side effect rates greater than 1 % (bolded). These studies are documented in more detail 
below.  
All studies with neck transcutaneous vagal nerve stimulation: 
Altavilla 2015 study for chronic migraine used one dose for 90 seconds with 0%SE and 0%SE/100 h. 
Davies 2016 study for hemicrania continua; 0%SE. 
Frangos 2016 study involving experimental changes on fMRI had 0%SE and 0% SE/100 h. 
Gaul 2015 study for cluster headaches had 25% SE and 4.65 %SE/100 h. 
Goadsby 2014 for migraines had 13% SE and nothing recorded (NR) for %SE/100 h. 
Grazze 2014 study for migraine had 1% SE and 0% SE/100 h 
[Grazzi 2016 study for menstrual migraines had no data] 
Grazzi 2016 study for migraine without aura had 0% SE  
Kinfe 2015 study for cluster tic syndrome in one patient and 0% SE 
Kinfe 2015 study for migraine, sleep disturbance had 4% SE and 1.67 %SE/100 h 
[Lerman 2016 study for healthy volunteers’ nociceptive effects and no data on SE] 
[Magis 2013 study for headaches had no data on SE] 
Marin 2016 study for cluster headaches had 0% SE 
Paulon 2015 for gastroparesis had 0% SE and 0%SE/100 h 
Schulz-Stubner 2011 case report for hiccups had 1% SE 
[Silberstein 2016 study for migraine had no data] 
Silberstein 2016 for cluster headache had 6% SE and no data for %SE/100 hr 
Steyn 2013 case study for asthma had 0% SE and 0%SE/100 h 
 
Four studies with side effects greater than 1%: 

The Gaul study2 in 2015 investigating cluster headaches found similar adverse effects in the control 
group (no VNS) with 13/49 (27%) reporting adverse effects and the test group (with VNS) of 18/48 (38%) 
reporting any adverse effects.  They had four serious side effects (2 in each group) including cholecystitis, 
hematoma after surgery, genital herpes, and CH exacerbation.  None were considered to be related to 
VNS device. Their mild to moderate side effects included: cluster headaches, headaches, 
nasopharyngitis, dizziness, oropharyngeal pain, and neck pain.  Seven people discontinued the study due 
to side effects.  Four were in the control group and had chest pain, fatigue, depressed mood, or cluster 
headaches.  Three were in the VNS group and had complaints of hot, malaise, hematoma after planned 
surgery, and depressed mood.  
The Goadsby study3 in 2014 investigating acute migraine in 30 patients had mild stiff neck occur 4 times, 
frequent urination occur 4 times, lip or facial droop occur 2 times, and shoulder pain or spasm occur 2 
times. There were one each of the following: raspy voice, tinnitus in ear, moderate stiff neck, neck 
twitch, mild neck redness, moderate neck redness, mild neck swelling, cough, mild confusion X 2 hours, 
moderate dizzy, dizzy up to 60 miutes, fever, and joint pain. 
The Kinfe study4 in 2015 investigating migraines in 20 patients had a 4 % side effect rate with mild 
adverse effects including neck twitching and skin redness. They recorded a 1.67% side effect rate per 100 
hours of use. All these events were transient, occurred with period of stimulation and resolved quickly.  
There were no severe side effects.  Of note, this team used the same device as is planned in our study, 
the electroCore device, and used it in the same fashion.  
The Silberstein study5 in 2016 investigating cluster headaches was a very large, randomized, double 
blind, sham controlled trial of 150 people and used a VNS on half and a sham VNS treatment on another 
half of the patients.  This study utilized the electroCore device as well. Adverse device effects (ADEs) 
were reported by 35/150 (VNS 11 and sham 24) in the double-blind phase. Only one patient had a 
serious adverse effect during that double blind phase.  This patient had a cluster headache, multiple left 
extremity deep vein thromboses, abdominal aortic aneurysm, pneumonia, anasarca, respiratory failure, 
and urethral trauma.  These were categorized as non-device side effects. The common side effects in the 
Silberstein study were burning/tingling/soreness in 9 patients, skin irritation/redness in 9 patients, lip, or 
facial drooping/pulling/twitching in 8 patients and 7 with dysgeusia/metallic taste.  
CONCLUSION:  Upon review of all the studies utilizing the neck transcutaneous vagal nerve stimulation 
technique, 71% of these studies had patients that reported a very low rate of any side effects (0-1% of 
patients). In the studies that had higher than 1% of their patients report any side effects, the common 
side effects were primarily transient with use of the device and dissipated shortly after the stimulation.  
They were all primarily mild as well. These are detailed below: 
 
Adverse Effects: 
Skin irritation at neck site:  Common side effects included mild tingling, mild soreness, mild redness with 
use of the device.  A rare side effects included a stinging sensation. 
Neck and facial changes:  Common side effects that were concurrent with device usage included: lip or 
facial drooping, lip pulling, lip twitching, oropharyngeal pain, mild neck twitch, and mild neck stiffness. 

