Cerebral Cortical Influences on Autonomic Function

This is an exploratory neurophysiological study that will determine the impact of non-invasive brain stimulation on autonomic regulation, with a focus on gastrointestinal function. These studies should provide a basis for future brain-based neurotherapeutic strategies in patients with functional GI disorders.

Study Overview

• Status: Active, not recruiting
• Conditions: Functional Dyspepsia; Irritable Bowel Syndrome; Healthy Subjects
• Intervention / Treatment: Device: rTMS

Detailed Description

The overall goal of this study is to determine the impact of non-invasive brain stimulation on autonomic function in human subjects without functional gastrointestinal disorders and in subjects with Irritable Bowel Syndrome (IBS) or Functional Dyspepsia (FD).

Aim 1: Determine whether repetitive transcranial magnetic stimulation (rTMS) of specific cortical areas alters physiologic measures of gastrointestinal and cardiac function.

The investigators will use rTMS to transiently induce changes in neural excitability within specific cortical regions identified as being linked to autonomic regulation. Based on preliminary neuroanatomical data, one of the leading candidate cortical areas associated with sympathetic regulation lies within the trunk representation of the primary motor cortex. Thus, the investigators first plan on targeting this region of the primary motor cortex with rTMS and assess the effect of various parameters of rTMS on gastrointestinal and cardiac function in healthy human subjects. The investigators will then perform additional experiments using rTMS targeted to other specific cortical sites, such as the dorsal premotor area and rostral cingulate cortex that have also been linked to autonomic control. Each of these identified cortical regions may make unique contributions to autonomic reactivity.

Aim 2: Determine whether patients with functional gastrointestinal disorders demonstrate altered physiological reactivity to targeted rTMS.

The investigators will use the optimal parameters of rTMS and regions of interest determined in Aim 1 to assess the gastrointestinal and cardiac reactivity in participants with functional dyspepsia (FD) and/or irritable bowel syndrome (IBS). These physiological responses will be correlated with assessments of disease severity, mood, and quality of life.

--This study description has been revised since its original posting. Because all study procedures are performed in all subjects, regardless of being a healthy subject or one with FD and/or IBS, rather than a three arm trial, this trial should be regarded as having a single arm study design.

• Study Type: Interventional
• Enrollment (Estimated): 244
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Paul HM Kullmann, PhD; Phone Number: 412-647-1533; Email: phmk@pitt.edu
• Study Contact Backup: Name: David J Levinthal, MD/PhD; Phone Number: 412-303-0525; Email: levinthald@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adults between age 21 and 60
• Participants without gastrointestinal symptoms (Healthy Subjects)
• Participants with gastrointestinal symptoms compatible with functional dyspepsia (FD) and or irritable bowel syndrome (IBS)

Exclusion Criteria:

• history of myocardial infarction, supplemental oxygen requirement, or diabetes
• history of chronic gastrointestinal symptoms (for healthy subjects only)
• history of gastric surgery
• psychosis or altered cognitive status
• history of head injury, metal in the skull, stroke, or a history of seizures
• implantable devices, such as a pacemaker or nerve stimulator
• current use of the following medications or use of substances which are known to lower the seizure threshold: amitriptyline (Elavil), nortriptyline (Pamelor), imipramine (Tofranil), doxepin (Sinequan), clozapine (Clozaril), chlorpromazine (Thorazine), amphetamines or methamphetamine, Ecstasy, Ketamine, Angel Dust/phencyclidine (PCP), cocaine, or 3 or more alcoholic drinks per day
• pregnancy
• Body-Mass-Index (BMI) > 35

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Study subjects; At the baseline session, measures of autonomic activity (electrogastrogram - EGG, electrocardiogram - ECG, cardiac impedance - CI) will be monitored from about 15 minutes before up to 1 hour after consumption of a test meal, water or a nutrient drink. In addition, motor-evoked potentials (MEPs) elicited with paired pulse transcranial magnetic stimulation (ppTMS) will be assessed before and after the meal or drink. In subsequent sessions, repetitive transcranial magnetic stimulation (rTMS) is applied before the meal or drink. Based on responses to symptom surveys (IBS-SSS and PAGI-SYM), study subjects will be characterized as healthy or as having functional dyspepsia and/or IBS.

Device: rTMS; In subsequent sessions, the same measures of autonomic activity and MEPs will be monitored but different patterns of repetitive TMS (rTMS) will be applied to motor cortex or other areas before the test meal, water or nutrient drink is consumed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electrogastrogram (EGG)	The EGG will be analyzed in the frequency domain using fast Fourier Transformation (FFT). The power spectrum will be divided into frequency bands (normal gastric activity (~3 cycles per minute), slower than normal (bradygastria) and faster than normal (tachygastria)). rTMS-induced shifts in the power distribution across these frequency bands after consumption of water or a nutrient drink or a test meal will be compared to water or nutrient drink or test meal without rTMS.	EGG will be monitored for 15 minutes before and up to 1 hour after consumption of the nutrient drink or the test meal
Volume threshold to satiety	rTMS-induced shift in the volume of water or nutrient drink a subject can consume within a 5 min period before reaching satiety	volumes will be determined immediately after the 5 min drinking window and compared across study sessions

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MEP responses	rTMS-induced change in the amplitude of motor evoked potentials (MEP) elicited by paired pulse TMS	before and up to 1 hour after rTMS
Heart rate variability	rTMS-induced change in heart rate variability elicited by Valsalva maneuver or diaphragmatic breathing	before and up to 1 hour after rTMS
Cardiac Impedance	rTMS-induced change in cardiac impedance variability during Valsalva maneuver or diaphragmatic breathing	before and up to 1 hour after rTMS

Collaborators and Investigators

• Sponsor: David Levinthal
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: David J Levinthal, MD/PhD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2019
• Primary Completion (Estimated): October 3, 2025
• Study Completion (Estimated): October 3, 2025

Study Registration Dates

• First Submitted: February 19, 2019
• First Submitted That Met QC Criteria: March 7, 2019
• First Posted (Actual): March 11, 2019

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Dyspepsia; Irritable Bowel Syndrome
• Other Study ID Numbers: STUDY19010027; 5K08DK101756-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: There is no current plan to share with specific individuals, but individual participant data and supporting information (below) that are the basis for the published results will be made available after de-identification.
• IPD Sharing Time Frame: Beginning 3 months after article publication and up to 5 years thereafter.
• IPD Sharing Access Criteria: Proposals to access trial data should be directed to the Principal Investigator (Dr. David Levinthal) at levinthald@upmc.edu, and if the researcher has a sound basis for the proposal, then requestors will be asked to sign a data access agreement (link to be determined).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

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