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 癫痫病是一种复杂的疾病，涉及癫痫发作的障碍。正如民族强调的 癫痫的公共卫生维度委员会学院赞助的委员会，1癫痫 伴随着一系列相关的合并健康状况，这些状况可能具有重要的健康状况 生活质量的影响。在这些合并症中，认知障碍是最常见的障碍之一， 癫痫的令人痛苦的方面。因为认知障碍的风险在幼儿中最大，所以 教育，职业，社会和经济影响是巨大的。值得注意的是，只有少数 试图理解早期认知障碍的病理生理基础的实验室 癫痫发作（EL）。在预防，限制和逆转认知之前，我们实验室的观点是 合并症，必须了解发育功能障碍的神经生物学基础 与EL相关。解码复杂问题的主要困难之一 儿童中的EL是行为/心理领域之间的海湾 既是这些缺陷的原因又是基本的生理/发育领域 以及最可能的治疗和干预领域。基于显示的强大初步数据 EL后，认知障碍的率和时间编码异常，我们提出异常 神经回路动力学是认知障碍的神经生理基础。在这个建议中，我们 希望严格研究EL使用多站点单细胞和局部字段的时间编码的后果 潜力。要从相关性到因果实验，我们将首先确定是否认知康复 以下ELS逆转了编码异常。其次，我们将使用光遗传学诱导的调制 神经元电路可修改编码异常和正确的空间认知缺陷。基于引人注目 初步数据，我们认为我们的发现将支持动态神经脱节的概念 ELS之后的认知功能障碍的因素。