# Non-invasive vagus nerve stimulation targeting cortical spreading depression in migrane prophylaxis

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $373,558

## Abstract

Project Summary/Abstract
Migraine is a highly prevalent, disabling, chronic episodic and progressive disorder affecting up to a fifth of the
entire world population with tremendous socioeconomic impact. Despite recent advances in our understanding
of migraine pathophysiology, treatment options are limited and have poor efficacy. Novel therapeutic modalities
in migraine are an urgent unmet need.
Cortical spreading depression (CSD) is an intense depolarization wave that is the electrophysiological
substrate of migraine aura and a headache trigger. CSD is considered among the most reliable and robust
experimental models of migraine, and CSD susceptibility is widely accepted as a validated platform to screen
for migraine therapies. We recently discovered that vagus nerve stimulation (VNS), a novel neuromodulatory
treatment already in clinical use for epilepsy and depression, acutely suppresses CSD susceptibility,
suggesting potential therapeutic efficacy in migraine. More importantly, non-invasive cervical transcutaneous
VNS (nVNS) was at least as effective as invasive VNS (iVNS) by an implanted electrode, increasing the
translational potential. Pilot data show that nVNS inhibition of CSD is mediated by vagal afferent fibers
projecting to the brainstem, and involves, at least in part, central serotonergic and norepinephrinergic systems.
Building on these discoveries, we propose two aims to (1) establish the therapeutic profile and (2) gain insight
into the mechanisms of action of VNS as a novel neuromodulatory intervention targeting CSD. Aim 1 will
determine dose/frequency-response, side-specificity, duration of action, additive or synergistic interactions with
migraine prophylactic drugs, and chronic daily prophylaxis. In addition, using optogenetics to induce CSD non-
invasively, we will test VNS efficacy in clinically more relevant freely behaving female mice expressing human
migraine mutations. This translational aim will inform future clinical trials. Aim 2 will interrogate the cerebral
circuitry in a logical and linear fashion to understand how VNS inhibits CSD. We will determine the
contributions of efferent vs. afferent vagal fibers, map VNS-induced brain activation/inhibition by fMRI, lesion
the nucleus tractus solitarius to show its relay role, pharmacologically interrogate the central neurotransmitter
systems that may contribute to VNS efficacy on CSD, and using in vivo microdialysis, we will link these to
curbing cortical glutamate release as the final common step in CSD suppression by VNS.
Altogether, we will fill significant gaps in our knowledge on the therapeutic potential of VNS in migraine and its
mechanisms of action on CSD using validated models and innovative, proprietary nVNS technology. The
knowledge we gain will also shed light on other diseases where CSD plays a significant role, including
traumatic brain injury and ischemic or hemorrhagic stroke, as collateral benefits.

## Key facts

- **NIH application ID:** 10189715
- **Project number:** 5R01NS102969-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Cenk Ayata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,558
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189715

## Citation

> US National Institutes of Health, RePORTER application 10189715, Non-invasive vagus nerve stimulation targeting cortical spreading depression in migrane prophylaxis (5R01NS102969-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10189715. Licensed CC0.

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