Autonomic Reactivity and Personalized Neurostimulation

February 11, 2026 updated by: Katja Karrento, Medical College of Wisconsin

Autonomic Reactivity to Restore a Dysregulated Brain-Gut Axis Via Targeted Therapy

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53005
        • Recruiting
        • Medical College of Wisconsin
        • Contact:
        • Contact:
        • Principal Investigator:
          • Katja Karrento, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: PENFS (percutaneous electrical nerve field stimulation) therapy
Personalized PENFS therapy x 6 weeks based on weekly autonomic nervous system assessments
Device: Percutaneous electrical nerve field stimulation
Percutaneously nerve stimulator applied to the external auricle weekly for several consecutive weeks of therapy
Active Comparator: PENFS (percutaneous electrical nerve field stimulation) therapy + Hypnotherapy
Personalized PENFS therapy x 6 weeks based on weekly autonomic nervous system assessments + adjuntive hypnotherapy
Device: Percutaneous electrical nerve field stimulation
Percutaneously nerve stimulator applied to the external auricle weekly for several consecutive weeks of therapy
Behavioral: Hypnotherapy
Gut-directed hypnotherapy delivered via audio recordings

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-37
Time Frame: From enrollment to end of treatment at 6 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
2. Patient Assessment of upper GastroIntestinal Symptom Severity Index
Time Frame: From enrollment to the end of treatment at 6 weeks.
Upper gastrointestinal symptoms including symptoms of gastroparesis will be assessed via this 20-item instrument with scores ranging from 0 (minimum) to 5 (maximum). Higher scores indicate worse outcome.
From enrollment to the end of treatment at 6 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical College of Wisconsin

Collaborators

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

Investigators

  • Principal Investigator: Katja Karrento, MD, Medical College of Wisconsin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 24, 2025

Primary Completion (Estimated)

December 1, 2028

Study Completion (Estimated)

June 1, 2029

Study Registration Dates

First Submitted

March 3, 2025

First Submitted That Met QC Criteria

March 3, 2025

First Posted (Actual)

March 7, 2025

Study Record Updates

Last Update Posted (Actual)

February 13, 2026

Last Update Submitted That Met QC Criteria

February 11, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO00051003
  • 1R01DK140255-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The investigators plan to share anonymized, IPD including primary outcome data (PAGI-SYM results) through the publicly accessible Vivli Center for Global Clinical Research Data repository, an NIH supported repository and global data-sharing platform that promotes sharing of individual, participant-level clinical data from clinical trials.

IPD Sharing 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.

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Study Data/Documents

  1. Individual Participant Data Set

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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