Remote effects of focal hippocampal seizures on neocortical function

描述（由申请人提供）：癫痫发作对神经系统功能有局部和远程影响。颞叶癫痫（TLE）是一种常见的使人衰弱的神经系统疾病，其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。有趣的是，部分颞叶癫痫通常会导致功能缺陷，如意识受损，而这并不仅仅是局部海马损伤造成的。意识受损的人类局灶性颞叶癫痫与脑电图（EEG）慢波和远离海马体的新皮层脑血流量（CBF）减少有关。海马体局灶性癫痫引起新皮质功能抑制的机制尚不清楚。基于我们的初步研究，我们提出临界新皮层缓慢活动反映了一种独特的皮层功能抑制状态，更接近于深度麻醉或睡眠而不是癫痫活动。为了支持这一点，我们最近在一个大鼠模型中发现，自发和诱导的边缘癫痫发作在海马体中表现出高频放电，但在眶额叶皮层中表现出1-3 Hz的缓慢活动。初期新皮质活动缓慢的特征是神经元放电、脑血流、血氧水平依赖功能MRI （BOLD fMRI）、脑血容量和代谢减少，同时海马在所有这些指标中均显示出增加。我们还发现，通过破坏穹窿（海马体和皮层下核之间的主要连接，对觉醒很重要）和引入乙酰胆碱（皮层下觉醒核的主要神经递质）的替代品，可以防止临界新皮层缓慢活动。因此，我们的中心假设是局灶性边缘癫痫抑制皮层下唤醒系统（包括乙酰胆碱），导致类似睡眠的新皮层功能下降。我们计划在啮齿动物模型的网络、神经递质和神经元水平上研究这一假设。我们的目标是首先使用功能磁共振成像、局部场和多单元记录、局部刺激、断开和失活实验来定义导致部分边缘癫痫发作时新皮层缓慢活动的皮层和皮层下结构网络。其次，我们将通过应用神经递质激动剂/拮抗剂和体内生物传感器探针测量神经递质来研究产生新皮层缓慢活动的神经递质。第三，我们将通过细胞旁和细胞内的记录来确定与新皮层慢速活动有关的皮层和皮层下结构中已识别的神经元的放电模式和突触活动的变化。跨这些水平的信息整合将增加我们对TLE异常远程网络变化的理解，可能导致治疗这种疾病的新治疗选择。

DESCRIPTION (provided by applicant): Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy (TLE) is a common and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including the hippocampus. Interestingly, partial temporal lobe seizures often cause functional deficits such as impaired consciousness, which is not expected from local hippocampal impairment alone. Human focal temporal lobe seizures in which consciousness is impaired are associated with slow waves on electro- encephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex, distant from the hippocampus. The mechanisms by which focal seizures in the hippocampus cause depressed function in the neocortex are not known. Based on our preliminary studies, we propose that ictal neocortical slow activity reflects a distinct state of depressed cortical function, more closely resembling deep anesthesia or sleep than seizure activity. In support of this, we recently found in a rat model that spontaneous and induced limbic seizures exhibit high frequency discharges in the hippocampus, but slow 1-3 Hz activity in the orbital frontal cortex. Ictal neocortical slow activity was characterized by decreased neuronal firing, CBF, blood oxygen level dependent functional MRI (BOLD fMRI), cerebral blood volume, and metabolism, while at the same time the hippocampus showed increases in all of these measures. We also found that ictal neocortical slow activity could be prevented by disrupting the fornix (a main connection between the hippocampus and subcortical nuclei important for arousal) and by introducing a replacement for acetycholine (a major neurotransmitter of subcortical arousal nuclei). Therefore, our central hypothesis is that focal limbic seizures inhibit subcortical arousal systems (including acetylcholine) leading to depressed function in the neocortex resembling sleep. We plan to investigate this hypothesis at the level of networks, neurotransmitters, and neurons in a rodent model. Our aims are to first define the network of cortical and subcortical structures which cause ictal neocortical slow activity in partial limbic seizures using fMRI, local field and multiunit recordings, local stimulation, disconnection and inactivation experiments. Second, we will investigate the neurotransmitters producing neocortical slow activity through application of neurotransmitter agonists/antagonists, and neurotransmitter measurements using in vivo biosensor probes. Third, we will determine the changes in firing patterns and synaptic activity of identified neurons in the cortex and subcortical structures involved in ictal neocortical slow activity using juxtacellular and intracellular recordings. The integration of information across these levels will increase our understanding of abnormal long-range network changes in TLE, potentially leading to new therapeutic options in the treatment of this disorder. PUBLIC HEALTH RELEVANCE: Impaired function of the cerebral cortex and cognitive deficits have a large impact on quality of life in patients with temporal lobe epilepsy. Understanding the fundamental mechanisms of remote network impairment in focal epilepsy may lead to novel surgical, neurostimulation, or pharmacologic therapies for this disorder.