Clinical trial NCT04448327: Impact of Transcutaneous Vagal Nerve Stimulation on Stress Response in Major Depression
Official title: Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Major Depressive Disorder
Keywords: Autonomic Nervous System
Transcutaneous Vagus Nerve Stimulation
Stress Response Circuitry
Functional Magnetic Resonance Imaging
Sex Differences
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2020-06-25
Enrollment: 80
Sex: ALL
Minimum age (years): 50
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief 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). 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.

Eligibility criteria: Inclusion Criteria:

* Current or past diagnosis of recurrent Major Depressive Disorder

Exclusion Criteria:

* 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.)
* 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

Primary outcomes:
measure: Brain activity during functional magnetic resonance imaging (fMRI)
timeFrame: 1 hour
measure: Cardiac autonomic function during functional magnetic resonance imaging (fMRI)
timeFrame: 1 hour
Secondary outcomes:
measure: Change in serum cortisol levels
timeFrame: 2 hours
measure: Change in serum levels of pro-inflammatory cytokines
timeFrame: 2 hours
measure: Change in depressive symptoms assessed by the Beck Depression Inventory
timeFrame: 2 hours
Other outcomes:
Locations:
city: Charlestown
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Ronald G Garcia, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: