• Ronald G Garcia, Richard L Lin, Jeungchan Lee, Jieun Kim, Riccardo Barbieri, Roberta Sclocco, Ajay D Wasan, Robert R Edwards, Bruce R Rosen, Nouchine Hadjikhani, and Vitaly Napadow.
• aDepartment of Radiology, Martinos Center for Biomedical Imaging, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USAbNeurovascular Science Group, Fundación Cardiovascular de Colombia, Floridablanca, ColombiacDepartment of Medicine, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USAdHarvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, USAeClinical Research Division, Korea Institute of Oriental Medicine, Daejeon, KoreafDepartment of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, ItalygDepartment of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA, USAhDepartment of Radiology, Logan University, Chesterfield, MO, USAiDepartment of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USAjDepartment of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USAkGillberg Neuropsychiatry Center, Gothenburg University, Gothenburg, Sweden.
• Pain. 2017 Aug 1; 158 (8): 1461-1472.

AbstractMigraine pathophysiology includes altered brainstem excitability, and recent neuromodulatory approaches aimed at controlling migraine episodes have targeted key brainstem relay and modulatory nuclei. In this study, we evaluated the impact of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel neuromodulatory intervention based on an existing transcutaneous vagus nerve stimulation approach, in the modulation of brainstem activity and connectivity in migraine patients. We applied 3T-functional magnetic resonance imaging with improved in-plane spatial resolution (2.62 × 2.62 mm) in episodic migraine (interictal) and age- and sex-matched healthy controls to evaluate brain response to RAVANS (gated to either inhalation or exhalation) and sham stimulation. We further investigated RAVANS modulation of tactile trigeminal sensory afference response in the brainstem using air-puff stimulation directed to the forehead during functional magnetic resonance imaging. Compared with sham and inhalatory-gated RAVANS (iRAVANS), exhalatory-gated RAVANS (eRAVANS) activated an ipsilateral pontomedullary region consistent with nucleus tractus solitarii (NTS). During eRAVANS, NTS connectivity was increased to anterior insula and anterior midcingulate cortex, compared with both sham and iRAVANS, in migraine patients. Increased connectivity was inversely correlated with relative time to the next migraine attack, suggesting clinical relevance to this change in connectivity. Poststimulation effects were also noted immediately after eRAVANS, as we found increased activation in putative pontine serotonergic (ie, nucleus raphe centralis) and noradrenergic (ie, locus coeruleus) nuclei in response to trigeminal sensory afference. Regulation of activity and connectivity of brainstem and cortical regions involved in serotonergic and noradrenergic regulation and pain modulation may constitute an underlying mechanism supporting beneficial clinical outcomes for eRAVANS applied for episodic migraine.

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