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Impact of Transcutaneous Vagal Nerve Stimulation on Stress Response in Major Depression (tVNS_MDD_Sex)

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ClinicalTrials.gov Identifier: NCT04448327
Recruitment Status : Recruiting
First Posted : June 25, 2020
Last Update Posted : March 15, 2021
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Ronald Gerardo Garcia Gomez,M.D.,Ph.D., Massachusetts General Hospital

Brief Summary:
This study will identify the sex-dependent impact of expiratory-gated transcutaneous vagus nerve stimulation (tVNS) on the modulation of the stress response circuitry and associated physiology in major depressive disorder (MDD). We will evaluate a sample of 80 adults with recurrent MDD randomized to receive active or sham expiratory-gated tVNS during a functional magnetic resonance imaging (fMRI) session, with simultaneous mood and physiological assessments. We hypothesize that expiratory-gated tVNS will effectively modulate, in a sex-dependent manner, specific brainstem-cortical pathways of the stress circuitry and attenuate physiological deficits in MDD.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Device: active tVNS Device: Sham tVNS Not Applicable

Detailed Description:
Major depressive disorder (MDD) is a leading cause of morbidity and disability worldwide with abnormalities in the stress response circuitry and central autonomic network. Many of these regions are sexually dimorphic and related with sex differences in mood and hypothalamic-pituitary-adrenal (HPA) axis modulation, the dysregulation of which is associated with alterations of hormone and immune responses to stress, autonomic dysfunction and increased cardiovascular risk. The primary goal of this study is to use non-invasive neuromodulatory stimulation of the vagus to target the circuitry associated with stress-immune function and map its neuroanatomic and physiological effects in MDD by sex. Vagal nerve stimulation (VNS), FDA-approved for MDD, modulates brain circuitry implicated in mood/anxiety and autonomic regulation, however, it is implanted and thus invasive. We propose the use of a physiologically-enhanced transcutaneous VNS (tVNS) as a low risk, non-invasive, and inexpensive alternative. While tVNS has had beneficial effects on depressive symptomatology and autonomic regulation, current stimulation parameters are based on historical iVNS data that included mostly male populations. We propose that tVNS effects on the regulation of specific brainstem-cortical pathways is modulated by sex. Moreover, as the dorsal medullary vagal system operates in tune with respiration, we recently demonstrated that tVNS can be optimized by gating stimulation to respiration. Thus, this study proposes to identify the sex-dependent impact of expiratory-gated tVNS on the modulation of stress response circuitry alterations and physiological dysregulation of recurrent MDD. We will evaluate a sample of 80 adults with recurrent MDD randomized to receive active tVNS or sham stimulation during a functional magnetic resonance imaging (fMRI) session. The fMRI session will include a stress challenge designed to elicit a sympatho-excitatory state, with simultaneous mood and physiological assessments, including hormonal and dynamic cardiovagal heart rate variability (HRV) evaluations. We hypothesize that expiratory-gated tVNS will effectively modulate specific brainstem-cortical pathways of the stress response circuitry and will attenuate physiological deficits of recurrent MDD patients. We further hypothesize that tVNS will impact brain activity and physiology in sex-dependent ways.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression
Actual Study Start Date : March 1, 2021
Estimated Primary Completion Date : July 15, 2024
Estimated Study Completion Date : November 15, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: MRI Scans

Arm Intervention/treatment
Experimental: Active tVNS
Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle
Device: active tVNS
non-painful electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session
Other Name: transcutaneous vagus nerve stimulation

Sham Comparator: Sham tVNS
Sham transcutaneous vagus nerve stimulation on the left auricle
Device: Sham tVNS
Sham stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session
Other Name: transcutaneous vagus nerve stimulation




Primary Outcome Measures :
  1. Brain activity during functional magnetic resonance imaging (fMRI) [ Time Frame: 1 hour ]
    Changes in fMRI BOLD signal (percent BOLD signal change) of the stress response circuitry between active and sham tVNS.

  2. Cardiac autonomic function during functional magnetic resonance imaging (fMRI) [ Time Frame: 1 hour ]
    Changes in cardiac autonomic function (High Frequency power-Heart Rate Variability) between active and sham tVNS.


Secondary Outcome Measures :
  1. Change in serum cortisol levels [ Time Frame: 2 hours ]
    Changes in serum cortisol levels from baseline to post-stimulation will be assessed and compared between active and sham tVNS

  2. Change in serum levels of pro-inflammatory cytokines [ Time Frame: 2 hours ]
    Changes in serum levels of proinflammatory cytokines (IL1B, IL6, TNF alfa) from baseline to post-stimulation will be assessed and compared between active and sham tVNS

  3. Change in depressive symptoms assessed by the Beck Depression Inventory [ Time Frame: 2 hours ]
    Changes from baseline to post-stimulation in the score of the Beck Depression Inventory will be compared between active and sham tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms)



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Ages Eligible for Study:   50 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Current or past diagnosis of recurrent Major Depressive Disorder

Exclusion Criteria:

  • History of neuroleptic use
  • Any psychiatric disorder involving a history of psychosis (e.g. schizophrenia, bipolar I disorder)
  • Active suicidal ideation with intent and/or plan or history of a suicide attempt within the last year
  • Moderate or severe substance use disorder within the past 12 months
  • Diagnosis of significant cardiovascular or cerebrovascular disease (e.g. congestive heart failure, stroke, cardiac conduction disorders, history of asystole or non-sustained ventricular tachycardia)
  • Diseases affecting the CNS (e.g. MS, epilepsy, neurodegenerative diseases, etc.)
  • Traumatic brain injury with cognitive sequelae
  • MRI or tVNS contraindications (e.g. claustrophobia, metallic implants or devices)
  • Pregnancy (uncommon, given the age of this cohort is 50+ years) due to unknown health risks for the fetus

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): NCT04448327


Contacts
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Contact: Ronald G Garcia, MD, PhD 617-643-4265 rgarciagomez@mgh.harvard.edu
Contact: Vitaly Napadow, PhD 617-724-3402 vitaly@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Charlestown, Massachusetts, United States, 02129
Contact: Ronald G Garcia, MD, PhD    617-643-4265    rgarciagomez@mgh.harvard.edu   
Sponsors and Collaborators
Massachusetts General Hospital
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Ronald G Garcia, MD, PhD Massachusetts General Hospital
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Responsible Party: Ronald Gerardo Garcia Gomez,M.D.,Ph.D., Instructor, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04448327    
Other Study ID Numbers: 2020P001212
1U54MH118919-01A1 ( U.S. NIH Grant/Contract )
First Posted: June 25, 2020    Key Record Dates
Last Update Posted: March 15, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ronald Gerardo Garcia Gomez,M.D.,Ph.D., Massachusetts General Hospital:
Autonomic Nervous System
Transcutaneous Vagus Nerve Stimulation
Stress Response Circuitry
Functional Magnetic Resonance Imaging
Sex Differences
Additional relevant MeSH terms:
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Depressive Disorder
Depressive Disorder, Major
Mood Disorders
Mental Disorders