Major Depressive DisordertVNS_MDD_SexNCT04448327
Impact of Transcutaneous Vagal Nerve Stimulation on Stress Response in Major Depression
A study testing active tVNS in people with Major Depressive Disorder, run by Massachusetts General Hospital at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 50 to 65 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- active tVNS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 62 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Jan 2021to 14 Jun 2025
- 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 50 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Current or past diagnosis of recurrent Major Depressive Disorder
Who cannot join
- 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.)
Show all 9Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Charlestown, Massachusetts, 02129
About this study
Official title: 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.
Read the 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
- Being tested
- active tVNS, Sham tVNS
- Keywords
- Autonomic Nervous System, Transcutaneous Vagus Nerve Stimulation, Stress Response Circuitry, Functional Magnetic Resonance Imaging, Sex Differences
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
active tVNSDevice
Also called transcutaneous vagus nerve stimulation
non-painful electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session
Sham tVNSDevice
Also called transcutaneous vagus nerve stimulation
Sham stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session
| Study group | Role | What they receive |
|---|---|---|
| Active tVNS | Experimental | Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle Receives: Device: active tVNS |
| Sham tVNS | Sham comparator | Sham transcutaneous vagus nerve stimulation on the left auricle Receives: Device: Sham tVNS |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 1 hour
Secondary outcomes (3)
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
Measured: 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
Measured: 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)
Measured: 2 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jun 2020
- Study start29 Jan 2021
- Primary completion13 Jun 2025
- Study completion14 Jun 2025
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
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 62 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, Ronald Garcia, Massachusetts General Hospital
- Investigators
- Ronald G Garcia, MD, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04448327
- Sponsor's protocol ID
- 2020P001212
- Other IDs
- 1U54MH118919-01A1
- Acronym
- tVNS_MDD_Sex
- Status last verified
- Jul 2026
- First submitted
- 17 Jun 2020
- Last updated
- 13 Aug 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression
- ClinicalTrials.gov ID
- NCT04448327
- Acronym / sponsor ID
- tVNS_MDD_Sex / 2020P001212
- Conditions
- Major Depressive Disorder
- Keywords
- Autonomic Nervous System, Transcutaneous Vagus Nerve Stimulation, Stress Response Circuitry, Functional Magnetic Resonance Imaging, Sex Differences
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 29 Jan 2021 (actual)
- Primary completion
- 13 Jun 2025 (actual)
- Study completion
- 14 Jun 2025 (actual)
- First posted
- 25 Jun 2020 (actual)
- Results
- Posted 13 Aug 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Active tVNS | Experimental | Device: active tVNSExpiratory-gated transcutaneous vagus nerve stimulation on the left auricle |
| Sham tVNS | Sham comparator | Device: Sham tVNSSham transcutaneous vagus nerve stimulation on the left auricle |
Who may qualify
- Ages
- 50 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Current or past diagnosis of recurrent Major Depressive Disorder
Key exclusion criteria (9 listed)
- 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)
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 |
|---|---|---|
| active tVNSAlso: transcutaneous vagus nerve stimulationnon-painful electrical stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session | Device | Active tVNS |
| Sham tVNSAlso: transcutaneous vagus nerve stimulationSham stimulation of the auricle for 30 minutes during a functional magnetic resonance imaging session | Device | Sham tVNS |
Primary outcome
Change in Brain Activity (Average Beta Weights From Significantly Activated Regions) Evaluated Using Functional Magnetic Resonance Imaging (fMRI)
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 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.
Percent Change in Normalized High Frequency Power - Heart Rate Variability From Baseline
Time frame: 1 hour
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.
3 secondary outcomes
Change in Serum Cortisol Levels
Time frame: 2 hours
Change in Serum Levels of Pro-inflammatory Cytokines
Time frame: 2 hours
Change in Depressive Symptoms Assessed by the Beck Depression Inventory
Time frame: 2 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2026.
- 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.
Ronald G Garcia, MD, 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 active tVNS 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 1 inclusion and 9 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 13 Aug 2026. 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. Some participants in this study may receive a placebo. 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 13 Aug 2026). 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?
Change in Brain Activity (Average Beta Weights From Significantly Activated Regions) Evaluated Using Functional Magnetic Resonance Imaging (fMRI) (time frame: 1 hour). The study lists 2 primary outcomes in all. 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 13 Aug 2026.