EEG Abnormalities and Cognitive Impairment

脑电图异常和认知障碍

• 批准号: 7737349
• 负责人: Gregory L. Holmes
• 金额: $ 27.7万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737349
• 关键词: Accounting; Action Potentials; Address; Affect; Animals; Area; Arousal; Behavior; Cell physiology; Cells; Clinical; Clinical Research; Cognition; Cognitive; Coupled; Electrodes; Electroencephalography; Employee Strikes; Encephalopathies; Environment; Epilepsy; Fire - disasters; Flurothyl; Frequencies; Goals; Hippocampal Formation; Hippocampus (Brain); Impaired cognition; Impairment; Interneurons; Learning; Location; Memory; Modeling; Pathway interactions; Patient Care; Patients; Pattern; Performance; Phase; Play; Process; Pyramidal Cells; REM Sleep; Rattus; Recurrence; Role; Sampling; Seizures; Short-Term Memory; Silicon; Sleep; Slow-Wave Sleep; Source; Status Epilepticus; Structure; Synapses; Syndrome; Testing; Time; Wakefulness; Water; Work; awake; base; behavioral impairment; cognitive function; cognitive regression; density; disability; insight; long term memory; memory encoding; memory retention; non rapid eye movement; preference; prevent; research study

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.

描述（由申请人提供）：有越来越多的证据表明，发作性脑电图异常会导致暂时的认知障碍。在严重的情况下，充线尖峰（IS）主导了脑电图记录，可能会发生认知消退。尚不清楚导致认知障碍的机制。在初步研究中，我们已经表明，以下状态癫痫持续状态（SE）或复发性短暂的氟洛预癫痫发作很常见。在SE或复发性癫痫发作之后，与没有IS的大鼠相比，具有IS的动物显示出更大的损害。在初步工作中，我们发现这是导致在环境特定位置（所谓的位置细胞）发射的海马细胞中作用电位（AP）发射的可能性大大降低的。随后，这种降低的AP射击持续长达两秒钟。我们还有证据表明，通常在清醒状态和慢波睡眠巩固记忆过程中观察到的位置细胞射击的重播。我们的总体假设是，在关键时期干扰关键细胞的发射模式会导致认知障碍。在特定目标中，我们将通过防止准确编码和保留信息来解决干扰记忆，尤其是工作记忆的假设。我们将首先通过使用癫痫大鼠海马中的多接触深度电极进行电流源密度分析来确定IS的位置。为了严格解决干扰编码和保留记忆的假设，我们将利用位置偏好测试以及延迟的非匹配测试的延迟，这些任务使我们能够在动物进行空间记忆测试时记录位置单元。通过在有和没有的情况下，通过将空间性能与位置细胞发射进行比较，我们将直接确定IS对空间学习和记忆的影响。高度耦合到唤醒状态和脑电图状态将使我们能够控制的观察结果是通过操纵非theta活性来控制的频率。在特定的目标两个中，我们将解决睡眠期间通过在重播位置细胞发射模式期间的记忆巩固来损害认知功能的假设。在此目标中，我们将研究夜间峰值对在睡眠过程中使用先前遭受状态癫痫持续状态或复发性氟塞基癫痫发作的动物概括的位置细胞发射模式的影响，并且在清醒和睡眠状态下。 项目叙述：如果我们的假设得到证实，则发现对治疗癫痫性脑病患者的治疗将具有重要的临床意义。除了了解癫痫中认知障碍的大量知识外，我们的研究还将为参与正常编码和巩固记忆的过程提供深入的洞察力。

项目成果

Maturation of the human brain and epilepsy.

• DOI: 10.1016/b978-0-444-52898-8.00007-0
• 发表时间: 2012-01-01
• 期刊: Handbook of clinical neurology
• 作者: Holmes, Gregory L;Milh, M D Mathieu;Dulac, Olivier
• 通讯作者: Dulac, Olivier

Hippocampal interictal spikes disrupt cognition in rats.

• DOI: 10.1002/ana.21896
• 发表时间: 2010-02
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Kleen, Jonathan K.;Scott, Rod C.;Holmes, Gregory L.;Lenck-Santini, Pierre Pascal
• 通讯作者: Lenck-Santini, Pierre Pascal

What constitutes a relevant animal model of the ketogenic diet?

生酮饮食的相关动物模型由什么构成？

• DOI: 10.1111/j.1528-1167.2008.01836.x
• 发表时间: 2008
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Holmes,GregoryL