Mechanisms of Cognitive Impairment in Temporal Lobe Epilepsy

颞叶癫痫认知障碍的机制

• 批准号: 8655181
• 负责人: Gregory L. Holmes
• 金额: $ 34.22万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655181
• 关键词: Action Potentials; Affect; Animal Model; Animals; Attention; Awareness; Behavioral; Brain; Cells; Clinical; Code; Cognition; Cognitive; Cognitive deficits; Comorbidity; Data; Disease; Electrodes; Electroencephalography; Environment; Epilepsy; Evaluation; Event; Foundations; Functional disorder; Hippocampus (Brain); Human; Impaired cognition; Impairment; Implant; Laboratories; Learning; Life; Lithium; Measures; Memory; Memory impairment; Modeling; Neurons; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Performance; Personality; Phase; Physiology; Pilocarpine; Play; Prefrontal Cortex; Process; Property; Pyramidal Cells; Rattus; Reaction Time; Recording of previous events; Role; Seizures; Short-Term Memory; Stimulus; Structure; Syndrome; System; Temporal Lobe; Temporal Lobe Epilepsy; Therapeutic; Time; Travel; Uncertainty; Work; animal data; arm; attenuation; base; cognitive function; design; information processing; insight; neuronal patterning; prevent; relating to nervous system; stem; virtual

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.

描述（由申请人提供）：颞叶癫痫（TLE）是接受癫痫手术的人类最常见的癫痫。这些患者中有许多患有认知障碍，尤其是在记忆领域，这是时间，个人历史和意识所需的必不可少的认知功能。毫无疑问，认知障碍是导致该疾病的脑异常组合的结果，尽管这种关系的机制仍然是一个谜。我们的实验室最近采用了负责动态认知功能障碍的潜在机制，该模型的lithium-pilocarpine模型发现，间歇性尖峰（IIS），网络振荡活性（EEG节奏）的功能障碍（EEG节奏）的功能障碍和无协同的单内神经元点火会影响依赖性的动物的性能。现在，我们建议研究人类中是否有类似的机制在起作用。这些数据最终对于告知旨在最大程度地减少TLE的认知效应的治疗策略以及对动态水平上癫痫病理生理学的理解。提出了三个集成的特定目标。在第一个特定目的中，我们将确定IIS对人类海马依赖性记忆任务期间的记忆，反应时间和相关海马振荡的瞬态影响。我们假设IIS通过直接损害记忆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TLE患者的单个单位神经活动与海马振荡与性能之间的关系。由于广泛的动物工作，我们假设TLE患者的空间认知和记忆缺陷是由于单个单位射击和动作电位的时间编码受损所致。 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.综上所述，这三个目标将提供有关TLE认知障碍机制的大量见解。有了这些信息，具有科学基础的治疗策略将用于治疗这种毁灭性的合并症。