# Boosting mind-body mechanisms for mitigating central sensitization in migraine

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $479,173

## Abstract

Abstract 
 Migraine (MIG) is a prevalent (15-20%) and highly disabling disorder, with complex neurobiological 
underpinnings characterized by sensitization of the brainstem trigeminal sensory complex, leading to 
brainstem-mediated up-regulation of cortical and hypothalamic excitability. Our own pilot fMRI data found 
reduced habituation and amplified afferent input from the spinal trigeminal nucleus to cortical areas including 
posterior insula and hypothalamus. Reducing cortical/subcortical amplification and normalizing habituation may 
be an important therapeutic target. Multimodal approaches have shown improved clinical outcomes, and have 
been recommended in the recent Institute of Medicine report on pain. We propose that this is also the case for 
mind-body therapies. Mindfulness meditation (MM) has shown promise for migraine, and likely operates by 
top-down mechanisms, potentially reducing posterior insula and thalamic hyperexcitability. Furthermore, 
hyperexcitability may be mediated by the excitatory neurotransmitter glutamate, and recent MR spectroscopy 
(H-MRS) studies have found that increased glutamate in posterior insula is associated with hyperalgesia in 
chronic pain patients, while experienced meditators show reduced glutamate levels in the thalamus. 
Additionally, bottom-up therapies such as invasive and non-invasive auricular transcutaneous vagus nerve 
stimulation (tVNS) also reduce migraine frequency and disability. In tVNS, vagal afference relayed to nucleus 
tractus solitarii (NTS) in the medulla may modulate trigeminal sensory complex excitability and hyperexcitability 
in higher brain structures (i.e., a “bottom-up” pathway), possibly by recruitment of serotonergic (raphe nuclei) 
and noradrenergic (locus coeruleus, LC) pathways, via NTS afference. Furthermore, the dorsal medullary 
vagal system operates in synchrony with respiration: NTS receiving inhibitory inputs from medullary ventral 
respiratory group (VRG) nuclei during inhalation, and facilitatory input during expiration. This is a critically- 
important feature of this circuitry, as it suggests that interventions utilizing this NTS pathway should be 
synchronized with respiration. Hence, our group developed Respiratory-gated Auricular Vagal Afferent Nerve 
Stimulation (RAVANS), that optimizes tVNS targeting of NTS by stimulating only during the expiratory phase. 
Thus, RAVANS tVNS incorporates bottom-up modulation of cortical/subcortical hyperexcitability in regions 
such as the posterior insula and thalamus, which are also targeted by MM-relevant circuits. In sum, we 
propose that MM training incorporating RAVANS tVNS will have a synergistic effect in reducing posterior insula, 
thalamic, and hypothalamic hyperexcitability in migraine.

## Key facts

- **NIH application ID:** 10456008
- **Project number:** 5P01AT009965-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** VITALY NAPADOW
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $479,173
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456008

## Citation

> US National Institutes of Health, RePORTER application 10456008, Boosting mind-body mechanisms for mitigating central sensitization in migraine (5P01AT009965-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10456008. Licensed CC0.

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