Neuromodulation With Percutaneous Electrical Nerve Field Stimulation for Adults With Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study
Phase: NA
Conditions: Irritable Bowel Syndrome, Abdominal Pain, Autonomic Nervous System Imbalance
Sponsor: University of California, Los Angeles

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
1 
 
 
 
 
 
 
 
 
 
 
 
Neuromodulation with Percutaneous Electrical Nerve Field Stimulation for Adults with Irritable Bowel 
Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
NCT04428619 
 
12/27/2022 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
2 
 
Study Ti 
Investigator-initiated proposal 
Project Title: Neuromodulation with Percutaneous Electrical Nerve Field Stimulation for Adults 
with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
Principal Investigator: Lin Chang, MD1, 2 
Co-Investigator: Adrienne Lenhart, MD2 
Research Coordinators: Eileen Liu1,2, Cathy Liu1,2, Ariela Khandadash1,2 
Affiliation: 1G Oppenheimer Center for Neurobiology of Stress and Resilience, 2Vatche and Tamar 
Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at 
UCLA 
 
 
A. SUMMMARY: 
Irritable bowel syndrome (IBS) has a worldwide prevalence of 11.2%1 and is characterized by chronic or 
recurrent abdominal pain associated with altered bowel habits2. Visceral hypersensitivity and dysfunction 
within the autonomic nervous system (ANS) and immune function are important components contributing 
to the pathophysiology of irritable bowel syndrome (IBS). Despite recent advances in medical therapies for 
IBS, a significant subgroup of patients fails to experience satisfactory relief of abdominal pain. Given 
evidence of anti-inflammatory and anti-nociceptive components of vagal nerve pathways, peripheral field 
stimulation of the vagus nerve may help reduce visceral sensitivity in IBS patients. Percutaneous electrical 
nerve field stimulation (PENFS) administered via the IB-Stim device (Innovative Health Solutions, 
Versailles, IN, USA) has been shown to be efficacious in pediatric patients with abdominal-pain-related 
functional GI disorders3. PENFS was associated with a greater reduction in their worst abdominal pain and 
overall composite pain scores compared with a sham device after three weeks of treatment. These effects 
were sustained over an extended follow-up period with minimal to no side effects. This IB-Stim is the first 
device to be approved by the Food and Drug Administration (FDA) for the treatment of functional 
abdominal pain in adolescents aged 11-18 with IBS. However, the efficacy of PENFS in adults with IBS is 
not unknown. We propose to perform a double-blind, randomized, sham-controlled pilot study evaluating 
the efficacy of PENFS using IB-Stim for the treatment of IBS symptoms in adult patients with IBS.  
 
B. HYPOTHESIS AND SPECIFIC AIMS: 
 
Hypotheses: 
In adult patients with IBS, compared to sham therapy, PENFS therapy will be associated with: 
1. A greater reduction in IBS Severity Scoring System (IBS-SSS) scores after 4 weeks of treatment 
and at extended follow-up (8 weeks) compared to baseline in adult patients with IBS  
2. An increased proportion of abdominal pain responders after 4 weeks of treatment 
3. A greater improvement in weekly average worst abdominal pain score after 4 weeks of treatment 
and at extended follow-up (8 weeks) compared to baseline. 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
3 
 
4. A greater improvement in weekly average bloating scores after 4 weeks of treatment and at 
extended follow-up (8 weeks) compared to baseline.  
5. A greater reduction in cardiosympathetic/vagal tone as measured by heart rate variability (HRV)   
6. A greater improvement in disease-specific health related QOL (IBS-QOL). 
Primary Aim: 
1. To compare the efficacy of PENFS therapy versus sham therapy on the improvement of IBS 
symptom severity in adult IBS patients after 4 weeks of treatment compared to baseline, 
measured by the mean change in the IBS-SSS.  
 
Secondary Aims: 
To compare the efficacy of PENFS therapy versus sham therapy on:  
1. the change in mean IBS-SSS at week 8 compared to baseline.  
2. the proportion of adult patients with IBS who experience at least a 50-point reduction on the IBS-
SSS after 4 weeks of treatment and at the extended follow up period at week 8. These patients are 
considered clinical responders. 
3. the proportion of adult patients with IBS who experience an improvement of ≥30% from baseline 
in weekly average of the daily worst abdominal pain scores after 4 weeks of treatment. These 
participants are considered a responder.  
4. the change in mean weekly average of the daily worst abdominal pain scores after 4 weeks 
compared to baseline in adult patients with IBS.  
5. the change in average weekly abdominal pain symptoms after 4 weeks of treatment and at extended 
follow-up (8 weeks) compared to baseline, assessed through the PROMIS Gastrointestinal Belly 
Pain Scale. 
6. the change in average daily stool consistency after 4 weeks of treatment compared to baseline, 
assessed using the Bristol Stool Form Scale (BSFS). 
7. the change in average weekly bowel habits after 4 weeks of treatment and at extended follow-up 
(8 weeks) compared to baseline, assessed through the PROMIS Gastrointestinal Constipation Scale 
and Gastrointestinal Diarrhea Scale. 
8. the change in average weekly bloating symptoms after 4 weeks of treatment and at extended follow-
up (8 weeks) compared to baseline, assessed through the PROMIS Gastrointestinal Gas and 
Bloating Scale. 
9. the change in IBS-QOL in adult patients with IBS after 4 weeks of treatment and at extended 
follow-up (8 weeks) compared to baseline.  
10. the change in resting cardio-autonomic tone, i.e. HRV, over 4 weeks of treatment compared to 
baseline. 
11. the safety and tolerability of PENFS therapy versus sham therapy in adult patients with IBS.  
 
 
C. RESEARCH STRATEGY: 
Background and Clinical Significance: 
1. Irritable bowel syndrome: 
IBS is a chronic, functional gastrointestinal disorder (GI) disorder characterized by recurring episodes of 
abdominal pain, bloating, and changes in stool form and frequency. It represents one of the most commonly 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
4 
 
