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Cerebral Cortical Influences on Autonomic Function

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03869372
Recruitment Status : Suspended (Covid-19)
First Posted : March 11, 2019
Last Update Posted : June 5, 2020
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
David Levinthal, University of Pittsburgh

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthy Subjects Functional Dyspepsia Irritable Bowel Syndrome Device: rTMS Not Applicable

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 the effects of targeted rTMS on autonomic function are mediated through a specific branch of the autonomic nervous system.

In different sessions, the investigators will use FDA-approved pharmacological agents (hyoscyamine and metoprolol) to help determine whether the observed autonomic effects of cortical TMS are mediated primarily through the sympathetic or parasympathetic branches of the autonomic nervous system.

Aim 3: 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. In different sessions, the investigators will use FDA-approved pharmacological agents (hyoscyamine and metoprolol) to help determine whether any observed differences in physiological reactivity to targeted rTMS are primarily mediated through sympathetic or parasympathetic control.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Intervention Model Description: Subjects will act as their own controls: The investigators will assess measures of autonomic function at baseline and in response to rTMS exposure (with or without study medication) in three groups of subjects: 1) subjects without history of gastrointestinal disease, 2) subjects with Irritable Bowel Syndrome, and 3) subjects with Functional Dyspepsia.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Cerebral Cortical Influences on Autonomic Function
Actual Study Start Date : April 5, 2019
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Arm Intervention/treatment
Experimental: Healthy subjects

At the baseline session, measures of autonomic activity (electrogastrogram - EGG, electrocardiogram - ECG, cardiac impedance - CI, colonic motility) 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.

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.

Experimental: Subjects with IBS

At the baseline session, measures of autonomic activity (electrogastrogram - EGG, electrocardiogram - ECG, cardiac impedance - CI, colonic motility) 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.

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.

Experimental: Subjects with FD

At the baseline session, measures of autonomic activity (electrogastrogram - EGG, electrocardiogram - ECG, cardiac impedance - CI, colonic motility) 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.

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.




Primary Outcome Measures :
  1. Electrogastrogram (EGG) [ Time Frame: EGG will be monitored for 15 minutes before and up to 1 hour after consumption of the nutrient drink or the test meal ]
    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.

  2. Volume threshold to satiety [ Time Frame: volumes will be determined immediately after the 5 min drinking window and compared across study sessions ]
    rTMS-induced shift in the volume of water or nutrient drink a subject can consume within a 5 min period before reaching satiety

  3. Colonic motility [ Time Frame: before and within 20 min after consuming a test meal ]
    rTMS-induced change in the number of distal colon contractions after consuming a test meal


Secondary Outcome Measures :
  1. MEP responses [ Time Frame: before and up to 1 hour after rTMS ]
    rTMS-induced change in the amplitude of motor evoked potentials (MEP) elicited by paired pulse TMS

  2. Heart rate variability [ Time Frame: before and up to 1 hour after rTMS ]
    rTMS-induced change in heart rate variability elicited by Valsalva maneuver or diaphragmatic breathing

  3. Cardiac Impedance [ Time Frame: before and up to 1 hour after rTMS ]
    rTMS-induced change in cardiac impedance variability during Valsalva maneuver or diaphragmatic breathing



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Adults between age 18 and 75
  • Participants without a history of gastrointestinal disorders (control group)
  • Participants with functional dyspepsia (FD group)
  • Participants with moderate-to-severe irritable bowel syndrome (defined by IBS symptom severity scores (IBS-SSS) greater than 250) (IBS group)

Exclusion Criteria:

  • history of myocardial infarction, supplemental oxygen requirement, or diabetes
  • history of chronic gastrointestinal symptoms (for healthy control population 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03869372


Locations
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United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
David Levinthal
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: David J Levinthal, MD/PhD University of Pittsburgh
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Responsible Party: David Levinthal, Assistant Professor, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03869372    
Other Study ID Numbers: STUDY19010027
5K08DK101756-05 ( U.S. NIH Grant/Contract )
First Posted: March 11, 2019    Key Record Dates
Last Update Posted: June 5, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Analytic Code
Time Frame: Beginning 3 months after article publication and up to 5 years thereafter.
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).

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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
Additional relevant MeSH terms:
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Irritable Bowel Syndrome
Dyspepsia
Colonic Diseases, Functional
Colonic Diseases
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Signs and Symptoms, Digestive
Signs and Symptoms