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

NCT04448327 | Completed Results FDA Device

• 2 other identifiers: 2020P0012121U54MH118919-01A1
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Change in Brain Activity (Average Beta Weights From Significantly Activated Regions) Evaluated Using Functional Magnetic Resonance Imaging (fMRI)

  A functional magnetic resonance imaging (fMRI) analysis was used to evaluate changes in brain activity \[blood oxygenation level-dependent (BOLD) signal\] in response to a visual stress challenge during transcutaneous vagus nerve stimulation. For this analysis a General Lineal Model analysis with the statistical parametrical software (SPM) was used to model the change in BOLD signals during exposure to negative vs neutral images of the stress task. A voxel-wise height threshold of p\<0.001, and a cluster correction with FWE p-value \<0.05 was used to identify brain areas with significant activation in response to the task. Mean beta weights within each significant cluster were extracted for each participant, and average beta weights were estimated for each group. A positive value indicates increased activation of a particular brain region in response to the stress task during the stimulation, whereas a negative value indicates a reduction in brain activity.

  1 hour

• Percent Change in Normalized High Frequency Power - Heart Rate Variability From Baseline

  Cardiac pulsatility data were collected during baseline and exposure to a visual stress task. Interbeat intervals were estimated, and a point-process algorithm was then used to evaluate heart rate variability dynamics in the classic spectral components within the high-frequency (HF) and low-frequency (LF) ranges. Normalized HF \[HFn=(HF/(LF+HF))\] values were estimated during exposure to the stress task as a metric of parasympathetic regulation. The percent change in HFn (during the stress task vs baseline) was calculated for each intervention group. A positive percent change value indicates an increase in cardiovagal activity, whereas a negative change indicates a reduction in cardiovagal activity.

  1 hour

Secondary Outcomes (3)

• Change in Serum Cortisol Levels

  2 hours

• Change in Serum Levels of Pro-inflammatory Cytokines

  2 hours

• Change in Depressive Symptoms Assessed by the Beck Depression Inventory

  2 hours

Study Arms (2)

Active tVNS

EXPERIMENTAL

Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle

Device: active tVNS

Sham tVNS

SHAM COMPARATOR

Sham transcutaneous vagus nerve stimulation on the left auricle

Device: Sham tVNS

Interventions

active tVNS DEVICE

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

Also known as: transcutaneous vagus nerve stimulation

Active tVNS

Sham tVNS DEVICE

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

Also known as: transcutaneous vagus nerve stimulation

Sham tVNS

Eligibility Criteria

• Age: 50 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Current or past diagnosis of recurrent Major Depressive Disorder

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): collaborator
• Massachusetts General Hospital: lead

Study Sites (1)

Massachusetts General Hospital

Charlestown, Massachusetts, 02129, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Results Point of Contact

• Title: Ronald G. Garcia
• Organization: Massachusetts General Hospital, Harvard Medical School

rgarciagomez@mgh.harvard.edu

617-935-3895

Study Officials

• Ronald G Garcia, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Instructor

Study Record Dates

• First Submitted: June 17, 2020
• First Posted: June 25, 2020
• Study Start: January 29, 2021
• Primary Completion: June 13, 2025
• Study Completion: June 14, 2025
• Last Updated: August 13, 2026
• Results First Posted: August 13, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)