diagnosed GI disorders, with a prevalence around 11% worldwide1. IBS can negatively affect QOL, reduce 
work productivity, and lead to increased health care costs and expenditures of health care resources4. The 
pathogenesis of this disorder is complex and likely multifactorial, secondary to abnormalities in intestinal 
motility, visceral sensitivity, intestinal permeability, immune activation, the microbiome, and brain-gut 
interactions involving the afferent ascending and the efferent descending pathways2. 
Visceral hypersensitivity contributes to an intensified severity of abdominal pain in a large proportion of 
IBS patients, with an estimated prevalence ranging from 33-90% in different studies5-7. This phenomenon 
refers to altered sensation or enhanced perception of physiologic stimuli within the GI tract, which are 
interpreted as inducing pain or discomfort. It encompasses the notions of bothr hyperalgesia, which is 
defined as an intensified response to stimuli which typically induce pain, and allodynia, which denotes 
heightened nociception in the setting of benign stimuli. Although the pathophysiology of visceral 
hypersensitivity in IBS is not completely elucidated, proposed mechanisms include low grade mucosal 
inflammation, disturbed GI motility, and peripheral and central sensitization of the visceral afferent 
neuronal pathways8,9. 
The interactions between the gut and the central nervous system (CNS) are also exceedingly sophisticated 
and are responsible for modulating physiologic GI tract homeostasis10. The brain-gut axis encompasses 
both an intrinsic enteric nervous system primarily responsible for gut motility and peristalsis, as well as an 
extrinsic neural network made up of the vagus nerve (cranial nerve X) and spinal primary afferents that 
deliver sympathetic and parasympathetic innervation11-15. The vagus nerve represents one of the main 
components of the parasympathetic nervous system, conveying both afferent and efferent sensory 
information between the digestive tract and the CNS. Recent studies have also identified the vagus nerve 
as a potential modulator of intestinal immune function, exerting anti-inflammatory capabilities through the 
hypothalamic pituitary axis (HPA), the splenic sympathetic anti-inflammatory pathway, and the cholinergic 
anti-inflammatory pathway16. The vagus nerve is also believed to elicit anti-nociceptive effects, primarily 
through its projections to the nucleus tractus solitarius, which acts as a relay station to the rostral ventral 
medulla, hypothalamus, amygdala, and spinal cord, as well as through induced activation of the descending 
noradrenergic and serotonergic systems in the spinal cord that inhibit second order nociception neurons17-
19. The amygdala is an integral part of the limbic system, involved in fear conditioning, motivation, reward 
learning and emotional response to pain20. Interestingly, brain imaging studies have demonstrated altered 
functional connectivity between the amygdala and dorsal anterior insula within the default mode network 
in hypersensitive IBS21. 
An imbalance in autonomic nervous system (ANS) function in IBS patients may contribute to heightened 
visceral sensitivity and altered motility in response to stressors. Indicators of ANS dysfunction, include low 
vagal tone and increased sympathetic drive, in IBS patients compared to controls22-26. Cardio-vagal 
autonomic tone, expressed as heart rate variability (HRV), has therefore been utilized as a measure of 
overall as well as GI specific ANS function, with lower HRV associated with poorer autonomic health27. 
We and others have measured HRV in IBS compared to healthy controls. Studies have also shown that 
HRV correlates with rectal mucosal blood blow and colonic transit and may be attenuated in patients with 
IBS compared to healthy controls28. Different components of HRV can be used to describe function of the 
ANS, with power in high frequency (HF) signifying cardiovagal or cardiac parasympathetic activity, and 
the ratio of low-frequency (LF) power to HF power (LF/HF) representing cardio-sympathetic balance23,29-
33. 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
5 
 
Modulating central pain pathways through electrical stimulation of deep brain structures, the vagus nerve, 
and the spinal cord has also recently gained increased interest in the treatment of chronic pain syndromes, 
including IBS34,35. However, these aforementioned procedures are quite invasive, limiting their utility in 
many patients. Rather, a more ideal approach to treating chronic pain in IBS patients may be to potentially 
access central pain and vagal nerve pathways through peripheral, non-invasive techniques. A study in a rat 
model of post-inflammatory hyperalgesia showed that PENFS attenuated baseline firing of amygdala and 
lumbosacral spinal cord neurons, resulting in decreased visceral and somatic hypersensitivity36. This 
intriguing observation subsequently led to a pilot study in humans that demonstrated that a short course of 
PENFS targeting cranial nerves V,VII, IX, and X, could rapidly and effectively decrease the signs and 
symptoms of opioid withdrawal without the use of pharmacotherapy37. More recently, Kovacic et al 
conducted a double-blind, randomized, sham-controlled trial evaluating PENFS in children with 
abdominal-pain-related functional GI disorders3. Children in the PENFS group, who effectively underwent 
peripheral vagal nerve stimulation, had a greater reduction in their worst abdominal pain and overall 
composite pain scores compared with sham after three weeks of treatment. These effects were sustained 
over an extended follow-up period with minimal to no side effects. 
Despite the promise that PENFS has shown in the treatment of adolescents with IBS, there are currently no 
studies of PENFS in adult IBS patients. The discovery of non-pharmacologic options for adult IBS patients 
is paramount, because despite recent advances in dietary and medical therapies for IBS, a high percentage 
of patients do not completely respond to currently available treatments. For instance, in a randomized 
controlled trial evaluating the efficacy of a diet low in fermentable oligosaccharides, disaccharides, 
monosaccharides, and polyols (FODMAPs), around 50% of IBS patients did not report clinically significant 
reductions in IBS severity scores38. Linaclotide and plecanatide are both guanylate cyclase agonists that 
increase intracellular levels of cGMP, activating the cystic fibrosis transmembrane conductance regulator, 
which leads to secretion of chloride, bicarbonate, and fluid into the intestinal lumen and ultimately 
accelerates intestinal transit39. In animal models, linaclotide also reduces the firing of afferent pain fibers, 
presumably decreasing visceral hypersensitivity40. However, in a phase 3 randomized controlled trial of 
linaclotide in constipation predominant IBS (IBS-C) patients, 63.4% of patients failed to meet the criteria 
for endpoint abdominal pain response (improvement of  30% from baseline in average daily worst 
abdominal pain scores)41. In addition, 48% of patients receiving linaclotide failed to demonstrate clinically 
meaningful improvement in IBS-related QOL (IBS-QOL)41. Similarly, in two trials comparing different 
doses of plecanatide, between 69.8% and 78.5% of IBS-C patients did not achieve the combined endpoint 
of a  30% reduction from baseline in worst abdominal pain plus an increase in 1 complete spontaneous 
bowel movement42.  
The percentage of patients with diarrhea predominant IBS (IBS-D) who reported a clinically significant 
improvement in abdominal pain was slightly higher in trials of eluxadoline, a peripherally acting mixed -
opioid receptor agonist, --opioid receptor antagonist, and -opioid receptor agonist. However, after 12 
weeks of therapy, between 49.0% and 57.5% of patients still did not meet the endpoint response for 
improvement in abdominal pain43. In addition to low clinical response rates, many of these medications 
approved for IBS elicit undesirable side effects, which limit their use in certain individuals. Cognitive 
behavior therapy (CBT) has also been utilized successfully in IBS patients through targeting of the 
psychological factors that contribute to GI symptoms44,45. However, only a small proportion of IBS patients 
are actually referred for CBT, largely secondary to barriers including cost, therapist and resource 
availability, and underlying stigmas.  

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
6 
 
Overall, the high prevalence of IBS in adults, the negative effect of this disorder on QOL, and the lack of 
medications that successfully alleviate abdominal pain symptoms illustrate the need to develop effective, 
non-pharmacologic therapies to better treat IBS patients.  Given evidence of anti-inflammatory and anti-
nociceptive components of vagal nerve pathways, peripheral field stimulation of the vagus nerve may help 
reduce the visceral sensitivity component of abdominal pain in IBS patients. This technique of PENFS has 
already been successfully demonstrated in adolescents with functional abdominal pain, but trials in adults 
are lacking. If successful, PENFS could represent a favorable, non-pharmacologic treatment option for adult 
patients with debilitating IBS related abdominal pain and other symptoms.  
 
