Focal Thalamocortical Circuit Dysfunction Mediates Motor and Cognitive Deficits in Developmental Epilepsy

项目摘要/摘要 良性癫痫伴中央-颞叶棘波(BECTS)是最常见的儿童局灶性癫痫综合征， 以短暂的癫痫发作和感觉运动产生的大量癫痫样棘波为特征的 非快速眼动(NREM)睡眠时的大脑皮质。最近的发现表明，BECTS是一种发育障碍，具有 严重程度比之前所认识到的范围更广。除了癫痫，儿童还有注意力缺陷。 和运动协调性。BECTS的运动和认知症状存在严重程度不一的临床症状 与严重的癫痫脑病在基因上重叠，其特征是永久性和 大脑功能的进行性下降与睡眠激活的尖峰电位一致。目前还没有得到证实的 治疗策略，以解决BECTS或其他癫痫脑病的神经心理缺陷。 有几条证据，包括我们的初步发现，表明丘脑皮质回路功能障碍。 导致BECTS的运动和认知异常。首先，丘脑皮质结构环路异常。 BECTS。其次，患有BECTS的儿童睡眠纺锤体减少，这是对记忆至关重要的振荡 在NREM睡眠期间合并，并由丘脑皮质回路产生和传播。第三, 患有中央-颞区棘波的儿童丘脑皮质感觉门控受损，就像在 BECTS。在到达大脑皮层之前，有效地抑制或“门控”无关的感觉信息， 在注意力任务上的表现。尽管有这些证据，丘脑皮质之间的关系 BECTS的电生理学、连通性和认知症状尚未被研究。从长远来看 该项目的目标是验证局灶性丘脑皮质环路功能障碍的假设。 BECTS患者的运动和认知症状。我们的跨学科团队-由一名儿科医生组成 癫痫专家、神经心理学家和计算神经学家-将使用经过验证的实验 收集和分析连接丘脑皮质回路的多模式数据的范例和计算工具 BECTS儿童认知缺陷的异常。首先，我们将确定患有这种疾病的儿童 BECTS显示睡眠纺锤体活动异常，与睡眠依赖记忆巩固受损有关。 其次，我们将确定感觉门控和丘脑皮质连接受损是否与受损有关 请注意BECTS。第三，我们将测试药物和闭合环路听觉刺激对 BECTS患者的丘脑皮质纺锤体、门控和认知功能。提案目标的完成将 代表着在理解认知的病理生理机制方面的重大进步 BECTS的功能障碍以及治疗认知障碍的新靶点和新方法的确定 BECTS及相关癫痫脑病。 。

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. .