Boosting mind-body mechanisms for mitigating central sensitization in migraine

增强身心机制以减轻偏头痛的中枢敏化

• 批准号: 10456008
• 负责人: VITALY NAPADOW
• 金额: $ 47.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456008
• 关键词: Adult; Area; Brain; Brain Stem; Brain region; Breathing; Cell Nucleus; Clinical; Complex; Data; Disease; Dorsal; Education; Frequencies; Functional Magnetic Resonance Imaging; Glutamates; Hyperalgesia; Hypothalamic structure; Individual; Inhalation; Institute of Medicine (U.S.); Insula of Reil; Intervention; Link; Magnetic Resonance Spectroscopy; Mediating; Migraine; Mind-Body Intervention; Modeling; Neurobiology; Neurotransmitters; Nucleus solitarius; Operating System; Outcome; Pain; Pathway interactions; Patients; Phase; Randomized; Reporting; Respiration; Sensory; Severities; Structure; Structure of trigeminal nerve spinal tract nucleus; Sum; Thalamic structure; Training; Training and Education; Transcutaneous Electric Nerve Stimulation; Trigeminal System; Trigeminal nerve structure; Up-Regulation; afferent nerve; body-mind; central sensitization; chronic pain; chronic pain patient; disability; experience; expiration; habituation; improved; locus ceruleus structure; migraine treatment; mindfulness meditation; mindfulness-based stress reduction; multimodality; neuroimaging; noradrenergic; raphe nuclei; recruit; respiratory; response; sensory input; synergism; therapeutic target; trial design; vagus nerve stimulation

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.

抽象的 偏头痛（MIG）是普遍（15-20％）和高度残疾的疾病，具有复杂的神经生物学 以脑干三叉学感觉复合物的敏感性为特征的基础，导致 脑干介导的皮质和下丘脑刺激性上调。我们自己的飞行员fMRI数据找到了 从脊柱三叉神经核到皮质区域的习惯减少和放大传入的输入 后岛和下丘脑。减少皮质/皮质下扩增和归一化习惯可能 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，并具有 我们建议也是如此 思维体疗法。正念冥想（MM）已显示出对偏头痛的承诺，并可能通过 自上而下的机制，可能会减少后岛和丘脑过度刺激性。此外， 兴奋性神经递质谷氨酸和最近的MR光谱法介导了过度兴奋性 （H-MRS）研究发现，后绝缘中谷氨酸增加与痛觉过敏有关 慢性疼痛患者，而经验丰富的介质显示丘脑中的谷氨酸水平降低。 此外，自下而上的疗法，例如侵入性和非侵入性耳经穿神经神经 刺激（TVN）还会降低偏头痛的频率和残疾。在TVN中，迷走神经传播到核 髓质中的Tractus solitarii（NTS）可能会调节三叉神经感觉复杂性令人兴奋和过度兴奋 在较高的大脑结构（即“自下而上”途径）中，可以通过募集血清素能（Raphe Nuclei） 通过NTS传入，和去甲肾上腺素能（LC coeruleus，LC）途径。此外，背髓 迷走神经系统与呼吸同步运行：NTS从髓腹接收抑制性输入 吸入期间呼吸组（VRG）核和到期期间的促进输入。这是一个至关重要的 该电路的重要特征，这表明使用此NTS途径的干预措施应为 呼吸同步。因此，我们的小组出现了呼吸门控的耳走神经神经 刺激（Ravans），该刺激仅在到期阶段通过刺激来优化靶向NT的TVN。 那就是Ravans TVNS在区域内的皮质/皮质下过度刺激性的自下而上调制 例如后部岛和丘脑，也是由MM相关的电路瞄准的。总而言之，我们 提议MM培训纳入Ravans TVNS将对减少后部岛的协同作用， 丘脑和下丘脑性过度偏头痛。