Innovation: 
Percutaneous Electrical Nerve Field Stimulation (PENFS) 
An FDA-approved auricular device, IB-Stim, that utilizes the concept of PENFS to alleviate pain has 
recently been developed by Innovative Health Solutions (Versailles, IN, USA). This device uses 
discontinuous frequencies of stimulation to target central pain pathways through branches of cranial nerves 
V, VII, IX, and X that innervate the external ear and project to certain brainstem nuclei, including the 
nucleus tractus solitarius46-49.  As previously mentioned, Kovacic et al recently conducted a double-blind, 
randomized, sham-controlled trial evaluating PENFS in 115 children with abdominal-pain-related 
functional GI disorders3. Children in the PENFS group had a greater reduction in their worst abdominal 
pain and overall composite pain scores compared with sham after 3 weeks of treatment, and these effects 
were sustained over an extended follow-up period of 8-12 weeks.  
Children in the PENFS group also had a reduction in their worst pain of  30% from baseline to 3 weeks 
of treatment compared with children in the sham group. Additionally, children in the PENFS group had 
greater scores on the Symptom Response Scale (median score of 3) compared to children in the sham group 
(median score of 1) at the end of 3 weeks; however, these effects were no longer significant at extended 
follow-up. Patients who received PENFS also showed significant improvement in functional disability at 
extended follow-up compared to the sham group. Side effects from the therapy were minimal (6 patients 
reported ear discomfort, 3 reported an adhesive allergy, and 1 reported syncope from needle phobia) and 
no serious adverse events were observed. This is consistent with a previously published retrospective cohort 
study of over 1,200 patients that reported minimal to no side effects with PENFS used for other 
indications50. In June 2019, the FDA approved the use of Innovative Health Solutions’ device, IB-Stim, to 
treat functional abdominal pain associated with IBS in adolescent patients between the ages of 11 and 18 
years old. Again, there are currently no trials of PENFS in adult IBS patients.  
Smart Watch Technology 
In collaboration with a UCLA research group led by Dr. Ramenzani (IRB IRB#16-000166) participants 
will have the option to be given a SmartWatch system. This system includes ambient location and activity 
sensors, wireless data transmission, specialized software application, and analytic engine for functional and 
performance measurement. This platform allows for the detection and classification of patient motion and 
position with an accuracy of over 85%. In this study, we want to be able to monitor subject activity and 
abdominal pain in real time. Data will also be collected to measure HRV. With collected of HRV data in a 
standard manner with each in-person visit, we will be able to validate SmartWatch measurements of HRV. 
 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
7 
 
Research Approach: 
1. Trial Design and Participants 
We will perform a prospective, double-blind, randomized, sham-controlled pilot study evaluating the 
efficacy of PENFS for the treatment of adult patients with IBS. Patients will be recruited from the outpatient 
GI clinics within the Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, as well as 
through community advertisements for physiologic or treatment related clinical trials and research studies 
by the UCLA G. Oppenheimer Center for Neurobiology of Stress and Resilience. New IBS patients or 
returning IBS patients who have continued abdominal pain even in the presence of medical therapy will be 
identified for participation in the study. The study will be approved by the institutional review board at 
UCLA.  
An informed consent form will also be approved by the UCLA institutional review board and will be signed 
by all eligible patients prior to participation in the study (consent will be conducted via telephone and 
patients will bring signed consent form to the first visit). Patients will be compensated $25 each time they 
participate in device placement and/or questionnaires (total compensation $175). Parking will be provided 
at the Ronald Reagan UCLA Medical Center for each visit. Driving compensation will also be provided for 
eligible participants. $50 will be compensated to participants if they live greater than a 10 mile distance 
from UCLA and $75 will be compensated to participants if they live greater than a 25 mile distance. Driving 
compensation will be provided through either a gift card or through addition to the subject’s stipend, via 
the participant’s preference. 
Patients will be allowed to continue any medication regimens that they are on prior to enrollment in the 
study as long as the doses are stable, meaning there can be no changes to medication doses that have been 
shown to relieve abdominal pain within 60 days of enrollment in the trial and to all other medications within 
30 days. The use of all medications will be carefully monitored each week to ensure that patients maintain 
consistent medication doses during the entire study. The initiation of new medications or non-
pharmacologic treatment for abdominal pain or other IBS symptoms will not be permitted during the trial 
period. 
Allowed concomitant therapy will include: 
• 
Fiber supplements (i.e. psyllium) 
• 
Polyethylene glycol (PEG) 
• 
Lactulose 
• 
Milk of magnesium 
• 
Magnesium hydroxide  
• 
Bisacodyl 
• 
Sennosides 
• 
Lubiprostone 
• 
Linaclotide 
• 
Plecanatide 
• 
Loperamide 
• 
Eluxadoline 
• 
Cholestyramine, colestipol, colesevelam 
• 
Alosetron 
• 
Rifaximin 
• 
Dicyclomine 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
8 
 
• 
Hyoscyamine 
• 
Peppermint oil (i.e. IBgard) 
• 
Tricyclic antidepressants (i.e. amitriptyline, nortriptyline, imipramine, desipramine) 
• 
Selective serotonin reuptake inhibitors (i.e. citalopram, paroxetine, fluoxetine) 
• 
Selective norepinephrine reuptake inhibitors (i.e. duloxetine) 
• 
Probiotics 
 
During the consent call, participants will be introduced to the option of the SmartWatch system. The system 
includes a watch and sensors. The watch interacts with the passive Bluetooth sensors to track the wearers 
activity. If participants elect to use the SmartWatch system, they will receive a daily question on the watch 
related to abdominal pain. This will allow researchers to track abdominal pain in real time. If participants 
do not elect to use the SmartWatch, they will complete this same daily abdominal pain question via an 
online questionnaire.  
 
