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

Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: active tVNS; Device: Sham tVNS

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.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: transcutaneous vagus nerve stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Cortisol Levels	Changes in serum cortisol levels from baseline to post-stimulation will be assessed and compared between active and sham tVNS	2 hours
Change in Serum Levels of Pro-inflammatory Cytokines	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	2 hours
Change in Depressive Symptoms Assessed by the Beck Depression Inventory	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)	2 hours

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Ronald G Garcia, MD, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2021
• Primary Completion (Actual): June 13, 2025
• Study Completion (Actual): June 14, 2025

Study Registration Dates

• First Submitted: June 17, 2020
• First Submitted That Met QC Criteria: June 24, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): August 13, 2026
• Last Update Submitted That Met QC Criteria: July 22, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Autonomic Nervous System; Functional Magnetic Resonance Imaging; Transcutaneous Vagus Nerve Stimulation; Stress Response Circuitry; Sex Differences
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 2020P001212; 1U54MH118919-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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