Mechanisms of Cognitive Impairment in Temporal Lobe Epilepsy

描述(申请人提供)：颞叶癫痫(TLE)是人类接受癫痫手术后最常见的癫痫。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，这是一种基本的、更高的认知功能，需要在时间、个人历史和意识上保持连续性。这些认知障碍无疑是导致这种疾病的大脑异常组合的结果，尽管这种联系的机制仍然是一个谜。我们实验室最近在锂-匹罗卡品TLE模型中探索了导致动态认知功能障碍的潜在机制，发现发作间期尖峰电位(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身上发挥作用。这些数据最终将对指导旨在将TLE的认知影响降至最低的治疗策略以及在动态水平上更好地理解癫痫的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瞬时影响。我们假设IIS通过直接损害记忆中潜在的神经过程和破坏海马体振荡而导致TLE患者的记忆损害。在第二个目标中，我们将研究TLE患者的单个单位神经活动与海马区振荡和表现之间的关系。由于广泛的动物研究，我们假设TLE患者的空间认知和记忆缺陷是由于动作电位的单单位放电和时间编码受损所致。基于动物数据显示有癫痫史的大鼠的连贯性受损，在第三个目的中，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IIS导致的海马-前额叶皮质通路的连贯性受损和额外的一过性连贯性障碍。综上所述，这三个目标将为研究TLE中认知障碍的机制提供相当大的帮助。有了这些信息，具有科学基础的治疗策略将被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.