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: 10000034
• 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/10000034
• 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; 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.

摘要 偏头痛（Migraine，简称MGD）是一种常见的（15-20%）高度致残性疾病，具有复杂的神经生物学特性， 以脑干三叉神经感觉复合体的敏化为特征的基础，导致 脑干介导的皮质和下丘脑兴奋性上调。我们的初步功能磁共振成像数据发现 减少习惯和放大传入输入从三叉神经脊束核到皮质区，包括 后丘脑和下丘脑。减少皮层/皮层下放大和使习惯化正常化可以 成为重要的治疗靶点。多模式方法已经显示出改善的临床结果，并且 在最近的医学研究所关于疼痛的报告中被推荐。我们认为，这也是 身心疗法正念冥想（MM）已显示出对偏头痛的承诺，并可能通过以下方式运作： 自上而下的机制，潜在地减少后丘脑和丘脑的过度兴奋。此外，委员会认为， 兴奋性过度可能是由兴奋性神经递质谷氨酸介导的， 核磁共振波谱（H-MRS）研究发现，后颅窝中谷氨酸盐的增加与神经元的痛觉过敏有关。 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，如侵入性和非侵入性耳经皮迷走神经， 电刺激（tVNS）也可减少偏头痛频率和残疾。在tVNS中，迷走神经传入中继到核 延髓孤束（NTS）可调节三叉神经感觉复合体的兴奋性和过度兴奋性 在更高级的大脑结构中（即，一个“自下而上”的途径），可能是通过募集多巴胺能（中缝核） 和去甲肾上腺素能（蓝斑，LC）途径，通过NTS传入。此外，背髓 迷走神经系统与呼吸同步：NTS接受来自延髓腹侧的抑制性输入 呼吸组（VRG）核在吸气，和易化输入在呼气。这是一个关键的- 这一电路的重要特征，因为它表明，利用这一NTS途径的干预措施应该是 与呼吸同步。为此，本课题组研制了呼吸门控耳迷走传入神经 刺激（RAVANS），通过仅在呼气相进行刺激来优化NTS的tVNS靶向。 因此，RAVANS tVNS结合了自下而上的皮质/皮质下兴奋性调节， 例如后丘脑和丘脑，它们也是MM相关回路的目标。夏天我们 提出结合RAVANS tVNS的MM训练将在减少后部痉挛方面具有协同效应， 偏头痛中丘脑和下丘脑的过度兴奋。