Autonomic Reactivity and Personalized Neurostimulation

NCT ID: NCT06863207

Last Updated: 2026-02-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-24
• Study Completion Date: 2029-06-30

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.

Detailed Description

The investigators hypothesize that children with cyclic vomiting syndrome (CVS) and chronic nausea/vomiting with concurrent symptoms of autonomic nervous system (ANS) dysregulation have reduced vagal efficiency (VE) that can be captured by the ANS Tracker software and modulated via adjustable percutaneous electrical nerve field stimulation (PENFS). Our overall goals are to: 1) expand knowledge on mechanisms of disorders of gut brain interaction involving VE and gastric function, 2) test a software that allows point of care VE assessment, 3) personalize PENFS parameters with real-time assessments of VE and gastric function, 4) combine and assess efficacy of two proven, effective therapies for DGBI that both modulate CNS.

The specific aims of this study are as follows:

Aim 1: Test the feasibility of real-time autonomic nervous system (ANS) tracking in children with nausea/vomiting and ANS dysregulation The investigators will test feasibility of assessing real-time ANS regulation by the VE metric using a novel ANS tracker software in response to posture shifts during PENFS with 1) standard and 2) personalized stimulation parameters based on sensory thresholds in female children with nausea/vomiting.

Aim 2: Compare efficacy and ANS changes with personalized PENFS +/- adjunctive hypnotherapy The investigators will assess outcomes of 6 weeks of personalized PENFS based on sensory threshold (Aim 1) vs. personalized PENFS with adjunctive hypnotherapy via weekly assessments of VE and symptom response. Baseline VE measurements will be correlated with outcomes to assess ability to predict treatment response.

Aim 3: Investigate dynamic gastric function in response to personalized PENFS The investigators will test real-time gastric function pre and post therapy (Aim 2 interventions) by advanced MRI in a subset of female patients vs. healthy controls.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PENFS (percutaneous electrical nerve field stimulation) therapy

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

Group Type: EXPERIMENTAL

Percutaneous electrical nerve field stimulation

Intervention Type: DEVICE

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

PENFS (percutaneous electrical nerve field stimulation) therapy + Hypnotherapy

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

Group Type: ACTIVE_COMPARATOR

Percutaneous electrical nerve field stimulation

Intervention Type: DEVICE

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

Hypnotherapy

Intervention Type: BEHAVIORAL

Gut-directed hypnotherapy delivered via audio recordings

Interventions

Percutaneous electrical nerve field stimulation

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

Intervention Type: DEVICE

Hypnotherapy

Gut-directed hypnotherapy delivered via audio recordings

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

• 11 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.

Exclusion Criteria

• 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

• Minimum Eligible Age: 11 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Katja Karrento

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Katja Karrento, MD

Role: PRINCIPAL_INVESTIGATOR

Medical College of Wisconsin

Locations

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Elaina Schueler, BS

Role: CONTACT

eschueler@mcw.edu

4142663695

Facility Contacts

Lisa Nielson, BS

Role: primary

lnielson@mcw.edu

414-266-3695

Role: backup

kkarrento@mcw.edu

References

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.

Reference Type: BACKGROUND

PMID: 39888101 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30803865 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28826627 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28568908 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9616311 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22138367 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32732620 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 36716443 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20667005 (View on PubMed)

Study Documents

Document Type: Individual Participant Data Set

View Document

Related Links

https://vivli.org/

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

Other Identifiers

1R01DK140255-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

PRO00051003

Identifier Type: -

Identifier Source: org_study_id