2. Mandatory inclusion criteria: 
a. Adults, aged 18-60 years, who are able to provide written, informed consent 
b. Patients must meet Rome IV criteria for IBS2, confirmed by a gastroenterologist who 
specializes in functional GI disorders. Any of the IBS bowel habit subtypes (diarrhea, 
constipation, mixed bowel habits, unclassified) will be allowed.  
c. Average daily worst abdominal pain score between 4 and 8 (on a 0-10-point rating scale).  
d. Minimum of 2 days of abdominal pain/week prior to starting trial. 
e. At least moderate IBS symptom severity with an IBS-SSS 175 (total score range 0-500).  
3. Preferred, but not mandatory, inclusion criteria: 
a. Ability to wear SmartWatch on the upper extremity (left or right wrist)  
b. Willingness to have SmartWatch system sensors installed in home (30-60 minute process)  
 
4. Mandatory exclusion criteria: 
a. Patients under the age of 18 years or over the age of 60 years 
b. Patients who cannot provide informed consent or do not speak English 
c. Comorbid, organic medical conditions associated with abdominal pain, including: 
i. Inflammatory bowel disease, chronic liver disease, peptic ulcer disease, celiac 
disease, diverticulitis, appendicitis, colorectal cancer, endometriosis, pregnancy, 
other intestinal or extra-intestinal malignancies 
ii. Patients with overlapping functional GI disorders (i.e. functional dyspepsia) will 
not be excluded as long as IBS is their predominant disorder 
d. History of surgery involving CN V, VII, IX, or X. History of abdominal surgeries other 
than appendectomy or cholecystectomy at least 6 months before entry into trial. 
e. Patients on chronic opioids, benzodiazepines, or with illicit substance use 
f. Patients with underlying neurologic conditions, including history of: 
i. Seizures, CVA, uncontrolled migraines, traumatic brain injury, multiple sclerosis 
g. Patients with underlying psychiatric conditions 
h. Patients with dermatologic conditions affecting the ear, face, or neck region (i.e. psoriasis), 
or with cuts or abrasions to the external ear that would interfere with needle placement 
i. 
Patients with hemophilia or other bleeding disorders 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
9 
 
j. 
Patients with any implanted electrical device  
k. Patients who are pregnant or breastfeeding  
l. 
Movement disorder  
 
5. Preferred, but not mandatory, exclusion criteria: 
a. Unwillingness to wear the SmartWatch on upper extremity (left or right wrist) or have 
SmartWatch sensors installed in their home.  
 
6. Technology 
The IB-Stim/PENFS device consists of a battery activated generator and wire harness that connects to the 
generator. Four leads are also attached to the generator, each with a sterile 2 mm, titanium needle. Prior to 
device placement, the patient’s ear is cleaned with alcohol wipes and the ear is trans-illuminated to identify 
neurovascular bundles that are avoided during needle placement. The generator is attached with adhesive 
to the skin behind the patient’s ear, just above the mastoid process. Each of the 2 mm needles are inserted 
into the dorsal and ventral aspects of the ear, within 1-1.5 mm of the visualized vascular branches to create 
a field effect. The PENFS device settings are standardized and deliver 3.2 volts with alternating frequencies 
(1 ms pulses of 1 Hz and 10 Hz) every 2 s. This stimulation targets central pain pathways through branches 
of cranial nerves V, VII, IX, and X, which innervate the external ear. The PENFS device generator has a 
battery life of 5 days and delivers stimulations in 2-hour cycles. Patients remove the device at home on day 
6 of treatment. Original protocol from Kovacic et al3.  
 
 
 
 
 
 
 
 
Figures taken from Roberts et al (2016)50     
SmartWatch Software:  
Each SmartWatch contains a proprietary web-based application that is able to record, analyze and transmit 
activity data.  
Environmental Sensors/Beacons 
Sensors are 2.4 GHz radio using Bluetooth 4.0 Smart, also known as BLE or Bluetooth low energy beacons. 
These beacons are similar to small lighthouses that use only radio waves to communicate with any smart 
device in the range of 40-50 meters. . Smart devices, such as smartwatches, can receive the beacons’ signals 
and estimate the distance by measuring the received signal strength.                          
Patient with PENFS device 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
10 
 
 
7. Study Protocol 
Randomization and Masking: 
Patients who meet study eligibility criteria will be randomly assigned (1:1) in blocks of two and four, using 
a code generated by a randomization program to 4 weeks of stimulation with an active or inactive (sham) 
PENFS device. Allocation will be concealed, and all physicians, statisticians, participants, and research 
coordinators will be unaware of device codes. One research coordinator who has no patient contact (CL) 
will be unblinded and handle allocation and storage of devices.  
The sham devices will be identical to the active devices but will not administer electrical charges. Per 
manufacturer design and patient anecdotal experience from previous studies, both active stimulation and 
sham are below detectable sensation threshold. Per report from previous studies, some patients may 
experience a sensation around the ear after percutaneous needle placement; however, this sensation can 
occur with equal likelihood in the active or sham device3. All subjects will be asked if they believe they 
were randomized to the active PENFS therapy arm or the sham therapy arm at the end of 4 weeks of 
treatment, and these results will be analyzed.  
 
Assessments and Questionnaires: 
Administration of questionnaires throughout the study is shown in Table 1 and Figure 2.  
Patients will provide telephone consent for enrollment into the study. During the this phone call, the 
investigator will obtain the participant’s medical and medication history to check eligibility. After 
enrollment, patients will complete an online daily questionnaire to assess daily stool consistency (7-point 
Bristol Stool Form Scale [BSFS])51 and a daily question pertaining to daily worst abdominal pain (measured 
using an 11-point scale) that will be delivered by the smart watch, for one week prior to device placement. 
If patients do not elect to use the SmartWatch, then they will complete the daily question pertaining to daily 
worst abdominal pain via an online questionnaire. The questionnaires will provide a baseline for daily worst 
abdominal pain and stool consistency. In order to be enrolled into the study, patients must have an average 
daily worst abdominal pain score between 4 and 8, have a minimum of 2 days per week of abdominal pain, 
and have completed at least 4 out of 7 of the daily worst abdominal pain questionnaires.  
If enrollment criteria are met, patients will then present to the UCLA G. Oppenheimer Center for 
Neurobiology of Stress and Resilience one week after enrollment for their first visit, where they will get a 
physical examination, complete additional questionnaires, undergo a measurement of HRV, and have the 
initial PENFS device placed by a trained health care professional (LC, AL, EL). After initial device 
placement, patients will be instructed to return to UCLA every 7 days (leeway of +/- 2 days in each direction 
will be allowed) for a total of 4 visits for device replacement and completion of additional questionnaires. 
Four different devices will be placed in total (at the start of weeks 1, 2, 3, and 4).  
Although the IB-Stim device is currently FDA approved for use for 3 consecutive weeks, children in the 
original study by Kovacic et al actually received 4 consecutive weeks of device treatment3. The authors 
chose to analyze the data after 3 consecutive weeks as children did not return to the clinic after the 4th week 
of treatment. However, we will analyze IBS symptom severity, abdominal pain, bloating, and bowel habits 
after the completion of the 4th week of treatment. Again, actual stimulation time is 5 days per week with 2 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
11 
 
