Secondarily generalized tonic clonic seizure; a functional anatomy

继发性全身强直阵挛发作；

• 批准号: 10672269
• 负责人: Jaideep Kapur
• 金额: $ 55.74万
• 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/10672269
• 关键词: 3-Dimensional; Acute; Anatomical Sciences; 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; 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; Visualization; antagonist; computer science; digital imaging; falls; frontal lobe; image reconstruction; neonatal hypoxic-ischemic brain injury; neural; neuronal circuitry; neuroregulation; new therapeutic target; novel; novel therapeutic intervention; receptor; reconstruction; 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.

我们建议将焦点电机映射到双侧强调持续癫痫发作（FMBSS），这是最多的 危险的癫痫发作。这些癫痫发作增加了癫痫突然出重死亡的风险 （Sudep）并导致由于暴力跌落而导致的骨折和脱位。 Sudep是最常见的原因 癫痫患者死亡。我们提出，规范巡回法院发表在坎德尔的神经原理中 科学（2013），认为局灶性癫痫发作与脑皮层脑皮层相关，这导致 其次，普遍的强直性持续性癫痫发作过于简单。它与已知的神经解剖学一致 运动皮层和皮层结构对癫痫发作的调节。我们建议FMBS起源于 额叶皮层通过纹状体传播到帕利德斯，底底尼格拉和丘脑 除了直接扩散到丘脑外，间接途径。我们以三个目标检验了这一假设。目的 1：映射FMB在中尺度上散布，并将其与癫痫发作重点的解剖学连接进行比较 使用组织清除和3D成像的陷阱小鼠结合了道跟踪和电生理学 技术）。目标2以绘制FMB在微观尺度上通过皮层传播，并直接和间接 使用免疫组织化学的陷阱小鼠中的基底神经节电路。在AIM 3中，我们将研究2型多巴胺 使用多种技术组合，在中尺度和微电路水平上对癫痫发作的受体调节。 我们合并了由大脑计划在我们的实验室中开发的工具和技术，以移动 发作电路映射研究。我们使用了陷阱小鼠，清晰度技术，高分辨率， 高通量成像和图像的3D重建以可视化活化的神经元途径。我们有 建立了一个高度协作的团队，具有解剖学，电生理学和计算机科学专业知识 成像，这使我们能够生成和分析大量数据并基于彼此的创造力。 我们已经获得了足够的设备来执行这些研究。这些研究将为 通过深脑刺激调节癫痫发作。目前，此方法用于前丘脑 刺激和响应性神经刺激，但是将来，多个皮层结构可以用于 神经调节。已知调节基底神经节电路已知的受体和离子通道可能会出现为新型 抗惊厥性发展的目标。如果我们的研究确认癫痫发作通过纹状体，则II 了解潜在的细胞机制将很重要。