Autonomic Reactivity and Personalized Neurostimulation

NCT06863207 | Recruiting DMC FDA Device

• 2 other identifiers: PRO000510031R01DK140255-01
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Disorders of gut-brain interaction (DGBI) affect up to 25% of U.S. children. Patients often suffer from disabling, multisystem comorbidities that suggest a common root (sleep disturbances, fatigue, anxiety, etc). Yet, DGBI are defined and treated based on GI symptom origin (cyclic vomiting, dyspepsia, irritable bowel) rather than underlying pathophysiology. Many patients manifest comorbidities suggesting an underlying autonomic nervous system (ANS) dysregulation (palpitations, dizziness, cognitive dysfunction). Unfortunately, due to common features of anxiety and visceral hyperreactivity and lack of obvious pathology, children with DGBI are frequently diagnosed with psychosomatic or 'benign, functional disorders' and treated with empiric antidepressants despite lack of scientific support and risks of serious side effects. Little is known about the underlying brain-gut mechanisms linking these comorbidities. A lack of targeted treatment options naturally follows the paucity of mechanistic data. A dysregulated ANS response circuit via brainstem nuclei is linked to visceral hypersensitivity. As the team's prior research has shown, ANS regulation can be non-invasively measured via several validated indices of cardiac vagal tone. Using the novel vagal efficiency (VE) metric, the investigators have demonstrated inefficient vagal regulation in cyclic vomiting syndrome and pain-related DGBI and that low VE predicts response to non-invasive, auricular percutaneous electrical nerve field stimulation (PENFS) therapy. PENFS targets brainstem vagal afferent pathways and, along with brain-gut interventions such as hypnotherapy, are the only therapies currently proven effective for pediatric DGBI. Individualizing neurostimulation based on sensory thresholds while assessing dynamic ANS reactivity offers a path towards personalized medicine using the most effective therapies to date. This proposal will test the feasibility of an ANS tracking software in assessing real-time, autonomic regulation and providing individualized neurostimulation in children with nausea/vomiting and ANS imbalance.

Conditions

Cyclic Vomiting Syndrome; Functional Dyspepsia; Dysautonomia; Functional Gastrointestinal Disorders (FGIDs)

Keywords

autonomic dysfunction; auricular neurostimulation; gastric motor function; gut-directed hypnotherapy

Outcome Measures

Primary Outcomes (1)

• Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-37

  Validated quality of life instrument assessing physical, emotional, and psychosocial functioning in children across 6 domains (subscales). Scores range from 0 (minimum) to 5 (maximum). A lower score indicates improved quality of life for the Anxiety, Depression, Fatigue and Pain Interference domains/subscales. A higher scores indicates improvement in the Physical Function and Peer Relationships subscales. Scores are converted to a T-score where a score of 50 represents the mean.

  From enrollment to end of treatment at 6 weeks

Secondary Outcomes (1)

• 2. Patient Assessment of upper GastroIntestinal Symptom Severity Index

  From enrollment to the end of treatment at 6 weeks.

Study Arms (2)

PENFS (percutaneous electrical nerve field stimulation) therapy

EXPERIMENTAL

Personalized PENFS therapy x 6 weeks based on weekly autonomic nervous system assessments

Device: Percutaneous electrical nerve field stimulation

PENFS (percutaneous electrical nerve field stimulation) therapy + Hypnotherapy

ACTIVE COMPARATOR

Personalized PENFS therapy x 6 weeks based on weekly autonomic nervous system assessments + adjuntive hypnotherapy

Device: Percutaneous electrical nerve field stimulation; Behavioral: Hypnotherapy

Interventions

Percutaneous electrical nerve field stimulation DEVICE

Percutaneously nerve stimulator applied to the external auricle weekly for several consecutive weeks of therapy

PENFS (percutaneous electrical nerve field stimulation) therapy; PENFS (percutaneous electrical nerve field stimulation) therapy + Hypnotherapy

Hypnotherapy BEHAVIORAL

Gut-directed hypnotherapy delivered via audio recordings

PENFS (percutaneous electrical nerve field stimulation) therapy + Hypnotherapy

Eligibility Criteria

• Age: 11 Years - 18 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• to 18 years of age
• English speaking
• meeting Rome IV diagnostic criteria for cyclic vomiting syndrome or functional dyspepsia and willingness to participate and consent/assent to the study
• All subjects will have a constellation of chronic symptoms indicative of autonomic dysfunction for minimum 3 months: postural dizziness/lightheadedness, syncope, palpitations, fatigue, sleep disturbance, thermoregulatory abnormalities and cognitive impairment with upright position +/- abnormal autonomic testing if performed per standard of care as per American Autonomic Society consensus criteria.