days off during each of the 4 consecutive weeks. The device is not waterproof and should be protected from 
water exposure. Patients will be instructed to either place a washrag in a small bowl and hold it over the ear 
while showering or will be provided with dry shampoo.  
Bowel Habit Classification: 
Bowel habits, defined by IBS-C, IBS-D, IBS-mixed type (IBS-M), and IBS-unclassified (IBS-U) will be 
assessed at baseline using the Rome-IV questionnaire.  
Bowel Symptom Questionnaire (BSQ): 
The BSQ evaluates general abdominal symptoms, GI tract specific symptoms, and bowel habits. It measures 
the severity of abdominal pain over the preceding week using a numerical scale ranging from 0-20, with 0 
representing no pain and 20 representing the most intense pain imaginable. This questionnaire will also 
evaluate bloating and the severity of overall IBS symptoms over the previous week, again using numerical 
rating scales from 0-20, with 0 corresponding to “no sensation/symptoms” respectively, and 20 referring to 
the “most intense sensation/symptoms imaginable”.  The BSQ will be measured at visit 1 for each patient 
in the trial. 
UCLA CNSR Participant Demographics: 
The UCLA CNSR Participant Demographics questionnaire will collect demographic information from 
study participants. The CNSR Participant Demographic questionnaire will be completed at visit 1 for each 
participant.   
Primary Endpoint:  
IBS Severity Scoring System (IBS-SSS) 
The primary aim of this study is to compare the efficacy of PENFS versus sham therapy on the improvement 
of symptom severity after 4 weeks of treatment in adult patients with IBS, using the IBS-SSS. The primary 
endpoint is the mean change in IBS-SSS at the end of week 4 compared to baseline. This questionnaire is 
a validated measure of IBS symptom severity and has been shown to be responsive to treatment in different 
studies38,52-56. It assesses severity of abdominal pain, frequency of abdominal pain, severity of abdominal 
distention, dissatisfaction with bowel habits, and interference of IBS with daily life over a 10-day period. 
Each of the five categories will receive a score from 0-100, and the total IBS-SSS is calculated by taking 
the sum of these categories (total score range 0-500). Patients will complete the IBS-SSS at week 1, after 
week 4 of treatment, and at extended follow-up (after 8 weeks). The IBS-SSS will be completed in person 
at visit 1 and via an online survey at the end of week 4 and during the extended follow-up period at week 
8. The online survey will be emailed to the patients the day it is to be completed, and a reminder email will 
be sent if the survey is not submitted. Improvement in symptom severity will be assessed using a mean 
change in IBS-SSS score from baseline to 4 weeks after treatment and from baseline to 8 weeks after 
treatment. 
Secondary Endpoints: 
IBS-SSS Responder Rate 
In addition, one secondary endpoint of this study will be to assess the proportion of clinical responders, 
using the IBS-SSS.  Clinical responders at the end of 4 weeks and at extended follow-up will be defined as 
those that have  50-point decrease on the IBS-SSS score from baseline. This is based upon a study by 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
12 
 
Francis et al that demonstrated that a reduction in 50-points correlated with clinically meaningful 
improvement52. Another secondary endpoint is the mean change in IBS-SSS at the end of the extended 
follow up period at week 8 compared to baseline. 
Daily Worst Abdominal Pain 
Other secondary endpoints of this study is the change in weekly average of the daily worse abdominal pain 
after 4 weeks of treatment compared to baseline and the proportion of patients with a 30% reduction from 
baseline in the weekly average of the daily worst abdominal pain scores after 4 weeks of treatment. A 30% 
reduction in worst abdominal pain score is a recommended primary endpoint by the Food and Drug 
Administration for IBS treatment trials and has been used in multiple clinical trials57. As previously 
mentioned, if participants elect to use the SmartWatch system, the watch will deliver one question assessing 
daily worst abdominal pain to each participant’s watch for one week prior to device placement to obtain a 
baseline.  This daily worst abdominal pain will be measured using an 11-point numeric rating scale. The 
smart watch will then deliver the same question assessing daily worst abdominal pain for the duration of 
the study. If the participant elects to not use the SmartWatch system, then this same question pertaining to 
daily worst abdominal pain will be completed via an online questionnaire, for the duration of the study.  
Patient Reported Outcomes Measurement Information System (PROMIS)58 
The PROMIS Gastrointestinal Belly Pain Scale is a validated questionnaire that assesses the severity of 
abdominal pain in adult patients over the previous 7 days. This scale incorporates aspects of abdominal 
pain intensity, discomfort, location, frequency, predictability, and extent to which the pain is bothersome.  
The PROMIS Gastrointestinal Gas and Bloating Scale assesses the frequency and intensity/severity of 
bloating, the appearance of abdominal swelling, flatulence, and abdominal gurgling/rumbling, and the 
degree to which bloating is bothersome or interferes with daily activities over the past 7 days.  
The PROMIS Gastrointestinal Constipation Scale will be used to assess the frequency and intensity of 
incomplete evacuation, rectal pain, straining, and hard stools. This scale will measure the extent to which 
constipation is bothersome or interferes with daily activities over the past 7 days.  The PROMIS 
Gastrointestinal Diarrhea Scale will be utilized to evaluate the frequency and severity of loose to watery 
stools and urgency during the previous 7 days.  
Each of the above PROMIS GI scales will be scored using percentile scores that are based on the general 
population. In order to accurately obtain percentile scores, the scale of each PROMIS question will be 
converted from 1-5 to 0-4. PROMIS questionnaires assessing bowel habits and the severity of abdominal 
pain and bloating will be assessed at baseline (visit 1), after each week of treatment (after weeks 1-4), and 
at extended follow-up. The questionnaires will be completed in person at baseline (visit 1) and after weeks 
1-3 (visits 2-4), and via online surveys after 4 weeks and 8 weeks. Response will be assessed by the change 
in composite abdominal pain scores, bloating scores, constipation scores, and diarrhea scores from baseline 
to 4 weeks after treatment and from baseline to 8 weeks (extended follow up) after treatment.  
Daily Bowel Habits: 
Baseline daily stool consistency will be assessed for one week prior to device placement (using 7-point 
BSFS). Daily stool consistency will again be assessed for one week after the 4th device placement. We will 
then compare the 4-week change-from baseline in stool consistency between patients who received the 
PENFS therapy compared to sham therapy.  

