Effects of Respiratory-Gated Transcutaneous Vagal Nerve Stimulation in Major Depression (Phase 1)

A Translational Approach to Cardiorespiratory-Gated Stimulation of the Auricular Branch of the Vagus Nerve for the Treatment of Major Depression

This study will evaluate the short term effects of respiratory-gated transcutaneous vagus nerve stimulation on the regulation of cardiovagal activity, depressive symptomatology and immune function in subjects with major depression and determine the optimal stimulation frequency for this population.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Other: Active transcutaneous vagus nerve stimulation; Other: Sham transcutaneous vagus nerve stimulation

Detailed Description

This study will compare the acute effects of respiratory-gated transcutaneous vagus nerve stimulation (tVNS) at different stimulation frequencies and sham stimulation during five sessions within a 2 week period. Heart rate variability (HRV) point process adaptive filtering estimation algorithms will be used to evaluate changes in cardiac autonomic physiology in subjects with major depression in response to tVNS. The effects of tVNS on cardiovagal regulation will be evaluated at rest and in response to an emotion reactivity task. Depression rating scales (Beck's Depression Inventory) will be used to evaluate short term effects of tVNS on depressive symptoms in these subjects. In addition, the study will evaluate the acute effects of the stimulation on serum levels of pro-inflammatory cytokines. The stimulation frequency that produces the greatest regulatory effects on depressive symptoms and physiological variables in this population will be used in a second longitudinal phase of the study.

• Study Type: Interventional
• Enrollment (Actual): 15
• 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: 24 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of recurrent Major Depressive Disorder with a current active depressive episode
• Currently not taking psychiatric medications or on a stable therapeutic dose of psychiatric medication for at least 30 days prior to entering the study

Exclusion Criteria:

• History of cardio-, cerebro-, or peripheral vascular disease, diabetes mellitus, morbid obesity (BMI > 40 kg/m2), kidney or liver failure, history of unexplained fainting spells
• Any psychiatric disorder involving a history of psychosis (e.g. schizophrenia, bipolar disorders, severe personality disorders)
• Any chronic condition affecting movement, speech and/or ability to read or follow written instructions
• Substance use disorder, either mild, moderate, or severe within the past 12 months (excludes nicotine)
• History of suicide attempt within the last year or current active suicidal ideation
• History of a clinically defined neurological disorder including, but not limited to: Any condition likely to be associated with increased intracranial pressure; space occupying brain lesion; History of cerebrovascular accident; Transient ischemic attack within two years; Cerebral aneurysm; Dementia; Parkinson's Disease; Huntington's chorea; or Multiple sclerosis.
• Pregnant or nursing
• Metallic implants or devices contraindicating tVNS

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham tVNS; Sham transcutaneous vagus nerve stimulation on the left auricle	Other: Sham transcutaneous vagus nerve stimulation; stimulation of the auricle for 30 minutes; Other Names: transcutaneous vagus nerve stimulation
Experimental: Active tVNS - 2 Hz; Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 2 Hz stimulation frequency	Other: Active transcutaneous vagus nerve stimulation; respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)
Experimental: Active tVNS - 8 Hz; Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 8 Hz stimulation frequency	Other: Active transcutaneous vagus nerve stimulation; respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)
Experimental: Active tVNS - 30 Hz; Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 30 Hz stimulation frequency	Other: Active transcutaneous vagus nerve stimulation; respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)
Experimental: Active tVNS - 100 Hz; Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 100 Hz stimulation frequency	Other: Active transcutaneous vagus nerve stimulation; respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac autonomic function	Changes in cardiac autonomic function (High Frequency power-Heart Rate Variability) between active and sham tVNS.	1 hour
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)	1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in serum levels of pro-inflammatory cytokines	Changes in serum levels of proinflammatory cytokines (Interleukin 1B, Interleukin 6, Tumor necrosis factor alfa) from baseline to post-stimulation will be assessed and compared between active and sham tVNS	2 hours

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Brain & Behavior Research Foundation
• Investigators: Principal Investigator: Ronald G Garcia, MD, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2020
• Primary Completion (Actual): October 12, 2022
• Study Completion (Actual): October 12, 2022

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: October 22, 2020
• First Posted (Actual): October 29, 2020

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 28, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Transcutaneous Vagus Nerve Stimulation; Cardiac autonomic function; Depressive symptomatology
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 2019P003698; 26236 (Other Grant/Funding Number: Brain & Behavior Research Foundation)

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
• product manufactured in and exported from the U.S.: No