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Subcortical control of neocortical slowing during focal hippocampal seizures

局灶性海马癫痫发作期间新皮质减慢的皮质下控制

基本信息

批准号：
8321559
负责人：
Joshua Ethan Motelow
金额：
$ 4.66万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321559
关键词：
Acetylcholine Amnesia Anesthesia procedures Animals Anterior Hypothalamus Arousal Automobile Driving Biosensor Cell Nucleus Cerebrovascular Circulation Cognitive deficits Coma Complex Conscious Data Depressed mood Disease Drowning Electroencephalography Electrophysiology (science)Exhibits Focal Seizure Functional Magnetic Resonance Imaging Functional disorder Hippocampus (Brain)Human Image Impairment Infusion procedures Lateral Lead Lesion Limbic System Maps Measurement Measures Movement Neocortex Neurons Neurotransmitters Operative Surgical Procedures Partial Epilepsies Patients Performance Pharmacotherapy Play Quality of life Resolution Rodent Rodent Model Role Schools Seizures Signal Transduction Sleep Stigmatization Structure System Techniques Temporal Lobe Temporal Lobe Epilepsy Work awake blood oxygen level dependent improved inhibitory neuron neocortical neuroimaging neurotransmitter agonist prevent research study social therapy design vehicular accident

项目摘要

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is characterized by focal seizures arising from limbic structures including the hippocampus. Partial temporal lobe seizures often cause functional deficits beyond those expected from local hippocampal impairment. In addition to amnesia, patients typically exhibit impaired consciousness. In humans, focal temporal lobe seizures associated with impaired consciousness are positively correlated with 1-2 Hz ictal neocortical slow waves on electroencephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex. It is unknown how a focal seizure in the limbic system (including the hippocampus) creates ictal slowing in the neocortex and impaired consciousness. Preliminary data suggests that subcortical structures play an important role in both seizure activity and neocortical slowing. Our central hypothesis is that focal hippocampal seizures propagate to nuclei that inhibit subcortical arousal systems, leading to depressed function in the neocortex. We plan to investigate this phenomenon through a combination of neuroimaging, electrophysiology, and neurotransmitter techniques using a rodent model of focal hippocampal seizures. Our first aim will be to map the cortical and subcortical networks underlying ictal neocortical slow activity. We will accomplish this by imaging rodents during limbic seizures using blood oxygen level dependent (BOLD) fMRI. Once we have identified candidate regions involved in the network governing neocortical slowing, our second aim will be to probe the newly identified structures. In this aim, we will use electrophysiology techniques to record directly from, stimulate, disconnect, and inactivate candidate regions to determine which are critical for neocortical slow activity. Our third aim will be to identify neurotransmitter changes underlying ictal neocortical slow activity. Using our rodent model of partial temporal lobe epilepsy, we will measure neurotransmitter levels with biosensor probes to determine if activating neurotransmitters decrease in the neocortex during ictal slow activity. We will then reverse/create ictal neocortical slowing by local infusion of specific neurotransmitter agonists/antagonists. Impaired neocortical function and cognitive deficits significantly reduce the quality of life in patients with TLE. Understanding the fundamental mechanisms of remote network impairment in focal epilepsy may lead to improved surgical, neurostimulation or pharmacotherapies for this disorder.

描述（由申请人提供）：颞叶癫痫（TLE）的特征是由包括海马在内的边缘结构引起的局灶性癫痫发作。部分颞叶癫痫通常引起的功能缺陷超出了局部海马损伤的预期。除了健忘症，患者通常还表现出意识受损。在人类中，与意识受损相关的局灶性颞叶癫痫与脑电图（EEG）上1-2 Hz的新皮层慢波和新皮层脑血流量（CBF）减少呈正相关。目前尚不清楚边缘系统（包括海马体）的局灶性癫痫是如何造成新皮层的严重减速和意识受损的。初步数据表明，皮层下结构在癫痫发作活动和新皮层减缓中都起着重要作用。我们的中心假设是，局灶性海马癫痫传播到抑制皮层下唤醒系统的核，导致新皮层功能下降。我们计划通过神经成像、电生理学和神经递质技术的结合，利用啮齿动物局灶性海马癫痫模型来研究这一现象。我们的第一个目标将是绘制大脑皮层和皮层下的网络，这些网络隐藏在关键的新皮层慢活动之下。我们将通过使用血氧水平依赖（BOLD）功能磁共振成像（fMRI）在边缘癫痫发作时对啮齿动物进行成像来实现这一目标。一旦我们确定了参与控制新皮层减缓的网络的候选区域，我们的第二个目标将是探索新确定的结构。为此，我们将使用电生理学技术直接记录、刺激、断开和灭活候选区域，以确定哪些区域对新皮层慢活动至关重要。我们的第三个目标将是确定关键的新皮层慢活动背后的神经递质变化。使用我们的啮齿动物部分颞叶癫痫模型，我们将用生物传感器探针测量神经递质水平，以确定在急性慢活动期间，激活的神经递质是否在新皮层中减少。然后，我们将通过局部输注特定的神经递质激动剂/拮抗剂来逆转/创造临界新皮质减缓。新皮质功能受损和认知缺陷显著降低TLE患者的生活质量。了解局灶性癫痫中远程网络损伤的基本机制可能会改善这种疾病的手术、神经刺激或药物治疗。