BackgroundPopulation-based studies have highlighted a close relationship between migraine and stroke. Migraine, especially with aura, is a risk factor for both ischemic and hemorrhagic stroke. Interestingly, stroke risk is highest for migraineurs who are young and otherwise healthy.Main bodyPreclinical models have provided us with possible mechanisms to explain the increased vulnerability of migraineurs’ brains towards ischemia and suggest a key role for enhanced cerebral excitability and increased incidence of microembolic events. Spreading depolarization (SD), a slowly propagating wave of neuronal depolarization, is the electrophysiologic event underlying migraine aura and a known headache trigger. Increased SD susceptibility has been demonstrated in migraine animal models, including transgenic mice carrying human mutations for the migraine-associated syndrome CADASIL and familial hemiplegic migraine (type 1 and 2). Upon experimentally induced SD, these mice develop aura-like neurological symptoms, akin to patients with the respective mutations. Migraine mutant mice also exhibit an increased frequency of ischemia-triggered SDs upon experimental stroke, associated with accelerated infarct growth and worse outcomes. The severe stroke phenotype can be explained by SD-related downstream events that exacerbate the metabolic mismatch, including pericyte contraction and neuroglial inflammation. Pharmacological suppression of the genetically enhanced SD susceptibility normalizes the stroke phenotype in familial hemiplegic migraine mutant mice. Recent epidemiologic and imaging studies suggest that these preclinical findings can be extrapolated to migraine patients. Migraine patients are at risk for particularly cardioembolic stroke. At the same time, studies suggest an increased incidence of coagulopathy, atrial fibrillation and patent foramen ovale among migraineurs, providing a possible path for microembolic induction of SD and, in rare instances, stroke in hyperexcitable brains. Indeed, recent imaging studies document an accelerated infarct progression with only little potentially salvageable brain tissue in acute stroke patients with a migraine history, suggesting an increased vulnerability towards cerebral ischemia.ConclusionPreclinical models suggest a key role for enhanced SD susceptibility and microembolization to explain both the occurrence of migraine attacks and the increased stroke risk in migraineurs. Therapeutic targeting of SD and microembolic events, or potential causes thereof, will be promising for treatment of aura and may also prevent ischemic infarction in vulnerable brains.

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先兆和中风：关系以及我们从临床前模型中学到的知识

背景基于人群的研究强调了偏头痛和中风之间的密切关系。偏头痛，尤其是先兆偏头痛，是缺血性和出血性中风的危险因素。有趣的是，年轻且健康的偏头痛患者中风的风险最高。主体临床前模型为我们提供了可能的机制来解释偏头痛患者大脑对缺血的脆弱性增加，并表明大脑兴奋性增强和微栓塞事件发生率增加的关键作用。传播去极化 (SD) 是一种缓慢传播的神经元去极化波，是偏头痛先兆和已知头痛触发因素的电生理事件。SD 易感性增加已在偏头痛动物模型中得到证实，包括携带人类偏头痛相关综合征 CADASIL 和家族性偏瘫偏头痛（1 型和 2 型）突变的转基因小鼠。在实验诱导 SD 后，这些小鼠会出现先兆样神经症状，类似于携带相应突变的患者。偏头痛突变小鼠在实验性中风时也表现出缺血触发的 SD 频率增加，与梗塞生长加速和更差的结果相关。严重的中风表型可以通过 SD 相关的下游事件来解释，这些事件加剧了代谢失配，包括周细胞收缩和神经胶质炎症。对遗传性增强的 SD 易感性进行药物抑制可使家族性偏瘫偏头痛突变小鼠的中风表型正常化。最近的流行病学和影像学研究表明，这些临床前发现可以推断到偏头痛患者。偏头痛患者尤其面临心源性卒中的风险。与此同时，研究表明，偏头痛患者中凝血障碍、心房颤动和卵圆孔未闭的发病率有所增加，这为微栓塞诱导 SD 以及在极少数情况下导致过度兴奋的大脑中风提供了可能的途径。事实上，最近的影像学研究记录了有偏头痛病史的急性中风患者的梗死进展加速，只有很少的潜在可挽救的脑组织，这表明脑缺血的脆弱性增加。偏头痛发作的发生以及偏头痛患者中风风险的增加。针对 SD 和微栓塞事件或其潜在原因的治疗目标将有望用于治疗先兆，也可能预防脆弱大脑的缺血性梗塞。