Non-invasive vagus nerve stimulation targeting cortical spreading depression in migrane prophylaxis

非侵入性迷走神经刺激针对偏头痛预防中的皮质扩散抑制

• 批准号: 10189715
• 负责人: Cenk Ayata
• 金额: $ 37.36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189715
• 关键词: Acute; Address; Affect; Auras; Bilateral; Brain; Brain Stem; Brain hemorrhage; Case Series; Cell Nucleus; Cerebrum; Cervical; Chronic; Clinical; Clinical Trials; Complex; Data; Disease; Distal; Dose; Electrophysiology (science); Epilepsy; Experimental Models; Familial Hemiplegic Migraine; Female; Fiber; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic; Glutamates; Goals; Headache; Hour; Human; Implanted Electrodes; Intervention; Intractable Epilepsy; Ischemic Stroke; Knowledge; Lesion; Light; Link; Maps; Mediating; Mental Depression; Microdialysis; Migraine; Modality; Modeling; Mus; Mutation; Neurobiology; Neurologic; Neurotransmitters; Norepinephrine; Oxygen; Paper; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Play; Population; Predisposition; Preventive treatment; Productivity; Prophylactic treatment; Publishing; Randomized; Research; Role; Serotonin; Side; Specificity; Spreading Cortical Depression; System; Technology; Testing; Therapeutic; Traumatic Brain Injury; Treatment Efficacy; United States National Institutes of Health; Vagotomy; disability; experimental study; holistic approach; implantable device; in vivo; innovation; insight; neuroregulation; novel; novel therapeutics; open label; optogenetics; pilot trial; pre-clinical; prevent; prophylactic; public health relevance; response; socioeconomics; therapy development; treatment-resistant depression; vagus nerve stimulation; years lived with disability

Project Summary/Abstract Migraine is a highly prevalent, disabling, chronic episodic and progressive disorder affecting up to a fifth of the entire world population with tremendous socioeconomic impact. Despite recent advances in our understanding of migraine pathophysiology, treatment options are limited and have poor efficacy. Novel therapeutic modalities in migraine are an urgent unmet need. Cortical spreading depression (CSD) is an intense depolarization wave that is the electrophysiological substrate of migraine aura and a headache trigger. CSD is considered among the most reliable and robust experimental models of migraine, and CSD susceptibility is widely accepted as a validated platform to screen for migraine therapies. We recently discovered that vagus nerve stimulation (VNS), a novel neuromodulatory treatment already in clinical use for epilepsy and depression, acutely suppresses CSD susceptibility, suggesting potential therapeutic efficacy in migraine. More importantly, non-invasive cervical transcutaneous VNS (nVNS) was at least as effective as invasive VNS (iVNS) by an implanted electrode, increasing the translational potential. Pilot data show that nVNS inhibition of CSD is mediated by vagal afferent fibers projecting to the brainstem, and involves, at least in part, central serotonergic and norepinephrinergic systems. Building on these discoveries, we propose two aims to (1) establish the therapeutic profile and (2) gain insight into the mechanisms of action of VNS as a novel neuromodulatory intervention targeting CSD. Aim 1 will determine dose/frequency-response, side-specificity, duration of action, additive or synergistic interactions with migraine prophylactic drugs, and chronic daily prophylaxis. In addition, using optogenetics to induce CSD non- invasively, we will test VNS efficacy in clinically more relevant freely behaving female mice expressing human migraine mutations. This translational aim will inform future clinical trials. Aim 2 will interrogate the cerebral circuitry in a logical and linear fashion to understand how VNS inhibits CSD. We will determine the contributions of efferent vs. afferent vagal fibers, map VNS-induced brain activation/inhibition by fMRI, lesion the nucleus tractus solitarius to show its relay role, pharmacologically interrogate the central neurotransmitter systems that may contribute to VNS efficacy on CSD, and using in vivo microdialysis, we will link these to curbing cortical glutamate release as the final common step in CSD suppression by VNS. Altogether, we will fill significant gaps in our knowledge on the therapeutic potential of VNS in migraine and its mechanisms of action on CSD using validated models and innovative, proprietary nVNS technology. The knowledge we gain will also shed light on other diseases where CSD plays a significant role, including traumatic brain injury and ischemic or hemorrhagic stroke, as collateral benefits.

项目概要/摘要 偏头痛是一种非常普遍的、致残的、慢性发作性和进行性的疾病，影响多达五分之一的人 对整个世界人口产生巨大的社会经济影响。尽管我们的理解最近取得了进展 根据偏头痛的病理生理学，治疗选择有限且疗效不佳。新的治疗方式 偏头痛是一个未得到满足的迫切需求。 皮质扩散抑制 (CSD) 是一种强烈的去极化波，是电生理信号 偏头痛先兆和头痛触发因素的基质。 CSD 被认为是最可靠、最稳健的 偏头痛和 CSD 易感性的实验模型被广泛接受为经过验证的筛选平台 用于偏头痛治疗。我们最近发现迷走神经刺激（VNS）是一种新型神经调节剂 临床上已用于癫痫和抑郁症的治疗，可显着抑制 CSD 易感性， 表明对偏头痛具有潜在的治疗功效。更重要的是，无创宫颈经皮 VNS (nVNS) 至少与植入电极的侵入性 VNS (iVNS) 一样有效，增加了 翻译潜力。试验数据表明 nVNS 对 CSD 的抑制是由迷走神经传入纤维介导的 投射到脑干，并至少部分涉及中枢血清素能和去甲肾上腺素能系统。 基于这些发现，我们提出了两个目标：（1）建立治疗方案和（2）获得见解 研究 VNS 作为一种针对 CSD 的新型神经调节干预措施的作用机制。目标1将 确定剂量/频率反应、副作用、作用持续时间、相加或协同相互作用 偏头痛预防药物和长期日常预防。此外，利用光遗传学诱导 CSD 非 侵入性地，我们将测试 VNS 在临床上更相关的自由行为雌性小鼠中的功效，这些小鼠表达人类 偏头痛突变。这一转化目标将为未来的临床试验提供信息。目标2将询问大脑 以逻辑和线性方式了解 VNS 如何抑制 CSD 的电路。我们将确定 传出迷走神经纤维与传入迷走神经纤维的贡献，通过 fMRI 绘制 VNS 诱导的大脑激活/抑制图，病变 孤束核显示其中继作用，从药理学角度询问中枢神经递质 可能有助于 VNS 对 CSD 功效的系统，并使用体内微透析，我们将把它们与 抑制皮质谷氨酸释放是 VNS 抑制 CSD 的最后一个共同步骤。 总而言之，我们将填补 VNS 治疗偏头痛及其相关疾病的潜力方面的重大知识空白。 使用经过验证的模型和创新的专有 nVNS 技术对 CSD 采取行动机制。这 我们获得的知识还将揭示 CSD 发挥重要作用的其他疾病，包括 创伤性脑损伤和缺血性或出血性中风，作为附带好处。

项目成果

Spreading depression as an innate antiseizure mechanism.

• DOI: 10.1038/s41467-021-22464-x
• 发表时间: 2021-04-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Tamim I;Chung DY;de Morais AL;Loonen ICM;Qin T;Misra A;Schlunk F;Endres M;Schiff SJ;Ayata C
• 通讯作者: Ayata C

Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.

• DOI: 10.1161/strokeaha.120.029651
• 发表时间: 2020-10
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Yanagisawa T;Zhang H;Suzuki T;Kamio Y;Takizawa T;Morais A;Chung DY;Qin T;Murayama Y;Faber JE;Patel AB;Ayata C
• 通讯作者: Ayata C