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

NCT ID: NCT04448327

Last Updated: 2025-12-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-29
• Study Completion Date: 2026-05-31

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.

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.

Conditions

Major Depressive Disorder

Keywords

Autonomic Nervous System; Transcutaneous Vagus Nerve Stimulation; Stress Response Circuitry; Functional Magnetic Resonance Imaging; Sex Differences

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Active tVNS

Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle

Group Type: EXPERIMENTAL

active tVNS

Intervention Type: DEVICE

non-painful electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session

Sham tVNS

Sham transcutaneous vagus nerve stimulation on the left auricle

Group Type: SHAM_COMPARATOR

Sham tVNS

Intervention Type: DEVICE

Sham stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session

Interventions

active tVNS

non-painful electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session

Intervention Type: DEVICE

Sham tVNS

Sham stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session

Intervention Type: DEVICE

Other Intervention Names

transcutaneous vagus nerve stimulation; transcutaneous vagus nerve stimulation

Eligibility 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

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Ronald Garcia

Instructor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ronald G Garcia, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital

Charlestown, Massachusetts, United States

Countries

United States

Other Identifiers

1U54MH118919-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2020P001212

Identifier Type: -

Identifier Source: org_study_id