Major Depressive DisordertVNS-MDDNCT04467164
Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation
A study testing exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS) and Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS) in people with Major Depressive Disorder, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 25 to 40 years, women only
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS) and Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Apr 2015to 22 Sep 2018
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 40 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
None listed.
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Boston, Massachusetts, 02114
About this study
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.
Read the 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
- Conditions
- Major Depressive Disorder
- Being tested
- exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS), Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)
- Keywords
- Transcutaneous vagus nerve stimulation, Stress response circuitry, functional magnetic resonance imaging, respiration, depression
- Medical subject headings
- Depressive Disorder, Major, Respiratory Aspiration, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS)Other
Also called e-RAVANS
Non-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)Other
Also called i-RAVANS
Non-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session.
| Study group | Role | What they receive |
|---|---|---|
| Exhalatory-gated tVNS | Experimental | exhalatory-gated tVNS on the left auricle Receives: Other: exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS) |
| Inhalatory-gated tVNS | Active comparator | inhalatory-gated tVNS on the left auricle Receives: Other: Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Brain Activity Changes (Average Differences in Beta Weights From Significantly Activated Regions: Post-stimulation Minus Pre-stimulation) Evaluated Using Functional Magnetic Resonance Imaging.
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.
Measured: 1 hour
Secondary outcomes (2)
Change in Depressive Symptoms Assessed by the Beck Depression Inventory (1 Hour Post Intervention Minus Baseline)
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.
Measured: 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)
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.
Measured: 1 hour
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jul 2020
- Study start15 Apr 2015
- Primary completion15 Sep 2018
- Study completion22 Sep 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Jill M. Goldstein, Ph.D., Massachusetts General Hospital
- Investigators
- Jill M Goldstein, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04467164
- Sponsor's protocol ID
- 2013P001259
- Other IDs
- R21MH103468
- Acronym
- tVNS-MDD
- Status last verified
- Mar 2025
- First submitted
- 1 Jul 2020
- Last updated
- 27 Mar 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation
- ClinicalTrials.gov ID
- NCT04467164
- Acronym / sponsor ID
- tVNS-MDD / 2013P001259
- Conditions
- Major Depressive Disorder
- Keywords
- Transcutaneous vagus nerve stimulation, Stress response circuitry, functional magnetic resonance imaging, respiration, depression
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 15 Apr 2015 (actual)
- Primary completion
- 15 Sep 2018 (actual)
- Study completion
- 22 Sep 2018 (actual)
- First posted
- 10 Jul 2020 (actual)
- Results
- Posted 27 Mar 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Exhalatory-gated tVNS | Experimental | Other: exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS)exhalatory-gated tVNS on the left auricle |
| Inhalatory-gated tVNS | Active comparator | Other: Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)inhalatory-gated tVNS on the left auricle |
Who may qualify
- Ages
- 25 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (0 listed)
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS)Also: e-RAVANSNon-painful exhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session. | Other | Exhalatory-gated tVNS |
| Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)Also: i-RAVANSNon-painful inhalatory-gated electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session. | Other | Inhalatory-gated tVNS |
Primary outcome
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.
2 secondary outcomes
Change in Depressive Symptoms Assessed by the Beck Depression Inventory (1 Hour Post Intervention Minus Baseline)
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jill M Goldstein, PhD principal investigator
Massachusetts General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS) and Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS) in people with Major Depressive Disorder, run by Massachusetts General Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Mar 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2025.