Sensory plasticity in migraine

偏头痛的感觉可塑性

• 批准号: 9315949
• 负责人: Kevin Christopher Brennan
• 金额: $ 32.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315949
• 关键词: Acute; Affect; Animals; Astrocytes; Attenuated; Auras; Basic Science; Behavior; Biological Markers; Biological Neural Networks; Blinking; Blood Vessels; Brain; Brain Diseases; Brain Stem; Calcium; Cell physiology; Cells; Chemosensitization; Chronic; Chronic Disease; Clinical; Darkness; Data; Decision Making; Development; Disease; Electrophysiology (science); Environment; Equilibrium; Esthesia; Event; Evolution; Familial Hemiplegic Migraine; Flunarizine; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Head; Headache; Homeostasis; Human; Image; Individual; Interneurons; Label; Learning; Light; Lighting; Malignant - descriptor; Maps; Memantine; Microscopy; Migraine; Modification; Mus; Neurobiology; Neurons; Neurosciences; Optics; Pain; Pain Disorder; Pathway interactions; Patients; Perception; Pharmaceutical Preparations; Photophobia; Physiological; Physiology; Population; Positioning Attribute; Preparation; Process; Publishing; Pyramidal Cells; Resolution; Role; Sensory; Sensory Disorders; Signal Transduction; Spreading Cortical Depression; Structure; System; Techniques; Testing; Touch sensation; Transgenic Mice; Translating; Visual Cortex; Whole-Cell Recordings; awake; base; burden of illness; casein kinase I; clinically relevant; depression model; experimental study; in vivo calcium imaging; insight; mutant; nervous system disorder; neurovascular coupling; neurovascular unit; potential biomarker; preference; public health relevance; release of sequestered calcium ion into cytoplasm; response; sensory cortex; sensory input; somatosensory; sound; spreading depression; therapeutic target; treatment strategy; two-photon

DESCRIPTION (provided by applicant): Migraine affects 12% of the world population. Chronic migraine, which completely disrupts the lives of sufferers, affects close to 3%, and is extremely difficult to treat. It appears that there is an evolution or 'kindling' from an episodic to a chronc migraine state. Migraine is a pain disorder, but more fundamentally it is a disorder of brain excitability, whose fundamental manifestation is an increase in the 'volume' of sensory input. We have identified changes in brain sensory responses after cortical spreading depression (CSD), a wave of brain activity that is thought to underlie the migraine aura. Remarkably, these changes resemble what is seen in the brain during plasticity - i.e. during learning. Our core hypothesis is that CSD and other migraine-related events co-opt the normal learning machinery of the sensory brain to cause a form of dysfunctional learning - or malignant plasticity. We suspect that the development of an acute migraine attack, and the progression of migraine, is driven by this negative plasticity process. We will use imaging and electrical recordings in mice expressing genes found in migraine patients to test this hypothesis. Our first aim focuses on the changes in individual cellular function caused by CSD, which is thought to underlie the migraine aura. We have identified structural and functional changes in neurons, astrocytes, and blood vessels after CSD, each of which might explain the change in sensory network response we observed. Our second aim broadens our approach to look at larger neural networks disrupted by CSD. In addition to pain, migraine also involves changes in perception of light; photophobia or aversion to light is extremely common. We will image the visual cortex of awake mice as they decide on their preference for light levels, before and after CSD. Our third aim will try to apply the insighs we have gained to the development of migraine treatments. Sensory map sharpening - one of the markers of sensory learning we identified after CSD - may be identifiable in humans using fMRI. We will test whether sharpening of sensory maps occurs on chronic CSD stimulation, and thus might serve as a biomarker of migraine progression. Finally, on the basis of our cellular findings, we will test two clinically-relevant medications whose mechanism may be suppression of excessive calcium activity after CSD. Overall, our experiments should uncover basic mechanisms underlying the development of a migraine attack and the progression of migraine, and point to treatment strategies that arrest the 'malignant learning' that takes place in this disease.

描述（由申请人提供）：偏头痛影响世界人口的 12%。慢性偏头痛完全扰乱了患者的生活，影响了近 3% 的患者，而且极其难以治疗。似乎存在从偶发性偏头痛状态到慢性偏头痛状态的演变或“点燃”。偏头痛是一种疼痛障碍，但更根本的是，它是一种大脑兴奋性障碍，其根本表现是感觉输入“量”的增加。我们已经确定了皮质扩散抑制（CSD）后大脑感觉反应的变化，这种大脑活动波被认为是偏头痛先兆的基础。值得注意的是，这些变化类似于大脑在可塑性过程中（即学习过程中）所看到的变化。我们的核心假设是 CSD 和其他偏头痛相关事件共同选择了感觉脑的正常学习机制，导致某种形式的功能障碍性学习，或恶性可塑性。我们怀疑急性偏头痛的发生和偏头痛的进展是由这种负可塑性过程驱动的。我们将使用表达偏头痛患者基因的小鼠的成像和电记录来检验这一假设。我们的第一个目标集中于 CSD 引起的个体细胞功能的变化，这被认为是偏头痛先兆的基础。我们已经确定了 CSD 后神经元、星形胶质细胞和血管的结构和功能变化，每一个变化都可以解释我们观察到的感觉网络反应的变化。我们的第二个目标拓宽了我们研究受 CSD 破坏的更大神经网络的方法。除了疼痛之外，偏头痛还涉及光感知的变化。畏光或厌恶光是非常常见的。我们将对清醒小鼠在 CSD 前后决定其对光照水平的偏好时的视觉皮层进行成像。我们的第三个目标是尝试将我们获得的见解应用于偏头痛治疗的开发。感觉图锐化——我们在 CSD 后发现的感觉学习的标志之一——可能可以使用功能磁共振成像在人类中进行识别。我们将测试慢性 CSD 刺激时是否会出现感觉图的锐化，从而可能作为偏头痛进展的生物标志物。最后，根据我们的细胞研究结果，我们将测试两种临床相关药物，其机制可能是抑制 CSD 后过量的钙活性。总的来说，我们的实验应该揭示偏头痛发作和偏头痛进展的基本机制，并指出阻止这种疾病中发生的“恶性学习”的治疗策略。

项目成果

A migraine management training program for primary care providers: An overview of a survey and pilot study findings, lessons learned, and considerations for further research.

• DOI: 10.1111/head.12803
• 发表时间: 2016-04
• 期刊: Headache
• 影响因子: 5
• 作者: Minen M;Shome A;Halpern A;Tishler L;Brennan KC;Loder E;Lipton R;Silbersweig D
• 通讯作者: Silbersweig D