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-阵挛性癫痫（FMBSs），这是最常见的