EEG Abnormalities and Cognitive Impairment

描述（由申请人提供）：越来越多的证据表明，间歇期脑电图异常可导致短暂性认知障碍。在严重的情况下，间歇峰（IS）主导脑电图记录，可能会发生认知衰退。IS导致认知障碍的机制尚不清楚。在初步研究中，我们已经表明，继发癫痫持续状态（SE）或复发性氟乙基诱发的短暂癫痫发作是常见的。在SE或反复发作后，患有IS的动物比没有IS的大鼠表现出更多的损伤。在初步研究中，我们发现IS导致海马细胞中动作电位（AP）放电的可能性大大降低，这些细胞在环境的特定位置，即所谓的位置细胞中放电。这种AP射击的减少会在IS之后持续2秒。我们也有证据表明IS干扰位置细胞放电的回放，通常在清醒状态和慢波睡眠巩固记忆期间观察到。我们的总体假设是，is通过在关键时刻干扰关键细胞的放电模式，导致认知障碍。在具体目标一中，我们将通过阻止信息的准确编码和保留来解决IS干扰记忆，特别是工作记忆的假设。我们将首先通过在癫痫大鼠的海马体中使用多接触深度电极进行电流源密度分析来确定IS的位置。为了严格解决IS干扰记忆编码和保留的假设，我们将利用位置偏好测试和延迟不匹配样本测试，这些任务允许我们在动物进行空间记忆测试时记录位置细胞。通过比较空间表现和位置细胞放电在有和没有IS的时期，我们将直接确定IS对空间学习和记忆的影响。观察到IS与觉醒和脑电图状态高度耦合，将允许我们通过操纵非θ活动来控制IS频率。在具体目标二中，我们将解决睡眠期间IS通过在位置细胞放电模式回放期间破坏记忆巩固而损害认知功能的假设。为此，我们将研究夜间尖峰对睡眠中位置细胞放电模式再现的影响，使用在清醒和睡眠状态下遭受癫痫持续状态或复发性氟醚发作和IS的动物。项目描述：如果我们的假设得到证实，研究结果将对癫痫性脑病患者的治疗具有重要的临床意义。除了对癫痫的认知障碍有更多了解外，我们的研究还将为正常的记忆编码和巩固过程提供大量的见解。

DESCRIPTION (provided by applicant): There is increasing evidence that interictal EEG abnormalities can result in transitory cognitive impairment. In severe cases, where interictal spikes (IS) dominate the EEG recording, cognitive regression can occur. The mechanisms by which IS result in cognitive impairment are not known. In preliminary studies we have shown that following status epilepticus (SE) or recurrent brief flurothyl-induced seizures IS are common. Following SE or recurrent seizures, animals with IS show more impairment than rats without IS. In preliminary work we found that IS result in a substantially reduced likelihood of action potentials (AP) firing in the hippocampal cells that fire in a particular location of the environment, the so-called place cells. Such reduction in AP firing lasts for up to two seconds following the IS. We also have evidence that IS interfere with the replay of place cell firing, normally observed during the awake state and during slow wave sleep consolidation of memory. Our overall hypothesis is that IS, by interfering with firing patterns of critical cells at critical times, result in cognitive impairment. In Specific Aim One we will address the hypothesis that IS interfere with memory, and particularly working memory, by preventing accurate encoding and retention of information. We will first determine location of IS by performing current source density analyses using multi-contact depth electrodes in the hippocampus of epileptic rats. To rigorously address the hypothesis that IS interfere with encoding and retention of memory we will take advantage of the place preference test and the delayed non-matching to sample test, tasks which allow us to record place cells while the animal is engaged in a test of spatial memory. By comparing spatial performance with place cell firing during periods with and without IS we will directly determine the effect of IS on spatial learning and memory. The observation that IS are highly coupled to arousal and EEG state will allow us to control IS frequency by manipulating non-theta activity. In Specific Aim Two we will address the hypothesis that IS during sleep impair cognitive function through disruption of consolidation of memory during replay of place cell firing patterns. In this aim, we will study the effect of nocturnal spikes on recapitulation of place cells firing patterns during sleep using animals previously subjected to status epilepticus or recurrent flurothyl seizures and IS during the awake and sleep states. Project Narrative: If our hypotheses are confirmed the findings would have major clinical implication in regards to the treatment of patients with epileptic encephalopathies. In addition to learning much about the cognitive impairment in epilepsy, our studies will provide enormous insight into processes involved in normal encoding and consolidation of memory.