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

局灶性丘脑皮质回路功能障碍介导发育性癫痫的运动和认知缺陷

• 批准号: 10570912
• 负责人: Catherine J Chu
• 金额: $ 68.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570912
• 关键词: Absence Epilepsy; Acoustic Stimulation; Address; Attention; Benign; Cerebrum; Characteristics; Child; Childhood; Clinical; Cognitive; Cognitive deficits; Data; Development; Diazepam; Disease; Electrophysiology (science); Epilepsy; Focal Seizure; Functional disorder; Generalized seizures; Goals; Impaired cognition; Impairment; Intervention; Knowledge; Learning; Link; Mediating; Motor; Neurobehavioral Manifestations; Neuropsychology; Performance; Pharmaceutical Preparations; Physiology; Schools; Seizures; Sensory; Severities; Sleep; Sleep Deprivation; Sleep disturbances; Symptoms; Syndrome; Testing; Work; childhood epilepsy; cognitive function; cognitive performance; common treatment; computerized tools; density; developmental disease; diagnostic criteria; epileptic encephalopathies; epileptiform; functional outcomes; improved; indexing; memory consolidation; motor deficit; motor impairment; motor learning; motor symptom; multimodal data; non rapid eye movement; sensory gating; sleep abnormalities; sleep spindle; treatment strategy

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. .

项目概要/摘要 伴有中央颞区棘波的良性癫痫（BECTS）是最常见的局灶性儿童癫痫综合征， 其特征是短暂的癫痫发作和感觉运动引起的大量癫痫样尖峰 最近的研究结果表明，BECTS 是一种发育障碍，伴有非快速眼动 (NREM) 睡眠期间的大脑皮层。 除了癫痫发作之外，儿童还存在注意力缺陷。 BECTS 中的运动和认知症状在临床上存在多种严重程度。 并且与严重癫痫性脑病有遗传重叠，其特点是永久性和 大脑功能的逐渐衰退与睡眠激活峰值同时发生，目前尚无证据证明。 解决 BECTS 或其他癫痫性脑病的神经心理缺陷的治疗策略。 包括我们的初步发现在内的几条证据表明丘脑皮质回路存在功能障碍 导致 BECTS 中的运动和认知异常。首先，丘脑皮质结构回路异常。 其次，患有 BECTS 的儿童的睡眠纺锤波（对记忆至关重要的振荡）减少了。 NREM 睡眠期间的巩固，由丘脑皮质回路产生和传播。 患有中央颞叶棘波的儿童丘脑皮质感觉门控受损，就像在 BECTS。在到达皮层之前有效抑制或“门控”不相关的感觉信息，调解 尽管有这些证据，丘脑皮质之间的关系。 BECTS 中的电生理学、连通性和认知症状尚未得到长期研究。 该项目的目标是检验局灶性丘脑皮质回路功能障碍介导的假设 BECTS 的运动和认知症状 我们的跨学科团队 - 由儿科人员组成。 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 收集和分析多模态数据以连接丘脑皮质回路的范式和计算工具 BECTS 儿童的认知缺陷异常 首先，我们将确定儿童是否患有 BECTS。 BECTS 显示异常的睡眠纺锤体活动，与睡眠依赖性记忆巩固受损有关。 其次，我们将确定受损的感觉门控和丘脑皮质连接是否与受损有关 第三，我们将测试药物和闭环听觉刺激对注意力的影响。 BECTS 中的丘脑皮质纺锤体、门控和认知功能将完成提案目标。 在理解认知背后的病理生理机制方面取得了重大进展 BECTS 功能障碍，以及治疗认知缺陷的新目标和方法的确定 BECTS 和相关的癫痫性脑病。 。