Boosting mind-body mechanisms for mitigating central sensitization in migraine

摘要 偏头痛(MIG)是一种流行的(15%-20%)高度致残性疾病，具有复杂的神经生物学特征 以脑干三叉神经感觉复合体敏化为特征的基础，导致 脑干介导的皮质和下丘脑兴奋性的上调。我们自己的飞行员fMRI数据发现 习惯化减弱和三叉神经脊束核向皮质区域的传入输入增加，包括 后脑岛和下丘脑。减少皮质/皮质下放大和正常化习惯化可能 成为重要的治疗靶点。多模式方法已显示出改善的临床结果，并已 在最近的医学研究所关于疼痛的报告中推荐使用。我们建议，这种情况也适用于 心身疗法。正念冥想(MM)已经显示出治疗偏头痛的希望，并可能通过 自上而下的机制，潜在地减少后脑岛和丘脑的过度兴奋。此外， 兴奋性亢进可能是由兴奋性神经递质谷氨酸和最近的磁共振波谱介导的。 (h-MRS)研究发现，后脑岛谷氨酸增加与痛觉过敏有关。 慢性疼痛患者，而有经验的冥想者显示丘脑中的谷氨酸水平降低。 此外，自下而上的治疗方法，如侵入性和非侵入性耳廓经皮迷走神经 刺激(TVNS)还可以减少偏头痛的频率和致残率。迷走神经传入在迷走神经核内传递 延髓孤束可能调节三叉神经感觉复合体兴奋性和超兴奋性 在高级大脑结构中(即“自下而上”的途径)，可能通过5-羟色胺能(中缝核团)的募集。 去甲肾上腺素能(蓝斑，LC)通路，通过NTS传入。此外，延髓背侧 迷走神经系统与呼吸同步运行：NTS接受延髓腹侧抑制传入 吸气时呼吸群(VRG)核，呼气时易化输入。这是一场至关重要的- 这个回路的重要特征，因为它表明利用这个NTS通路的干预应该是 与呼吸同步。因此，我们组开发了呼吸门控的耳迷走神经传入神经。 刺激(RAVANS)，通过仅在呼气相刺激来优化tVNS对NTS的靶向。 因此，RAVANS的tVNS结合了自下而上的区域皮质/皮质下超兴奋性的调制 如后脑岛和丘脑，也是MM相关回路的靶点。总而言之，我们 建议MM训练结合RAVANS TVNS将在缩小后岛方面具有协同效应， 偏头痛患者的丘脑和下丘脑的过度兴奋性。

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.