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
13 
 
IBS Quality of Life (IBS-QOL) 
Health-related QOL will be assessed using the IBS-QOL, a validated IBS specific survey containing 
questions that assess disease-specific QOL over the past 30-days, with lower scores indicative of poorer 
health-related QOL (score range 1-100). Patients will complete the IBS-QOL at baseline/visit 1 (in person) 
and at extended follow-up (week 8) using an online survey questionnaire.  
Hospital Anxiety and Depression Scale (HADS) and Visceral Sensitivity Index (VSI) 
Psychological symptoms will be evaluated using the HAD scale for depression and anxiety (each with a 
score range from 0-21). GI symptom related anxiety will be measured using the VSI. This questionnaire 
contains statements regarding how individuals may potentially react with anxiety, worry, or fear to different 
GI symptoms. Patients respond with how strongly they agree or disagree with each statement (0-strongly 
disagree to 5-strongly agree), with total scores ranging from 0-90. Patients will complete both the HADS 
and VSI at baseline/visit 1 and will also complete the VSI after 8 weeks of extended follow-up using online 
survey questionnaires.   
Heart Rate Variability (HRV) 
HRV will be assessed at baseline/visit 1 and at the end of weeks 1, 2, and 3 (visits 2, 3, and 4 respectively) 
of treatment, with the goal to determine if HRV (cardio-autonomic tone) changes over 4 weeks of PENFS 
treatment vs. sham treatment and if HRV predicts response to PENFS.  The previous protocols used for 
HRV analysis have previously been published by members of our research group and are summarized 
below59. HRV will be recorded for 5-minute intervals using a 2-lead electrocardiogram (ECG) attached to 
patients’ upper chest. ECG data will be collected using the BioPac recording system (MP100A-CE; BioPac 
Inc., Santa Barbara, CA, USA) and will be manually screened for artifacts. The AcqKnowledge peak 
detection algorithm (V3.8.2; BioPac, Inc.) will be used to determine intervals between adjacent QRS 
complexes. The interbeat (R-R) interval data will be used for HRV analysis (Kubios HRV 2.0, Biosignal 
Analysis and Medical Imaging Group, Dept. of Physics, University of Kuopio, Finland). Autoregression 
(AR) frequency analysis and Fast Fourier transform (FFT) analysis were performed on one continuous 2-
minute segment (epoch) of data to avoid inclusion of artifacts, which can distort HRV data60. The AR and 
FFT analyses should yield measures of HF power in normalized power based on a frequency band of 0.15-
0.4 Hz and the LF/HF ratio with LF power defined as the interval between 0.04 and 0.15 Hz. A model order 
of 16 will be used in the AR analysis with no spectral factorization. FFT analysis will use Welch’s 
periodogram method with a window width of 256 s and window overlap of 50%.  
The timing of device placements, questionnaires, and HRV assessment is further outlined in Table 1 and 
Figure 2. 
 
 
 
 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
14 
 
Table 1: Timing of PENFS vs Sham Interventions, Questionnaires, and HRV 
 
Daily  
Baseline 
Screening 
(Visit 1)  
End of 
Week 1 
(Visit 
2) 
End of 
Week 2 
(Visit 3) 
End of 
Week 3 
(Visit 4) 
End of 
Week 4 
8-week 
follow 
up 
Consent + 
Enrollment 
 
X 
 
 
 
 
 
 
History 
 
X 
 
 
 
 
 
 
Daily Worst 
Abdominal Pain 
(via Smart Watch) 
X 
X (daily for 
1 week) 
 
X (daily 
during 
week 1) 
X (daily 
during 
week 2) 
X (daily 
during 
week 3) 
X (daily 
during 
week 4) 
 
Daily BSFS 
 
X (daily for 
1 week) 
 
 
 
 
X (daily 
during 
week 4) 
 
Physical 
 
 
X 
 
 
 
 
 
PENFS vs Sham 
Device Placement 
 
 
X 
X 
X 
X 
 
 
Rome IV  
 
X 
 
 
 
 
 
 
Bowel Symptom 
Questionnaire 
(BSQ) 
 
 
X 
 
 
 
 
 
UCLA CNSR 
Participant 
Demographics 
 
 
X 
 
 
 
 
 
IBS-SSS 
 
X 
X 
X 
X 
X 
X 
X 
PROMIS 
Questionnaires 
 
 
X 
X 
X 
X 
X 
X 
IBS-QOL 
 
 
X 
 
 
 
X 
X 
HAD 
 
 
X 
 
 
 
 
 
VSI 
 
 
X 
 
 
 
X 
 
Heart Rate 
Variability 
 
 
X 
X 
X 
X 
 
 
 
8. Data Collection and Monitoring 
Demographic data and medical history information including co-morbid illness and medication history will 
be collected and recorded on password protected Excel documents. Questionnaire data collected at different 
visits will also be stored on password protected Excel documents. We will also monitor for and document 
any adverse events that occur during this trial. Patients will be given a phone number to call if any questions, 
concerns, or symptoms related to the device occur.  

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
15 
 
Secure Data Analytics For SmartWatches:  
As is the case in IRB #16-000166, data collected from the SmartWatch sensors and radio frequency beacons 
will be encrypted and transmitted through secure socket protocol (SSL). The SSL guarantees encryption 
and secure data transmission from patient’s home or rehab center to the server. Servers hosting the data are 
HIPAA compliant machines located on UCLA campus.  
9. Statistical Considerations 
Sample Size Calculation 
Power calculations determined that at least 22 patients would be needed in each arm in order to achieve 
95% power to detect at least a 30% reduction in worst daily abdominal pain scores. This power calculation 
was based on a study by Krasaelap et al61, which evaluated the efficacy of PENFS on at least a 30% 
reduction of worst abdominal pain severity in adolescents with IBS.  
We will aim for a sample size that will surpass the number needed to achieve at least 95% power, with a 
goal of 35 patients in each arm. We will also aim to enroll an additional 5 patients in each arm to account 
for potential dropouts or losses to follow-up. We will perform an interim analysis about one year after study 
enrollment has started or when each group has achieved completion of 22 subjects, whichever occurs first 
(will compare group data but not break the code). An estimate of the study profile is presented in Figure 1.  
Statistical Analysis 
Fisher tests will be used to evaluate for differences in categorical variables and a 2-tailed t-test and Mann-
Whitney-U (MWU) test will be used for assessing differences between normally distributed continuous 
data and non-normally distributed continuous data, respectively. The data will be analyzed using R 
statistical analysis software. 
The change in IBS-SSS score from baseline will be computed using a generalized linear mixed effect 
model. We will include treatment, time, and treatment x time as covariates. Tukey's honestly significant 
difference will be used for multiple comparisons. Data will be analyzed based on a modified intention-to-
treat approach. Specifically, patients with less than one full week of data will be excluded from the study.  
For all the secondary Aims, a simple 2-sample analysis (T-, MWU or Fisher’s) test for changes in outcomes 
will be performed. 
 
Figure 1. Study Profile 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
16 
 
 
 
 
BUDGET AND JUSTIFICATION 
IHS budget and devices 
We are requesting the supply at least 150 PENFS devices and 150 sham devices, by Innovative Health 
Solutions (IHS). Each completed subject will use 4 devices. We estimated the average number of devices 
used for a subject who drops out of the study to be 2. The breakdown for each group is the following: 
35 completed PENFS subjects x 4 PENFS devices per subject = 140 active devices 
35 completed sham subjects x 4 sham devices per subject= 140 sham devices 
5 PENFS dropouts x 2 PENFS devices per subject = 10 active devices 
5 sham group dropouts x 2 sham devices per subject = 10 sham devices  
 
Total number of devices is 300 with 150 PENFS devices and 150 sham devices.  
We are also requesting $100 payment per each completed patient (n=70) from IHS. This does not include 
the indirect cost associated with the direct cost.   
IHS Budget 
IHS will also provide $100 stipend reimbursement 
for 70 subjects (35 subjects/group)  
Direct Costs 
$7,000  

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
17 
 
Indirect Costs 
$1,820  
$8,820  
Direct Costs ($7,000) 
IHS will also provide $100 stipend reimbursement for 70 subjects (35 subjects/group) 
Indirect Costs ($1,820) 
University of California, Los Angeles federally negotiated indirect cost rate is 26.0% of modified total 
direct costs (excluding tuition, equipment, and subaward amounts over $25,000) per our F&A Rate 
Agreement with DHHS. 
 
