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都有相关的认知障碍，特别是在记忆领域，这是一种重要的，更高的认知功能，需要时间的连续性，个人历史和意识。认知障碍无疑是导致这种疾病的大脑异常的综合结果，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，发现间歇峰（IIS）、网络振荡活动功能障碍（EEG节律）和不协调的单神经元放电影响动物在海马依赖任务中的表现。我们现在提议调查类似的机制是否在人类中起作用。这些数据最终将对制定治疗策略以最大限度地减少TLE的认知影响以及更好地了解癫痫的动态病理生理学具有重要意义。提出了三个综合的具体目标。在第一个特定目标中，我们将确定IIS在人类海马依赖记忆任务中对记忆、反应时间和相关海马振荡的短暂影响。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，我们将研究单单位神经活动和海马振荡之间的关系，以及TLE患者的表现。基于大量的动物实验，我们假设TLE患者的空间认知和记忆缺陷是由于单单元放电和动作电位的时间编码受损所致。基于显示有癫痫史的大鼠连贯性受损的动物数据，在第三个目标中，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海马-前额叶皮质通路的连贯性受损和IIS造成的额外的短暂连贯性干扰。综上所述，这三个目标将为认知障碍的机制提供相当大的见解。有了这些信息，有科学依据的治疗策略将用于治疗这种毁灭性的合并症。

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.