Mechanisms of Cognitive Impairment Following Early-Life Seizures

早期癫痫发作后认知障碍的机制

• 批准号: 9889192
• 负责人: Gregory L. Holmes
• 金额: $ 37.67万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889192
• 关键词: Action Potentials; Address; Adult; Attenuated; Behavior; Behavioral; Brain; Cells; Child; Clinical; Clinical Research; Code; Cognition; Cognitive; Cognitive deficits; Complex; Data; Development; Dimensions; Disease; Distress; Electroencephalography; Epilepsy; Etiology; Frequencies; Glean; Health; Hippocampus (Brain); Impaired cognition; Impairment; Intervention; Laboratories; Lead; Learning Disabilities; Life; Measures; Medial; Modeling; Neurobiology; Neurons; Noise; Outcome; Pattern; Physiological; Prefrontal Cortex; Property; Psyche structure; Public Health; Quality of life; Rattus; Rehabilitation therapy; Risk; Seizures; Site; Systems Biology; Therapeutic; Training; United States National Academy of Sciences; base; childhood epilepsy; cognitive rehabilitation; comorbidity; economic implication; experimental study; high risk; improved; insight; neural circuit; neural network; neuronal circuitry; neurophysiology; optogenetics; prevent; relating to nervous system; restoration; social implication

Project Summary Epilepsy is a complex disorder which involves much more than seizures. As emphasized by the National Academy of Science-sponsored Committee on the Public Health Dimensions of the Epilepsies,1 epilepsy may be accompanied by a range of associated co-morbid health conditions that can have significant health and quality of life implications. Of these comorbidities, cognitive impairment is one of the most common and distressing aspects of epilepsy. Because the risk of cognitive impairment is greatest in young children, the educational, vocational, social and economic implications are enormous. Remarkably, there are only a handful of laboratories attempting to understand the pathophysiological basis of cognitive disturbances in early-life seizures (ELS). It is the view of our laboratory that prior to preventing, limiting and reversing cognitive comorbidities, it is essential to understand the neurobiological basis of developmental cognitive dysfunction associated with ELS. One of the major difficulties in decoding the complex issue of cognitive outcomes following ELS in children is the gulf between the behavioral/mental spheres in which these deficits are substantiated and the underlying physiological/developmental domains that are both the cause of these deficits and the most likely domains for therapy and intervention. Based on strong preliminary data showing abnormalities in rate and temporal coding in cognitive impairment following ELS, we propose that aberrant neural circuit dynamics are the neurophysiological underpinnings of cognitive impairment. In this proposal, we wish to rigorously study the consequences of ELS on temporal coding using multi-site single cell and local field potentials. To move from correlative to causal experimentation, we will first determine if cognitive rehabilitation following ELS reverses coding abnormalities. Secondly, we will use optogenetic-induced modulation of neuronal circuits to modify coding abnormalities and correct spatial cognitive deficits. Based on compelling preliminary data, we believe our findings will support the concept of dynamic neural discoordination as a causal factor of cognitive dysfunction following ELS.

项目摘要 癫痫是一种复杂的疾病，涉及的不仅仅是癫痫发作。正如《国家 科学院赞助的癫痫公共卫生方面委员会，1癫痫可能 伴有一系列相关的共病健康状况，这些健康状况可能具有显著的健康和 生活质量的影响。在这些合并症中，认知障碍是最常见的， 癫痫病的危害由于认知障碍的风险在幼儿中最大， 对教育、职业、社会和经济的影响是巨大的。值得注意的是， 试图了解早期认知障碍的病理生理学基础的实验室 癫痫发作（ELS）。我们实验室的观点是，在预防、限制和逆转认知障碍之前， 共病，了解发育性认知功能障碍的神经生物学基础是至关重要的 与ELS有关。解读认知结果这一复杂问题的主要困难之一， 儿童ELS之后是行为/心理领域之间的鸿沟，这些缺陷是 证实和潜在的生理/发育领域，这两个缺陷的原因 以及最有可能进行治疗和干预的领域。根据初步数据显示， 在ELS后认知障碍的速率和时间编码异常，我们提出， 神经回路动力学是认知损伤的神经生理学基础。在本提案中，我们 我希望严格研究ELS对使用多位点单细胞和局部场的时间编码的影响 潜力为了从相关实验转向因果实验，我们将首先确定认知康复是否 以下ELS反转编码异常。其次，我们将使用光遗传学诱导的调节， 神经元回路，以修改编码异常和纠正空间认知缺陷。基于引人注目的 初步数据，我们相信我们的研究结果将支持动态神经失调作为因果关系的概念。 ELS后认知功能障碍的因素。