Mechanisms of Cognitive Impairment in Temporal Lobe Epilepsy

描述（由申请人提供）：颞叶癫痫（TLE）是接受癫痫手术的人类中最常见的癫痫。这些患者中的许多人具有相关的认知障碍，特别是在记忆领域，这是时间、个人历史和意识连续性所需的基本的、更高的认知功能。认知障碍无疑是导致这种疾病的大脑异常组合的结果，尽管这种关系的机制仍然是一个谜。我们的实验室最近在TLE的锂-匹罗卡品模型中研究了导致动态认知功能障碍的潜在机制，发现发作间期尖峰（IIS）、网络振荡活动（EEG节律）中的功能障碍和不协调的单神经元放电影响动物在海马依赖性任务中的表现。我们现在打算研究类似的机制是否在人类中起作用。这些数据最终将是重要的通知治疗策略，旨在尽量减少TLE的认知影响，以及更好地了解癫痫的病理生理学的动态水平。提出了三个综合的具体目标。在第一个具体的目标，我们将确定短暂的影响IIS对记忆，反应时间和相关的海马振荡在人类的海马依赖性记忆任务。我们假设IIS通过直接损害记忆基础的神经过程和海马振荡的破坏而导致TLE患者的记忆障碍。在第二个目标中，我们将研究单个单位神经活动和海马振荡之间的关系，并在TLE患者的性能。由于大量的动物实验，我们假设TLE患者的空间认知和记忆缺陷是由于单个单位放电和动作电位的时间编码受损。基于动物数据显示受损的连贯性与癫痫发作史的大鼠，在第三个目标，我们将确定TLE和相关的IIS对神经元网络振荡和认知的影响，假设TLE患者的工作记忆缺陷是由于受损的连贯性在海马-前额叶皮层通路和额外的短暂的连贯性障碍，由于IIS。这三个目标合在一起，将为TLE认知障碍的机制提供相当多的见解。有了这些信息，有科学依据的治疗策略将被用来治疗这种毁灭性的并发症。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common epilepsy in humans undergoing epilepsy surgery. Many of these patients have associated cognitive impairments, particularly in the domain of memory which is an essential, higher cognitive function required for continuity in time, personal history and awareness. The cognitive impairments are no doubt a result of a combination of the brain abnormalities responsible for the disorder, although the mechanisms of this relation remain a mystery. Our laboratory has recently pursued the underlying mechanisms responsible for dynamic cognitive dysfunction in the lithium-pilocarpine model of TLE finding that interictal spikes (IIS), dysfunctions in network oscillation activity (EEG rhythms) and uncoordinated single-neuron firing impact the performance of the animal in a hippocampal- dependent task. We now propose to investigate whether similar mechanisms are at play in humans. These data will ultimately be important for informing therapeutic strategies designed to minimize the cognitive effects of TLE, as well as a better understanding of the pathophysiology of epilepsy on a dynamic level. Three integrated specific aims are proposed. In the first specific aim we will determine the transient effects of IIS on memory, reaction time and related hippocampal oscillations during a hippocampal-dependent memory task in humans. We hypothesize that IIS contribute to memory impairment in patients with TLE through direct impairment of neural processes underlying memory and by disruption of hippocampal oscillations. In the second aim we will investigate the relationships between single unit neural activity and hippocampal oscillations and performance in patients with TLE. Owing to extensive animal work, we hypothesize that deficits in spatial cognition and memory in patients with TLE are due to impaired single unit firing and temporal coding of action potentials. Based on animal data showing impaired coherence in rats with a prior history of seizures, in the third aim we will determine the impact of TLE and related IIS on neuronal network oscillation and cognition, hypothesizing that deficits in working memory in patients with TLE are due to impaired coherence in hippocampal-prefrontal cortex pathways and additional transient coherence disturbances due to IIS. Taken together these three aims will provide considerable insight into the mechanisms of cognitive impairment in TLE. Armed with this information, therapeutic strategies with a scientific basis will be used to treat this devastating comorbidity.