Secondarily generalized tonic clonic seizure; a functional anatomy

继发性全身强直阵挛发作；

• 批准号: 10317485
• 负责人: Jaideep Kapur
• 金额: $ 55.44万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317485
• 关键词: 3-Dimensional; Acute; Anatomy; Anterior; Anticonvulsants; Axon; BRAIN initiative; Basal Ganglia; Bilateral; Brain; Cause of Death; Cells; Chronic; Cobalt; Collaborations; Corpus striatum structure; Creativeness; Dangerousness; Data; Deep Brain Stimulation; Development; Dislocations; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Electrodes; Electrophysiology (science); Engineering; Epilepsy; Equipment; Excision; Focal Seizure; Fracture; Frontal Lobe Epilepsy; Future; Genetic Recombination; Globus Pallidus; Image; Imaging Techniques; Immunohistochemistry; Infusion procedures; Ion Channel; Label; Laboratories; Laboratory Research; Laboratory Study; Lead; Maps; Mediating; Methods; Microscopic; Modeling; Motor; Motor Cortex; Motor Seizures; Mus; Neuroanatomy; Neurons; Output; Partial Epilepsies; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Prosencephalon; Publishing; Recurrence; Reporter; Research; Resolution; Risk; Science; Secondary to; Seizures; Site; Status Epilepticus; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Synaptophysin; Techniques; Testing; Thalamic structure; Thick; Thinness; Three-Dimensional Imaging; Tissues; Tonic - clonic seizures; Violence; Viral; computer science; digital imaging; falls; frontal lobe; image reconstruction; neonatal hypoxic-ischemic brain injury; neuronal circuitry; neuroregulation; new therapeutic target; novel; novel therapeutic intervention; receptor; reconstruction; relating to nervous system; sudden unexpected death in epilepsy; temporal measurement; tool

We propose to map focal motor to bilateral tonic-clonic seizures (FMBSs), which are the most dangerous epileptic seizures. These seizures increase the risk of sudden unexpected death in epilepsy (SUDEP) and lead to fractures and dislocations due to violent falls. SUDEP is the most common cause of death in patients with epilepsy. We propose that the canonical circuit published in Kandel's Principles of Neural Science (2013), which posits that focal seizures engage diencephalic thalamocortical circuits, which leads to secondarily generalized tonic-clonic seizures is too simplistic. It is not consistent with known neuroanatomy of the motor cortex, and modulation of seizures by subcortical structures. We propose that FMBSs originating in the frontal cortex spread through the striatum to the globus pallidus, substantia nigra and thalamus via the indirect pathway, in addition to spreading directly to the thalamus .. We test this hypothesis in three aims. Aim 1: to map FMBS spread at the mesoscale and compare it to anatomical connections of the seizure focus in TRAP mice using tissue clearing and 3D imaging combined with tract tracing and electrophysiological techniques). Aim 2 to map FMBS spread at the microscopic scale through the cortex and direct and indirect basal ganglia circuits in TRAP mice using immunohistochemistry. In aim 3, we will study dopamine type 2 receptor modulation of seizures at the mesoscale and microcircuit levels using a combination of techniques. We incorporated tools and techniques developed by the BRAIN initiative in our laboratory to move seizure circuit mapping research forward. We have used TRAP mice, the CLARITY technique, high resolution, high-throughput imaging, and 3D reconstruction of images to visualize activated neuronal pathways. We have constructed a highly collaborative team with expertise in anatomy, electrophysiology and computer science of imaging, which allows us to generate and analyze large volumes of data and build on each other's creativity. We have acquired sufficient equipment to perform these studies. These studies will generate new targets for the modulation of seizures by deep brain stimulation. Currently, this method is used for anterior thalamic stimulation and responsive neurostimulation, but in the future, multiple subcortical structures could sites for neuromodulation. Receptors and ion channels known to modulate basal ganglia circuits may emerge as novel targets for anticonvulsant development. If our studies confirm seizure passage through the striatum, then ii would be important to understand the underlying cellular mechanisms.

我们建议将局部运动映射到双侧强直-阵挛发作(FMBS)，这是最常见的 危险的癫痫发作。这些癫痫发作增加了癫痫患者猝死的风险。 (SUDEP)，并因猛烈跌落而导致骨折和脱位。SUDEP是最常见的 癫痫患者的死亡。我们提出了发表在《坎德尔神经原理》中的正则电路 科学(2013)，它假设局灶性癫痫发作涉及间脑丘脑皮质回路，这导致 二次泛发性强直阵挛发作过于简单化。这与已知的神经解剖学不一致。 运动皮质，以及皮质下结构对癫痫发作的调制。我们建议，起源于 额叶皮质通过纹状体到达苍白球、黑质和丘脑。 间接途径，除了直接扩散到丘脑外..我们从三个方面检验这一假设。目标 1：绘制散布在中尺度上的FMB图，并将其与癫痫灶的解剖联系进行比较 组织清除和3D成像结合轨迹追踪和电生理诱捕小鼠 技术)。目的2绘制在微观尺度上通过大脑皮质传播的FMB以及直接和间接的FMB 用免疫组织化学方法研究TRAP小鼠的基底节环路。在目标3中，我们将研究多巴胺2 使用多种技术在中尺度和微电路水平上对癫痫发作的受体调制。 我们在实验室里整合了大脑计划开发的工具和技术来移动 癫痫电路图研究向前推进。我们使用了捕鼠器，透明技术，高分辨率， 高通量成像和图像的3D重建，以可视化激活的神经元路径。我们有 构建了一个高度协作的团队，拥有解剖学、电生理学和计算机科学方面的专业知识 成像，它使我们能够生成和分析大量数据，并建立在彼此的创造力之上。 我们已经获得了足够的设备来进行这些研究。这些研究将产生新的目标 脑深部刺激对癫痫发作的调节。目前，这种方法用于丘脑前部。 刺激和反应性神经刺激，但在未来，多个皮质下结构可能是 神经调节。已知的调节基底节环路的受体和离子通道可能作为新的出现 抗惊厥药物开发的靶点。如果我们的研究证实癫痫发作通过纹状体，那么II 对于理解潜在的细胞机制是很重要的。