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;158(8):1461-1472. doi: 10.1097/j.pain.0000000000000930.
Migraine 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.
偏头痛的病理生理学包括脑干兴奋性的改变，最近针对控制偏头痛发作的神经调节方法针对关键的脑干中继和调节核。在这项研究中，我们评估了呼吸门控耳迷走神经传入神经刺激（RAVANS）对偏头痛患者脑干活动和连通性的影响，RAVANS 是一种基于现有经皮迷走神经刺激方法的新型神经调节干预措施。我们应用具有改进的平面内空间分辨率（2.62×2.62mm）的 3T 功能磁共振成像，在发作性偏头痛（间歇期）和年龄及性别匹配的健康对照者中评估 RAVANS（门控吸气或呼气）和假刺激对大脑的反应。我们进一步使用空气喷刺激法在功能磁共振成像期间刺激额部，研究了 RAVANS 对脑干三叉感觉传入反应的调制。与假刺激和吸气门控 RAVANS（iRAVANS）相比，呼气门控 RAVANS（eRAVANS）激活了与孤束核（NTS）一致的同侧桥脑延髓区。在偏头痛患者中，与假刺激和 iRAVANS 相比，eRAVANS 激活时，NTS 的连通性增加到前岛叶和前扣带皮质。连通性的增加与下一次偏头痛发作的相对时间呈负相关，表明这种连通性变化具有临床相关性。刺激后效应也在 eRAVANS 后立即被注意到，因为我们发现对三叉感觉传入的反应中，假定的桥脑 5-羟色胺能（即中央中缝核）和去甲肾上腺素能（即蓝斑核）核的活性增加。参与 5-羟色胺能和去甲肾上腺素能调节以及疼痛调制的脑干和皮质区域的活动和连通性的调节可能构成支持应用于发作性偏头痛的 eRAVANS 的有益临床结果的潜在机制。
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