UCLA budget and costs 
The remaining costs of the personnel, equipment, patient stipends, and statistical support will be provided 
by the PI and Division of Digestive Diseases. This will include a research coordinator to assist with patient 
recruitment and coordination for this project. Equipment to measure HRV is also available through the 
UCLA G. Oppenheimer Center for Neurobiology of Stress and Resilience at no additional cost. Budget is 
outlined in Table 2.  
Human Subject Stipends. Patient stipend payments include parking. Parking rate at UCLA is $13 per in-
person visit, each subject will have 4 in-person visits ($52/subject total). Patients will be paid stipends of 
$25 per set of questionnaires and we expect each subject to complete 7 sets of questionnaires not 
including the daily abdominal pain questionnaire (baseline, 4 visits, week 4 follow-up, week 8 follow-up). 
This equates to $175/subject, making the total payment per subject to be $227 with an additional driving 
compensation if applicable.  
 
Table 2. Budget and Justification 
Number subjects needed to meet 
“n” (15% drop out) 
 
 
N=35 per group + 5 
estimated dropouts 
per group (n=80 
total) 
Supplies 
$/unit 
#/subject 
 
Dry Shampoo 
$4.19 
4 
$1,357.56 
Urine Pregnancy Tests 
$2.00 
4 
$648 
PENFS Devices 
$0 
4 
$ -  
Sham Devices 
$0 
4 
$ -  
Subject Payments 
 
 
 
Questionnaires 
$25.00 
7 
$14,175.00 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
18 
 
Parking 
$13.00 
4 
$4,212.00 
Total Cost 
 
 
$20,392.56 
Funds from IHS (direct cost) 
$100 
70 
$7,000.00 
Remaining Cost to PI/UCLA 
 
 
$13, 392.56 
 
Figure 2. Timeline of Interventions and Questionnaires and Associated Cost 
 
  
 
 
References: 
1. 
Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-
analysis. Clin Gastroenterol Hepatol 2012;10:712-21.e4. 
2. 
Mearin F, Lacy BE, Chang L, et al. Bowel Disorders. Gastroenterology 2016. 
3. 
Kovacic K, Hainsworth K, Sood M, et al. Neurostimulation for abdominal pain-related functional 
gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet 
Gastroenterol Hepatol 2017;2:727-37. 
4. 
Pare P, Gray J, Lam S, et al. Health-related quality of life, work productivity, and health care 
resource utilization of subjects with irritable bowel syndrome: baseline results from LOGIC (Longitudinal 
Outcomes Study of Gastrointestinal Symptoms in Canada), a naturalistic study. Clin Ther 2006;28:1726-
35; discussion 10-1. 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
19 
 
5. 
Gwee KA, Lu CL, Ghoshal UC. Epidemiology of irritable bowel syndrome in Asia: something old, 
something new, something borrowed. J Gastroenterol Hepatol 2009;24:1601-7. 
6. 
Kanazawa M, Palsson OS, Thiwan SI, et al. Contributions of pain sensitivity and colonic motility 
to IBS symptom severity and predominant bowel habits. Am J Gastroenterol 2008;103:2550-61. 
7. 
van der Veek PP, Van Rood YR, Masclee AA. Symptom severity but not psychopathology predicts 
visceral hypersensitivity in irritable bowel syndrome. Clin Gastroenterol Hepatol 2008;6:321-8. 
8. 
Grundy D, Al-Chaer ED, Aziz Q, et al. Fundamentals of neurogastroenterology: basic science. 
Gastroenterology 2006;130:1391-411. 
9. 
Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology 
1994;107:271-93. 
10. 
Coss-Adame E, Rao SS. Brain and gut interactions in irritable bowel syndrome: new paradigms 
and new understandings. Curr Gastroenterol Rep 2014;16:379. 
11. 
Blackshaw LA, Brookes SJ, Grundy D, Schemann M. Sensory transmission in the gastrointestinal 
tract. Neurogastroenterol Motil 2007;19:1-19. 
12. 
Hansen MB. The enteric nervous system I: organisation and classification. Pharmacol Toxicol 
2003;92:105-13. 
13. 
Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst 2000;81:87-96. 
14. 
Delgado-Aros S, Camilleri M. Visceral hypersensitivity. J Clin Gastroenterol 2005;39:S194-203; 
discussion S10. 
15. 
Videlock EJ CL. Irritable Bowel Syndrome. In: Podolsky D CM, Fitz JG, Kalloo AN, Shanahan R, 
Wang TC, ed. Yamada’s Textbook of Gastroenterology: John Wiley & Sons, Ltd; 2015:1495-521. 
16. 
Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain-Gut Axis in 
Psychiatric and Inflammatory Disorders. Front Psychiatry 2018;9:44. 
17. 
Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann 
Neurol 1978;4:451-62. 
18. 
Randich A, Aicher SA. Medullary substrates mediating antinociception produced by electrical 
stimulation of the vagus. Brain Res 1988;445:68-76. 
19. 
Ren K, Randich A, Gebhart GF. Modulation of spinal nociceptive transmission from nuclei tractus 
solitarii: a relay for effects of vagal afferent stimulation. J Neurophysiol 1990;63:971-86. 
20. 
Simons LE, Moulton EA, Linnman C, Carpino E, Becerra L, Borsook D. The human amygdala and 
pain: evidence from neuroimaging. Hum Brain Mapp 2014;35:527-38. 
21. 
Mayer EA, Labus J, Aziz Q, et al. Role of brain imaging in disorders of brain-gut interaction: a 
Rome Working Team Report. Gut 2019. 
22. 
Thompson JJ, Elsenbruch S, Harnish MJ, Orr WC. Autonomic functioning during REM sleep 
differentiates IBS symptom subgroups. Am J Gastroenterol 2002;97:3147-53. 
23. 
Heitkemper M, Jarrett M, Cain KC, et al. Autonomic nervous system function in women with 
irritable bowel syndrome. Dig Dis Sci 2001;46:1276-84. 
24. 
Burr RL, Heitkemper M, Jarrett M, Cain KC. Comparison of autonomic nervous system indices 
based on abdominal pain reports in women with irritable bowel syndrome. Biol Res Nurs 2000;2:97-106. 
25. 
Waring WS, Chui M, Japp A, Nicol EF, Ford MJ. Autonomic cardiovascular responses are impaired 
in women with irritable bowel syndrome. J Clin Gastroenterol 2004;38:658-63. 
26. 
Aggarwal A, Cutts TF, Abell TL, et al. Predominant symptoms in irritable bowel syndrome 
correlate with specific autonomic nervous system abnormalities. Gastroenterology 1994;106:945-50. 
27. 
Wheat AL, Larkin KT. Biofeedback of heart rate variability and related physiology: a critical 
review. Appl Psychophysiol Biofeedback 2010;35:229-42. 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
20 
 
