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.

我们建议将局灶性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。这些癫痫发作会增加癫痫患者突然意外死亡的风险 （SUDEP）并因剧烈跌倒而导致骨折和脱臼。 SUDEP 是最常见的原因 癫痫患者死亡。我们建议坎德尔的神经原理中发表的规范电路 Science (2013)，假设局灶性癫痫发作涉及间脑丘脑皮质回路，从而导致 继发性全身性强直阵挛性癫痫发作过于简单化。这与已知的神经解剖学不一致 运动皮层，以及皮层下结构对癫痫发作的调节。我们建议 FMBS 源自 额叶皮质通过纹状体传播到苍白球、黑质和丘脑 除了直接传播到丘脑之外，还有间接途径。我们在三个目标上测试了这一假设。目的 1：绘制 FMBS 在中尺度的扩散图，并将其与癫痫病灶的解剖连接进行比较 TRAP 小鼠使用组织透明化和 3D 成像结合纤维束追踪和电生理学 技术）。目标 2 绘制 FMBS 通过皮层在微观尺度上的直接和间接传播图 使用免疫组织化学研究 TRAP 小鼠的基底神经节回路。在目标 3 中，我们将研究 2 型多巴胺 使用组合技术在中尺度和微电路水平上对癫痫发作进行受体调节。 我们在实验室中采用了 BRAIN 计划开发的工具和技术来移动 癫痫回路测绘研究的进展。我们使用了 TRAP 小鼠、CLARITY 技术、高分辨率、 高通量成像和图像 3D 重建以可视化激活的神经元通路。我们有 建立了一支高度协作的团队，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发挥彼此的创造力。 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 通过深部脑刺激调节癫痫发作。目前，该方法用于丘脑前部 刺激和反应性神经刺激，但在未来，多个皮层下结构可以定位 神经调节。已知调节基底神经节回路的受体和离子通道可能会成为新颖的 抗惊厥开发的目标。如果我们的研究证实癫痫发作通过纹状体，那么 ii 了解潜在的细胞机制非常重要。