# Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression

> **NIH NIH U54** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $209,852

## Abstract

PROJECT 2. SUMMARY
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 overall clinical discovery mission of this SCORE proposal
is to identify the sex-dependent impact of stress-immune pathway dysregulation, beginning in fetal
development, on mood circuitry, MDD per se, immune physiology, and central and peripheral vascular
function in midlife. The primary goal of Project 2 is to use non-invasive neuromodulatory stimulation of the
vagus (i.e., autonomic nervous system) 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, Project 2 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 (ages 51-64, equally divided by sex) randomized to
receive active tVNS or active sham stimulation (earlobe 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. Although Project 2 is not a clinical trial or intervention, ultimately,
translation of results may lead to a novel sex-dependent intervention with beneficial effects prior to later-life
health outcomes a...

## Key facts

- **NIH application ID:** 9853485
- **Project number:** 1U54MH118919-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** VITALY NAPADOW
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,852
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853485

## Citation

> US National Institutes of Health, RePORTER application 9853485, Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression (1U54MH118919-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853485. Licensed CC0.

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