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

• 批准号: 7998967
• 负责人: Joshua Ethan Motelow
• 金额: $ 4.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/7998967
• 关键词: Amnesia; Arousal; Biosensor; Cell Nucleus; Cerebrovascular Circulation; Cognitive deficits; 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; Lead; Limbic System; Maps; Measures; Neocortex; Neurotransmitters; Operative Surgical Procedures; Partial Epilepsies; Patients; Performance; Pharmacotherapy; Play; Quality of life; Rodent; Rodent Model; Role; Schools; Seizures; Stigmatization; Structure; System; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Work; blood oxygen level dependent; improved; neocortical; neuroimaging; neurotransmitter agonist; public health relevance; social; therapy design; vehicular accident

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. PUBLIC HEALTH RELEVANCE: Impaired consciousness and cortical dysfunction during temporal lobe seizures causes motor vehicle accidents, drowning, poor work and school performance, and social stigmatization. Through understanding the underlying mechanisms of complex partial temporal lobe seizures, we may successfully design therapies to preserve consciousness and improve patient quality of life.

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。部分颞叶癫痫发作通常会导致超出局部海马损伤预期的功能缺陷。除了健忘症外，患者通常还表现出意识障碍。在人类中，与意识障碍相关的局灶性颞叶癫痫发作与脑电图 (EEG) 上的 1-2 Hz 发作性新皮质慢波和新皮质脑血流量 (CBF) 减少呈正相关。目前尚不清楚边缘系统（包括海马体）的局灶性癫痫如何导致新皮质的发作减慢和意识受损。初步数据表明，皮质下结构在癫痫活动和新皮质减慢中发挥着重要作用。我们的中心假设是局灶性海马癫痫发作传播到抑制皮质下唤醒系统的核，导致新皮质功能下降。我们计划通过结合神经影像学、电生理学和神经递质技术，使用局灶性海马癫痫发作的啮齿动物模型来研究这一现象。我们的首要目标是绘制发作期新皮质慢活动背后的皮质和皮质下网络。我们将通过使用血氧水平依赖性（BOLD）功能磁共振成像对啮齿动物边缘癫痫发作期间的成像来实现这一目标。一旦我们确定了参与控制新皮质减慢网络的候选区域，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质缓慢活动至关重要。我们的第三个目标是确定发作期新皮质缓慢活动背后的神经递质变化。使用我们的部分颞叶癫痫啮齿动物模型，我们将用生物传感器探针测量神经递质水平，以确定在发作性缓慢活动期间新皮质中的激活神经递质是否减少。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/产生发作性新皮质减慢。新皮质功能受损和认知缺陷显着降低 TLE 患者的生活质量。了解局灶性癫痫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。 公共卫生相关性：颞叶癫痫发作期间意识受损和皮质功能障碍会导致机动车事故、溺水、工作和学习表现不佳以及社会耻辱。通过了解复杂的部分颞叶癫痫发作的潜在机制，我们可以成功地设计治疗方法来保留意识并改善患者的生活质量。