Subcortical control of neocortical slowing during focal hippocampal seizures

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。部分性颞叶癫痫发作经常引起超出局部海马损伤预期的功能缺陷。除了健忘症，患者通常表现出意识受损。在人类中，与意识受损相关的局灶性颞叶癫痫发作与脑电图（EEG）上的1-2 Hz发作性新皮质慢波和新皮质中的脑血流量（CBF）减少呈正相关。目前还不清楚边缘系统（包括海马体）的局灶性癫痫发作如何在新皮层中引起发作减慢和意识受损。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起重要作用。我们的中心假设是，局灶性海马癫痫发作传播到抑制皮层下唤醒系统的核团，导致新皮层功能低下。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种现象。我们的第一个目标将是映射皮层和皮层下网络潜在的发作新皮层慢活动。我们将通过使用血氧水平依赖（BOLD）功能磁共振成像成像在边缘癫痫发作期间对啮齿动物进行成像来实现这一点。一旦我们确定了参与控制新皮层减慢的网络的候选区域，我们的第二个目标将是探测新发现的结构。在这个目标中，我们将使用电生理学技术直接记录，刺激，断开连接，并重新定位候选区域，以确定哪些是关键的新皮层慢活动。我们的第三个目标将是确定神经递质的变化，潜在的发作新皮层慢活动。使用我们的部分颞叶癫痫的啮齿动物模型，我们将用生物传感器探针测量神经递质水平，以确定在发作缓慢活动期间新皮层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/创建发作性新皮质减慢。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。了解局灶性癫痫远程网络损伤的基本机制可能会导致改善这种疾病的手术，神经刺激或药物治疗。

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.