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.

项目总结/文摘

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