You may not qualify if:

• Presence of organic disease that may explain symptoms
• Requirement for parenteral nutrition
• Developmental delays precluding accurate symptom report
• Severe dermatological condition or active infection of external or middle ear
• Implanted electrical device
• Severe mental health disorder not controlled by therapy (schizophrenia, bipolar disease, severe depression, post-traumatic distress disorder) and/or psychotic features which could influence symptom report or ANS measurements and result in adverse reactions to hypnosis therapy

Sponsors & Collaborators

• Medical College of Wisconsin: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Medical College of Wisconsin

Milwaukee, Wisconsin, 53005, United States

RECRUITING

Related Publications (9)

• Kolacz J, Roath OK, Lewis GF, Karrento K. Cardiac Vagal Efficiency Is Enhanced by Percutaneous Auricular Neurostimulation in Adolescents With Nausea: Moderation by Antidepressant Drug Exposure. Neurogastroenterol Motil. 2025 May;37(5):e15007. doi: 10.1111/nmo.15007. Epub 2025 Jan 30.

  PMID: 39888101 BACKGROUND

• Sclocco R, Garcia RG, Kettner NW, Isenburg K, Fisher HP, Hubbard CS, Ay I, Polimeni JR, Goldstein J, Makris N, Toschi N, Barbieri R, Napadow V. The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study. Brain Stimul. 2019 Jul-Aug;12(4):911-921. doi: 10.1016/j.brs.2019.02.003. Epub 2019 Feb 10.

  PMID: 30803865 BACKGROUND

• Kovacic K, Hainsworth K, Sood M, Chelimsky G, Unteutsch R, Nugent M, Simpson P, Miranda A. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol. 2017 Oct;2(10):727-737. doi: 10.1016/S2468-1253(17)30253-4. Epub 2017 Aug 18.

  PMID: 28826627 BACKGROUND

• Menys A, Keszthelyi D, Fitzke H, Fikree A, Atkinson D, Aziz Q, Taylor SA. A magnetic resonance imaging study of gastric motor function in patients with dyspepsia associated with Ehlers-Danlos Syndrome-Hypermobility Type: A feasibility study. Neurogastroenterol Motil. 2017 Sep;29(9). doi: 10.1111/nmo.13090. Epub 2017 May 31.

  PMID: 28568908 BACKGROUND

• Holtmann G, Goebell H, Jockenhoevel F, Talley NJ. Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia. Gut. 1998 Apr;42(4):501-6. doi: 10.1136/gut.42.4.501.

  PMID: 9616311 BACKGROUND

• Lewis GF, Furman SA, McCool MF, Porges SW. Statistical strategies to quantify respiratory sinus arrhythmia: are commonly used metrics equivalent? Biol Psychol. 2012 Feb;89(2):349-64. doi: 10.1016/j.biopsycho.2011.11.009. Epub 2011 Dec 3.

  PMID: 22138367 BACKGROUND

• Kovacic K, Kolacz J, Lewis GF, Porges SW. Impaired Vagal Efficiency Predicts Auricular Neurostimulation Response in Adolescent Functional Abdominal Pain Disorders. Am J Gastroenterol. 2020 Sep;115(9):1534-1538. doi: 10.14309/ajg.0000000000000753.

  PMID: 32732620 BACKGROUND

• Kolacz J, Kovacic K, Dang L, Li BUK, Lewis GF, Porges SW. Cardiac Vagal Regulation Is Impeded in Children With Cyclic Vomiting Syndrome. Am J Gastroenterol. 2023 Jul 1;118(7):1268-1275. doi: 10.14309/ajg.0000000000002207. Epub 2023 Jan 30.

  PMID: 36716443 BACKGROUND

• Venkatesan T, Prieto T, Barboi A, Li B, Schroeder A, Hogan W, Ananthakrishnan A, Jaradeh S. Autonomic nerve function in adults with cyclic vomiting syndrome: a prospective study. Neurogastroenterol Motil. 2010 Dec;22(12):1303-7, e339. doi: 10.1111/j.1365-2982.2010.01577.x.

  PMID: 20667005 BACKGROUND

Related Links

• Global clinical research data sharing platform that will be used as repository to share participant-level data once results are available.

MeSH Terms

Conditions

Gastrointestinal Diseases; Familial cyclic vomiting syndrome; Autonomic Nervous System Diseases; Primary Dysautonomias

Interventions

Hypnosis

Condition Hierarchy (Ancestors)

Digestive System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Mind-Body Therapies; Complementary Therapies; Therapeutics; Psychotherapy; Behavioral Disciplines and Activities

Study Officials

• Katja Karrento, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elaina Schueler, BS

CONTACT

4142663695; eschueler@mcw.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: March 3, 2025
• First Posted: March 7, 2025
• Study Start: January 24, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): June 1, 2029
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Scientific data will be made available no later than the time of an associated publication or the end of the performance period (June 2029), whichever comes first. The investigators anticipate that data will be available for approximately 7-10 years, provided that software upgrades during that time allow compatibility.
• Access Criteria: Any researcher can access de-identified IPD including study protocol, manual of operations, any data collection forms and results of primary outcome via Vivli Center for Global Clinical Research Data Repository.

Locations

US (1)