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: 8127801
• 负责人: Joshua Ethan Motelow
• 金额: $ 4.68万
• 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/8127801
• 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; public health relevance; research study; 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)的特征是边缘结构包括海马体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区损伤预期的功能缺陷。除了健忘症，患者通常还会出现意识障碍。在人类中，与意识受损相关的局灶性颞叶癫痫发作与脑电(EEG)上1-2赫兹发作的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)的局灶性癫痫是如何导致新皮质发作性减慢和意识受损的。初步数据表明，皮质下结构在癫痫发作活动和新皮质减慢中都发挥着重要作用。我们的中心假设是，海马局灶性癫痫发作传播到抑制皮质下觉醒系统的核团，导致新皮质功能受抑。我们计划通过神经成像、电生理学和神经递质技术的结合，使用海马局灶性癫痫的啮齿动物模型来研究这一现象。我们的第一个目标将是绘制发作中新皮质缓慢活动的皮质和皮质下网络图。我们将通过使用血氧水平依赖(BOLD)功能磁共振成像对边缘癫痫发作期间的啮齿动物进行成像来实现这一点。一旦我们确定了控制新皮质减速的网络中涉及的候选区域，我们的第二个目标将是探索新发现的结构。在这个目标中，我们将使用电生理学技术直接记录、刺激、断开和失活候选区域，以确定哪些是新皮质缓慢活动的关键。我们的第三个目标将是确定发作期新皮质缓慢活动背后的神经递质变化。利用我们的部分颞叶癫痫的啮齿动物模型，我们将使用生物传感器探针测量神经递质水平，以确定在发作期缓慢活动期间新皮质中激活的神经递质是否减少。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/创造发作性新皮质减慢。新皮质功能受损和认知缺陷显著降低了TLE患者的生活质量。了解局灶性癫痫远端网络损害的基本机制可能有助于改进这种疾病的手术、神经刺激或药物治疗。 公共卫生相关性：在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、工作和学习成绩不佳以及社会污名。通过了解复杂部分颞叶癫痫的潜在机制，我们可能成功地设计出保护意识和提高患者生活质量的治疗方法。