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

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: exhalatory-gated transcutaneous vagus nerve stimulation (e-RAVANS); Device: Inhalatory-gated transcutaneous vagus nerve stimulation (i-RAVANS)

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. Thus, the development of novel interventions that regulate this system may have a significant impact on the improvement of clinical and physiological alterations of MDD.

Vagal nerve stimulation (VNS) is an FDA approved treatment for MDD that modulates circuitry implicated in mood regulation. Recently, a non-invasive variant of VNS, transcutaneous auricular vagus nerve stimulation (tVNS), which targets the auricular branch of the vagus nerve (ABVN) has been proposed. Moreover, previous studies have suggested that the dorsal medullary system receiving vagal afference inputs operates in tune with respiration and that tVNS 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).

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: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exhalatory-gated tVNS; exhalatory-gated tVNS on the left auricle	Device: 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	Device: 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

Outcome Measure	Measure Description	Time Frame
Brain activity changes [percent blood oxygenation level dependent signal change] evaluated using functional magnetic resonance imaging during a visual stress challenge	Changes in functional magnetic resonance imaging- blood oxygenation level dependent signal (percent signal change) in response to a visual stress challenge compared between exhalatory and inhalatory-gated tVNS	1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in depressive symptoms assessed by the Beck Depression Inventory	Changes from baseline to post-stimulation in the total score of the Beck Depression Inventory compared between exhalatory and inhalatory-gated tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms)	2 hours
Changes in cardiac autonomic function during functional magnetic resonance imaging	Changes from baseline to post-stimulation in cardiac autonomic function (percent change of High Frequency power index) compared between exhalatory- and inhalatory-gated tVNS.	1 hour

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Jill M Goldstein, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2015
• Primary Completion (Actual): September 15, 2018
• Study Completion (Actual): September 22, 2018

Study Registration Dates

• First Submitted: July 1, 2020
• First Submitted That Met QC Criteria: July 9, 2020
• First Posted (Actual): July 10, 2020

Study Record Updates

• Last Update Posted (Actual): July 10, 2020
• Last Update Submitted That Met QC Criteria: July 9, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: functional magnetic resonance imaging; depression; respiration; Transcutaneous vagus nerve stimulation; Stress response circuitry
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID 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: Yes