Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation (tVNS-MDD)

March 9, 2025 updated by: Jill M. Goldstein, Ph.D., Massachusetts General Hospital
This study characterized the impact of respiratory-gated transcutaneous vagus nerve stimulation (tVNS) on the modulation of the stress response circuitry, vagal tone and depressed mood in patients with major depressive disorder (MDD). Twenty premenopausal women with recurrent MDD in an active episode were recruited into a single-blind cross-over study that included two functional MRI visits within a one week period with simultaneous mood and physiological assessments. Randomization to exhalatory- or inhalatory-gated tVNS was performed to control for order effects. The study hypothesis was that exhalatory-gated tVNS would have a significantly greater impact on the regulation of brain activity in stress response circuitry, vagal tone and depressed mood in MDD patients compared to inhalation-gated tVNS. This is not a clinical trial aimed to test a medical device, but a basic experimental study oriented to understand the effects of vagal afference modulation on brain and cardiovagal physiological response to stress in major depression.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Major depressive disorder (MDD) has been associated with alterations of the stress response circuitry, including the hypothalamus, amygdala, hippocampus, anterior cingulate cortex, ventromedial, dorsolateral and orbital prefrontal cortices. Many of these regions are morphologically and functionally sexually dimorphic and associated with vulnerability for sex differences in MDD. A major role for the stress response circuitry is to assess potentially stressful stimuli and respond with a neuroendocrine signal that coordinates homeostatic responses throughout the body. Neuroimaging studies have suggested that alterations in this circuitry are implicated in mood dysregulation, increased activation of the hypothalamic-pituitary-adrenal (HPA) axis, and imbalance between the sympathetic and parasympathetic nervous system in depressed persons. A better understanding of the mechanisms underlying alterations in physiological response to stress in major depression may contribute to the development of novel interventions that regulate this system with a significant impact on the improvement of clinical and physiological alterations of MDD.

It has been previously suggested that modulation of vagus nerve activity may have a significant effect on the modulation of the brain circuitry involved in the regulation of mood and stress response. Recently, a non-invasive approach for modulation of vagus nerve activity, transcutaneous auricular vagus nerve stimulation (tVNS), which targets the auricular branch of the vagus nerve (ABVN) has been proposed. Moreover, previous studies have shown that vagal afference is highly regulated by respiration and that modulation of vagus nerve activity may be optimized by gating ABVN stimulation to the exhalatory phase of the respiratory cycle. Thus, this study proposed to characterize the impact of respiratory-gated tVNS on the modulation of the stress response circuitry, vagal tone and depressed mood in patients with recurrent major depression (MDD). This is not a clinical trial aimed to test a medical device, but a basic experimental study oriented to understand the effects of vagal afference modulation on brain and cardiovagal physiological response to stress in major depression.

Twenty premenopausal women with recurrent MDD in an active episode were recruited into a single-blind cross-over study that included two functional MRI visits, within a one week period, with simultaneous mood and physiological assessments. Randomization to exhalatory- or inhalatory-gated tVNS was performed to control for order effects. Subjects were exposed to a mild visual stress challenge that preceded and followed 30 minutes of exhalatory- or inhalatory-gated tVNS. The study hypothesis was that exhalatory-gated tVNS would have a significantly greater impact on the regulation of brain activity in stress response circuitry, vagal tone and depressed mood in MDD patients compared to inhalation-gated tVNS

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

25 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria: Recurrent MDD diagnosis (≥ 2 episodes) with a current active depressive episode.

Exclusion Criteria:

  • History of Axis I psychiatric diagnosis other than MDD or anxiety disorder - e.g., substance use disorder, psychotic disorder, or bipolar disorder.
  • Current Suicidal Ideation with intent and/or plan or history of suicide attempt within the last year
  • Use of psychotropic medications within four weeks prior to study with the exception of Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Norepinephrine Reuptake Inhibitors (SNRIs) class of antidepressant medication only
  • Use of Tricyclic antidepressants (TCAs), Monoamine oxidase inhibitors (MAOIs), and Atypical agents
  • History of cardiovascular disease
  • History of neuroleptic use
  • Past history of substance abuse or dependence within the past 12 months (excludes nicotine)
  • Bleeding disorder or use of anticoagulants.
  • Pregnancy
  • Metallic implants or devices contraindicating magnetic resonance imaging.
  • Use of beta blockers

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Exhalatory-gated tVNS
exhalatory-gated tVNS on the left auricle
Other: exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS)
Non-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
Other Names:
  • e-RAVANS
Active Comparator: Inhalatory-gated tVNS
inhalatory-gated tVNS on the left auricle
Other: Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)
Non-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
Other Names:
  • i-RAVANS

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Brain Activity Changes (Average Differences in Beta Weights From Significantly Activated Regions: Post-stimulation Minus Pre-stimulation) Evaluated Using Functional Magnetic Resonance Imaging.
Time Frame: 1 hour
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 (post- and pre-stimulation). For this analysis a General Lineal Model analsysis 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 tasks. 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 differences in beta weights (Post minus Pre stimulation) were estimated for each group. A positive difference indicates increased activation of a particular brain region in response to the stimulation, whereas a negative difference indicates a reduction in brain activity.
1 hour

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in Depressive Symptoms Assessed by the Beck Depression Inventory (1 Hour Post Intervention Minus Baseline)
Time Frame: 2 hours
Changes from baseline to post-stimulation in the total score of the Beck Depression Inventory (BDI) compared between exhalatory and inhalatory-gated tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms). A positive difference at post-stimulation compared to baseline indicates an increase in depressive symptoms, whereas a negative difference indicates a reduction in depressive symptomatology.
2 hours
Changes in Cardiac Autonomic Function (Percent Change in Normalized High-frequency Power of Heart Rate Variability (HFn-HRV): Post-stimulation Versus Pre-stimulation)
Time Frame: 1 hour
Cardiac pulsatility data was collected during exposure to visual stress tasks pre- and post-stimulation and were used to estimate inter-beat intervals. A point process algorithm was then used to analyze the inter-beat intervals and evaluate heart rate variability (HRV) by separating its dynamics in the classic spectral components within the high-frequency (HF) and low-frequency (LF) ranges. Differences in normalized HF [HFn= (HF/(LF + HF))] were estimated during exposure to negative images in the fMRI stress task as a metric of parasympathetic cardiac regulation. Percent change in HFn-HRV values (Post vs Pre stimulation) were 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Massachusetts General Hospital

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Mental Health (NIMH)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Jill M Goldstein, PhD, Massachusetts General Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 15, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 15, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 22, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 1, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 9, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 10, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 27, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 9, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2013P001259
  • R21MH103468 (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

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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Conditions

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