Cortical Mechanisms of Headache: Beyond CSD

头痛的皮质机制：超越 CSD

• 批准号: 9276807
• 负责人: Rami Burstein
• 金额: $ 37.84万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276807
• 关键词: Accelerometer; Afferent Neurons; Animal Model; Animals; C Fiber; Cerebral cortex; Cervical; Chemicals; Clinical; Data Analyses; Development; Dura Mater; Electrocorticogram; Exhibits; Focal Seizure; Functional disorder; Generalized seizures; Generations; Headache; Human; Lead; Lidocaine; Mandible; Mediating; Meninges; Methods; Migraine; Modeling; Monitor; Neural Pathways; Neurons; Nociception; Nociceptors; Occipital lobe; Parietal Lobe; Pathway interactions; Patients; Pattern; Picrotoxin; Population; Population Study; Posterior Horn Cells; Process; Property; Rattus; Research; Role; Seizures; Sensory; Sinus; Site; Spreading Cortical Depression; Stimulus; Structure of trigeminal ganglion; Surface; System; Testing; Time; Trigeminal System; base; comparison group; dorsal horn; experimental study; insight; nerve supply; receptive field; response; spreading depression; theories; therapy development

Project Summary A large body of indirect evidence now strongly supports the idea that the nociceptive sensory pathway that innervates the intracranial meninges (the trigeminovascular system) is involved in the generation of some types of clinically occurring headaches, including migraine. The basic properties of this sensory pathway have been studied in detail in animal studies, but it is not yet well understood how this pathway becomes activated during a clinically occurring headache attack. One leading line of research has provided evidence in support of the CSD (cortical spreading depression) theory of migraine, including the recent findings of trigeminovascular neuron activation following CSD induction in animals. However, the study of CSD in migraine patients is necessarily somewhat anecdotal because CSD cannot be detected by routine methods in humans, and so it is not known how often it occurs, or what causes it to arise spontaneously. As a new avenue to further explore the mechanisms that can trigger headache and the potential role of cortical pathophysiology, we now propose to examine mechanisms of trigeminovascular neuron activation in an animal model of a common type of cortical pathophysiology that is well described and intensively studied in humans: cortical seizure. Based on the clinical observation that seizures are commonly followed by headache with features similar to migraine, we hypothesize that seizure can produce activation of the trigeminovascular system. We therefore propose to test this hypothesis, and to use seizure as a model to further investigate the mechanisms by which cortical processes can influence the trigeminovascular system, in the following Aims: (1) Employing single-unit recording to monitor changes in activity of first-order dura-sensitive neurons in the trigeminal ganglion, we will test the hypothesis that chemically-induced seizures can induce activation and/or sensitization of dural nociceptors. Seizure-induced effects will also be examined in trigeminal ganglion neurons that do not innervate the dura. (2) Using single-unit recording, changes in activity of second-order dural-responsive neurons in the superficial and deep laminae of the upper cervical and medullary dorsal horn will be examined following seizures in anesthetized rats. As in Aim 1, neurons that lack a dural response will also be studied. Data analysis will determine the latency, duration, and magnitude of changes in activity induced by seizure, and compare the seizure effects in dura-sensitive vs. dura-insensitive neurons. Experiments will test the hypothesis that neuronal activation will be produced by focal seizure in occipital but not parietal cortical sites, paralleling the regionally selective pattern found for the occurrence of postictal headache. In order to determine whether the seizure-induced discharge originates in terminals within the dural receptive field, lidocaine will be applied to the dura either prior to seizure induction or following seizure induction during the period of peak seizure- induced discharge.

项目概要 现在大量间接证据强烈支持这样的观点：伤害性感觉通路 神经支配颅内脑膜（三叉血管系统），参与某些神经元的产生 临床上发生的头痛类型，包括偏头痛。该感觉通路的基本特性是 已在动物研究中进行了详细研究，但尚不清楚该途径是如何被激活的 在临床上发生的头痛发作期间。一项领先的研究提供了证据支持 偏头痛的 CSD（皮质扩散性抑制）理论，包括三叉神经血管的最新发现 动物 CSD 诱导后的神经元激活。然而，偏头痛患者的 CSD 研究尚不明确。 这必然有些轶事，因为 CSD 无法通过常规方法在人类中检测到，因此 不知道它发生的频率，也不知道是什么原因导致它自发出现。作为进一步探索的新途径 引发头痛的机制以及皮质病理生理学的潜在作用，我们现在提出 检查常见类型动物模型中三叉血管神经元激活的机制 在人类中得到充分描述和深入研究的皮质病理生理学：皮质癫痫。基于 根据临床观察，癫痫发作后通常会出现头痛，其特征与偏头痛相似，我们 假设癫痫发作可以激活三叉血管系统。因此我们建议测试 这一假设，并使用癫痫发作作为模型来进一步研究皮质 过程可以影响三叉血管系统，目标如下：（1）采用单一单元 记录监测三叉神经节一级硬脑膜敏感神经元活动的变化，我们将 检验化学诱发的癫痫发作可以诱发硬脑膜激活和/或敏化的假设 伤害感受器。还将在不支配神经的三叉神经节神经元中检查癫痫引起的影响 硬脑膜。 (2) 使用单单元记录，二阶硬脑膜反应神经元的活动变化 以下将检查上颈椎的浅层和深层以及髓质背角 麻醉大鼠的癫痫发作。与目标 1 一样，缺乏硬脑膜反应的神经元也将被研究。数据 分析将确定癫痫发作引起的活动变化的潜伏期、持续时间和幅度，以及 比较硬脑膜敏感神经元与硬脑膜不敏感神经元的癫痫效果。实验将检验假设 枕叶而非顶叶皮质部位的局灶性癫痫发作将产生神经元激活，与此平行 发现发作后头痛发生的区域选择性模式。为了确定是否 癫痫发作引起的放电起源于硬脑膜感受野内的末端，将使用利多卡因 硬脑膜在癫痫发作诱导之前或在癫痫发作高峰期间的癫痫发作诱导之后 感应放电。