There were rare (1-2 person only) reports of raspy voice, tinnitus (ringing) in ear, neck swelling, 
moderate neck stiffness, and moderate neck/shoulder pain or spasm. 
Systemic changes: Common side effects included headache (in these headache prevention studies), mild 
dizziness, mild oropharyngeal pain, frequent urination, and metallic taste.  Rarely, patients have reported 
changes in temperature, malaise, depressed mood, fever, joint pain, moderate dizziness, transient 
confusion, and cough. 
 
Bibliography: 
1) Redgrave J, Day D, Laud PJ, Ali A, Lindert R, Majid A. Safety and tolerability of transcutaneous 
vagus nerve stimulation in humans/ a systematic review. Brain Stimulation. 2018;11; 1125-1238. 
Doi.org/10.1016/j.brs.2018.08.010.  
2) Gaul C, Diener HC, Silver N, Magis D, Reuter U, Anderson A, Liebler EJ, Staube A. Non-invasive 
vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache 
(PREVA): A randomized controlled study. Cephalalgia 2016, Vol. 36(6) 534–546. 
Doi.org/10.1177/0333102415607070.  
3) Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of noninvasive vagus nerve 
stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014 Oct;34(12):986-93. 
doi: 10.1177/0333102414524494. Epub 2014 Mar 7.PMID: 24607501 
4) Kinfe TM, Pintea B, Muhammad S, Zaremba S, Roeske S, Simon BJ. Et al. Cerical non-invasive 
vagus nerve stimulation (nVNS) for preventive and acute treatment of episodic and chronic 
migraine and migraine associated sleep disturbance:  preliminary findings from a prospective 
observational cohort study. J Headache Pain. 2015;16:101. Doi.org/10.1186/s10194-015-0582-9. 
Silberstein SD, Mechtler LL, Kudrow DB, Calhoun AH, McClure C, Saper JR, et al.  Non-invasive vagus 
nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-
blind, sham-controlled ACT1 study.  Headache. 2016:56:1317-32.  Doi.org/10.1111/head.12 
Experimental Design and Methods: 
Study Participants:  Patients will be recruited from the Mayo Clinic GPAM clinic. We will aim to recruit 
40 participants ages 12-19 years with Postural Orthostatic Tachycardia as diagnosed from a positive 
Mayo Clinic Autonomic Reflex Screen. Patient will have a 40 or greater increase in their heart rate during 
the tilt test without corresponding orthostatic hypotension (a fall in BP of >20 mmHg SBP or 10mm Hg 
DBP).  
Exclusion criteria:  Exclusion criteria includes orthostatic hypotension, pregnancy, prior neck surgery, 
any metallic implant near the stimulation site, known cardiac disorder (structural anomaly, prolonged 
QT interval, arrythmia or history of documented dysrhythmia), or use of feeding tubes. Additional 
exclusion criteria includes:  patients on other autonomic medications other than Metoprolol or 
Midodrine, inability to independently utilize the GammaCore device, inability to independently 
complete surveys, or patients receiving hormonal treatments other than OCPs.  
Informed consent: Participants (age 12-17 years of age) and guardians will review the informed 
assent/consent form (approved by Mayo Clinic’s institutional review board) with our study coordinator 

and signage is required by both the participant and a guardian prior to participation. Participants (age 
18-19 years of age) may sign their own consent forms. 
Stipend for return visit: A stipend of $60 will be provided to each patient who completes the repeat tilt 
table testing within 0-14 days of the study exit. 
Recruitment of subjects: Adolescent patients aged 12-19 years of age referred for autonomic 
dysfunction evaluation are recruited as potential subjects. The study coordinator will contact the 
patients prior to their arrival for the initial ARS and provide information regarding the possibility of 
enrolling in the research study if the patient meets the criterial for enrollment after clinic evaluation. 
Patients will undergo standard 3-part autonomic reflex screening (ARS). Those patients with a positive 
tilt test showing a heart rate increase of 40 or above (and no evidence of orthostatic hypotension) will 
be eligible for the study. Confirmation of negative pregnancy will be determined for each female 
participant prior to enrollment.  
Study design:  
A baseline Composite Autonomic Symptom Score (COMPASS-31) and a Child-Functional Disability 
Inventory will be completed upon enrollment. Subjects will also complete a patient health questionnaire 
(PHQ-9) for baseline observation. This will be completed every 2 weeks to monitor new onset or 
worsening depression as a side effect with the use of the device. For secondary analysis, our team will 
ask the participants to chart their daily aerobic exercise (minutes) and daily headache frequency (hours) 
plus estimated headache severity (mild, moderate, severe).  
All participants will be provided with our current standard POTS management recommendations 
including 4 key areas: non-caffeinated fluid intake of 90 ounces a day, increased intake of salty foods, 
recommendations to slowly increase daily aerobic exercise, and addition of medication (either 
metoprolol 25 mg po BID or Midodrine 5 mg po TID) per physician preference. See recovery STEPS 
protocol [6]. 
Patients will be randomly assigned to a group that receives the nVNS or a group that does not. 
Assignments will be stratified by sex. 
Enrolled patients will be taught how to use the vagus nerve stimulator on the right side of the neck for 
two 2-minute stimulations (termed “GammaCore intervention”). The nVNS should be self-administered 
3 times throughout each day utilizing two 2-minute stimulations per GammaCore intervention. 
At 4 and 8 weeks, each patient will again complete the COMPASS -31 symptoms list and the Child 
Functional Disability Inventory. The forms for charting daily headache frequency/severity and daily 
aerobic activity will be collected at 8 weeks.  
A repeat visit to Mayo Clinic is strongly encouraged at 8 weeks after baseline ARS testing for additional 
tilt table testing. 
Potential risks:  
Vagal neurostimulator possible adverse effects: pain, tingling, pruritus, and skin irritation. 