28. 
Emmanuel AV, Kamm MA. Laser Doppler flowmetry as a measure of extrinsic colonic innervation 
in functional bowel disease. Gut 2000;46:212-7. 
29. 
Elsenbruch S, Orr WC. Diarrhea- and constipation-predominant IBS patients differ in 
postprandial autonomic and cortisol responses. Am J Gastroenterol 2001;96:460-6. 
30. 
Elsenbruch S, Lovallo WR, Orr WC. Psychological and physiological responses to postprandial 
mental stress in women with the irritable bowel syndrome. Psychosom Med 2001;63:805-13. 
31. 
Tillisch K, Mayer EA, Labus JS, Stains J, Chang L, Naliboff BD. Sex specific alterations in autonomic 
function among patients with irritable bowel syndrome. Gut 2005;54:1396-401. 
32. 
Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. 
Task Force of the European Society of Cardiology and the North American Society of Pacing and 
Electrophysiology. Eur Heart J 1996;17:354-81. 
33. 
Berntson GG, Bigger JT, Jr., Eckberg DL, et al. Heart rate variability: origins, methods, and 
interpretive caveats. Psychophysiology 1997;34:623-48. 
34. 
Lind G, Winter J, Linderoth B, Hellstrom PM. Therapeutic value of spinal cord stimulation in 
irritable bowel syndrome: a randomized crossover pilot study. Am J Physiol Regul Integr Comp Physiol 
2015;308:R887-94. 
35. 
Bittar RG, Kar-Purkayastha I, Owen SL, et al. Deep brain stimulation for pain relief: a meta-
analysis. J Clin Neurosci 2005;12:515-9. 
36. 
Babygirija R, Sood M, Kannampalli P, Sengupta JN, Miranda A. Percutaneous electrical nerve 
field stimulation modulates central pain pathways and attenuates post-inflammatory visceral and 
somatic hyperalgesia in rats. Neuroscience 2017;356:11-21. 
37. 
Miranda A, Taca A. Neuromodulation with percutaneous electrical nerve field stimulation is 
associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective 
assessment. Am J Drug Alcohol Abuse 2018;44:56-63. 
38. 
Bohn L, Storsrud S, Liljebo T, et al. Diet low in FODMAPs reduces symptoms of irritable bowel 
syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology 
2015;149:1399-407.e2. 
39. 
Bryant AP, Busby RW, Bartolini WP, et al. Linaclotide is a potent and selective guanylate cyclase 
C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 2010;86:760-5. 
40. 
Castro J MC, Hughes PA, et al. A novel role of cyclic GMP in colonic sensory neurotransmission in 
healthy and TNBS-treated mice. Gastroenterology 2011;140:S-538. 
41. 
Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: 
a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J 
Gastroenterol 2012;107:1702-12. 
42. 
Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients 
with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J 
Gastroenterol 2018;113:735-45. 
43. 
Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for Irritable Bowel Syndrome with Diarrhea. 
N Engl J Med 2016;374:242-53. 
44. 
Ford AC, Lacy BE, Talley NJ. Irritable Bowel Syndrome. N Engl J Med 2017;376:2566-78. 
45. 
Lackner JM, Jaccard J, Keefer L, et al. Improvement in Gastrointestinal Symptoms After Cognitive 
Behavior Therapy for Refractory Irritable Bowel Syndrome. Gastroenterology 2018;155:47-57. 
46. 
Contreras RJ, Beckstead RM, Norgren R. The central projections of the trigeminal, facial, 
glossopharyngeal and vagus nerves: an autoradiographic study in the rat. J Auton Nerv Syst 1982;6:303-
22. 

 
 
PI Lin Chang                 
                                                           Neuromodulation with Percutaneous Electrical Nerve Field Stimulation 
for Adults with Irritable Bowel Syndrome: A Randomized, Double-Blind, Sham-Controlled Pilot Study 
 
 
9 December 2024 
21 
 
47. 
Zhang LL, Ashwell KW. The development of cranial nerve and visceral afferents to the nucleus of 
the solitary tract in the rat. Anat Embryol (Berl) 2001;204:135-51. 
48. 
Folan-Curran J, Hickey K, Monkhouse WS. Innervation of the rat external auditory meatus: a 
retrograde tracing study. Somatosens Mot Res 1994;11:65-8. 
49. 
van der Kooy D, Koda LY, McGinty JF, Gerfen CR, Bloom FE. The organization of projections from 
the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat. J Comp Neurol 
1984;224:1-24. 
50. 
Roberts A, Sithole A, Sedghi M, Walker CA, Quinn TM. Minimal adverse effects profile following 
implantation of periauricular percutaneous electrical nerve field stimulators: a retrospective cohort 
study. Med Devices (Auckl) 2016;9:389-93. 
51. 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol 1997;32:920-4. 
52. 
Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method 
of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther 1997;11:395-402. 
53. 
Drossman DA, Chang L, Bellamy N, et al. Severity in irritable bowel syndrome: a Rome 
Foundation Working Team report. Am J Gastroenterol 2011;106:1749-59; quiz 60. 
54. 
Kennedy T, Jones R, Darnley S, Seed P, Wessely S, Chalder T. Cognitive behaviour therapy in 
addition to antispasmodic treatment for irritable bowel syndrome in primary care: randomised 
controlled trial. Bmj 2005;331:435. 
55. 
Carruthers HR, Miller V, Morris J, Evans R, Tarrier N, Whorwell PJ. Using art to help understand 
the imagery of irritable bowel syndrome and its response to hypnotherapy. Int J Clin Exp Hypn 
2009;57:162-73. 
56. 
Lembo AJ, Conboy L, Kelley JM, et al. A treatment trial of acupuncture in IBS patients. Am J 
Gastroenterol 2009;104:1489-97. 
57. 
Guidance for industry: irritable bowel syndrome – clinical evaluation of drugs for treatment. 
Food and Drug Administration 2012 Available at:. at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory 
Information/Guidances/UCM205269.pdf. .) 
58. 
Spiegel BM, Hays RD, Bolus R, et al. Development of the NIH Patient-Reported Outcomes 
Measurement Information System (PROMIS) gastrointestinal symptom scales. Am J Gastroenterol 
2014;109:1804-14. 
59. 
Cheng P, Shih W, Alberto M, et al. Autonomic response to a visceral stressor is dysregulated in 
irritable bowel syndrome and correlates with duration of disease. Neurogastroenterol Motil 
2013;25:e650-9. 
60. 
Xhyheri B, Manfrini O, Mazzolini M, Pizzi C, Bugiardini R. Heart rate variability today. Prog 
Cardiovasc Dis 2012;55:321-31. 
61. 
Krasaelap A, Sood MR, Li BUK, et al. Efficacy of Auricular Neurostimulation in Adolescents With 
Irritable Bowel Syndrome in a Randomized, Double-Blind Trial. Clin Gastroenterol Hepatol 2019.