Focal thalamocortical circuit dysfunction mediates motor and cognitive deficits in developmental epilepsy

项目总结/摘要 良性癫痫伴中央颞区棘波（BECTS）是最常见的儿童局灶性癫痫综合征， 其特征在于短暂的癫痫发作和由感觉运动神经引起的大量癫痫样棘波 非快速眼动睡眠（NREM）最近的研究结果表明，BECTS是一种发育障碍， 比以前认识到的更广泛的严重程度。除了癫痫发作，孩子们的注意力也有缺陷 和运动协调。临床上，BECTS的运动和认知症状存在严重程度谱 并且在遗传上与严重的癫痫性脑病重叠，其特征是永久性的， 大脑功能的进行性下降与睡眠激活的尖峰一致。目前还没有证据表明 治疗策略，以解决BECTS或其他癫痫性脑病的神经心理缺陷。 包括我们的初步发现在内的几条证据都表明， 导致BECTS中的运动和认知异常。首先，丘脑皮质结构回路异常， 谢谢第二，患有BECTS的儿童睡眠纺锤波减少，这是对记忆至关重要的振荡 在NREM睡眠期间巩固，并由丘脑皮层回路产生和传播。第三、 中央颞区棘波儿童的丘脑皮质感觉门控受损，如 谢谢在到达皮层之前，有效地抑制或“门控”无关的感觉信息， 注意力任务的表现。尽管有这些证据， BECTS的电生理学、连通性和认知症状尚未研究。长期 本项目的目的是检验局灶性丘脑皮质回路功能障碍介导 BECTS中的运动和认知症状。我们的跨学科团队-由儿科 癫痫学家，神经心理学家和计算神经科学家-将使用经过验证的实验 范例和计算工具来收集和分析多模态数据，以连接丘脑皮层回路 BECTS儿童的认知缺陷异常。首先，我们将确定是否有儿童 BECTS显示与受损的睡眠依赖性记忆巩固相关的异常睡眠纺锤体活动。 其次，我们将确定受损的感觉门控和丘脑皮层连接是否与受损的 注意BECTS。第三，我们将测试药物治疗和闭环听觉刺激对 BECTS中的丘脑皮质纺锤体、门控和认知功能。提案目标的完成将 代表着对认知障碍的病理生理机制的理解的重大进展。 BECTS的功能障碍，并确定新的目标和方法来治疗认知缺陷， BECTS和相关癫痫性脑病。 .

Project Summary / Abstract Benign epilepsy with centrotemporal spikes (BECTS) is the most common focal childhood epilepsy syndrome, characterized by a transient period of seizures and abundant epileptiform spikes arising from the sensorimotor cortex during non-REM (NREM) sleep. Recent findings indicate that BECTS is a developmental disorder with a wider range of severity than previously appreciated. In addition to seizures, children have deficits in attention and motor coordination. The motor and cognitive symptoms in BECTS exist on a spectrum of severity, clinically and genetically overlapping with severe epileptic encephalopathies, which are characterized by permanent and progressive declines in cerebral function coincident with sleep activated spikes. There are currently no proven treatment strategies to address the neuropsychological deficits in BECTS or other epileptic encephalopathies. Several lines of evidence, including our preliminary findings, suggest a dysfunction in thalamocortical circuitry drives the motor and cognitive abnormalities in BECTS. First, thalamocortical structural circuits are abnormal in BECTS. Second, children with BECTS have reduced sleep spindles, oscillations that are critical for memory consolidation during NREM sleep and generated and propagated by thalamocortical circuitry. Third, thalamocortical sensory gating is impaired in children with centrotemporal spikes, like those observed in BECTS. Effective dampening or “gating” of irrelevant sensory information prior to reaching the cortex, mediates performance on attentional tasks. Despite this evidence, the relationship between thalamocortical electrophysiology, connectivity, and cognitive symptoms in BECTS has not been investigated. The long term goal of this project is to test the hypothesis that focal thalamocortical circuit dysfunction mediates the motor and cognitive symptoms in BECTS. Our interdisciplinary team - consisting of a pediatric epileptologist, a neuropsychologist, and a computational neuroscientist – will use validated experimental paradigms and computational tools to collect and analyze multimodal data to link thalamocortical circuit abnormalities to cognitive deficits in children with BECTS. First, we will determine whether children with BECTS show abnormal sleep spindle activity that relates to impaired sleep-dependent memory consolidation. Second, we will determine whether impaired sensory gating and thalamocortical connectivity relate to impaired attention in BECTS. Third, we will test the impact of medication and closed loop auditory stimulation on thalamocortical spindles, gating, and cognitive function in BECTS. Completion of the proposal goals will represent significant progress towards understanding the pathophysiological mechanisms underlying cognitive dysfunction in BECTS, and the identification of new targets and approaches for treating cognitive deficits in BECTS and related epileptic encephalopathies. .