Skin irritation at neck site:  Common side effects included mild tingling, mild soreness, mild redness with 
use of the device.  A rare side effects included a stinging sensation. 
Neck and facial changes:  Common side effects that were concurrent with device usage included: lip or 
facial drooping, lip pulling, lip twitching, oropharyngeal pain, mild neck twitch, and mild neck stiffness. 
There were rare (1-2 person only) reports of raspy voice, tinnitus (ringing) in ear, neck swelling, 
moderate neck stiffness, and moderate neck/shoulder pain or spasm. 
Systemic changes: Common side effects included headache (in these headache prevention studies), mild 
dizziness, mild oropharyngeal pain, frequent urination, and metallic taste.  Rarely, patients have reported 
changes in temperature, malaise, depressed mood, fever, joint pain, moderate dizziness, transient 
confusion, and cough. 
Tilt table side effects:  symptoms of dizziness, visual changes, lightheadedness, nausea, vomiting, 
syncope.  
Confidentiality:  All information, data, results will be used for research purposes only and confidentiality 
will be assured by use of identification codes. Electronic data will be kept in a secure database, requiring 
a password for entry, and limited to study investigators only.  
Protection:  Volunteers will be assessed for concerns or symptoms at 4 weeks into the study. All 
participants have been provided contact information for the study coordinator. Subjects will also 
complete a patient health questionnaire (PHQ-9) for baseline observation. This will be completed every 
2 weeks to monitor new onset or worsening depression as a side effect with the use of the device. 
Benefits:  Participants all contribute to additional medical understanding of treatment modalities to 
alleviate or lessen POTS symptoms. Participants randomized to the use of the Gamma Core device may 
have less symptoms and decreased symptom intensity. Patients will receive remuneration for the study 
of $60 after completing the second tilt table test. 
 
Statistical Analysis:   
Aim #1 COMPASS 31 score improves 10 vs 20% from mean of 25. 
 
 

Aim #2 FDI questionnaire with 10 % vs 20% improvement  from mean of 30. 
 
Aim #3 Tilt table heart rate decrease 0 vs 20% from mean of 40. 
 
 
 
Statistics may include the following methods. Fisher exact test for comparison of simple categorical data 
between two groups. Two-sided two sample t test for normal, continuous data, presented as mean +/- 1 
SD. Two-sided 2 sample Mann Whitney test for non- normal, continuous data, presented as median. 
Significance calculated as p values of <.05  and 95% confidence intervals. 
Summary:  There are not published data for mean and variance COMPASS 31 and cFDI data in 
adolescents with POTS. This makes power and number-to-treat estimates difficult.  
Project timeline: 
Participants are to be recruited into the study starting in May 2023 with a goal of 40 participants. Survey 
questionnaires and daily forms will be obtained at 4 and 8 weeks after entry. Second tilt table tests will 
be performed at 0-14 days post study completion. Data analysis will be performed after completion of 
the program by the 40 participants. 

Expected Outcomes:  
The use of noninvasive vagal nerve stimulation in adolescent patients with postural orthostatic 
tachycardia syndrome will result in a decrease in autonomic symptoms as per COMPASS-31 
questionnaire and a decrease in heart rate variability as seen in repeat tilt table testing. We expect to 
see a decrease in symptoms (COMPASS-31)  in our standard care group of 10% and an additional 
decrease of symptoms in our Gamma Core group of 10% (total decrease of 20% in the GammaCore 
group). We expect to see a 10% decrease in cFDI scores and an additional 10% decrease in cFDI scores in 
our Gamma Core group (total of 20% decrease). We expect to see a 20 % decrease in heart rate increase 
with repeat head up tilt table testing in the GammaCore group only. 
 
 
 
  
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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