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: 10158524
• 负责人: Catherine J Chu
• 金额: $ 68.93万
• 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/10158524
• 关键词: Absence Epilepsy; Acoustic Stimulation; Address; Attention; Benign; Cerebrum; Characteristics; Child; Childhood; Clinical; Cognitive; Cognitive deficits; Data; Development; Diagnostic; 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; Structure; Symptoms; Syndrome; Testing; Work; childhood epilepsy; cognitive function; cognitive performance; common treatment; computerized tools; density; developmental disease; epileptic encephalopathies; 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. .

项目摘要 /摘要 良性癫痫与中心颞上峰（VECTS）是最常见的焦点儿童癫痫综合征， 以癫痫发作的转移期和癫痫发作的大量峰值为特征 在非REM（NREM）睡眠期间的皮质表明，BECT是一种发育障碍 比严重程度更大 和运动协调。 并与严重的癫痫性脑病重叠，其特征是永久性和 脑部功能的逐渐下降与睡眠激活的尖峰一致。 处理VECT或癫痫性脑病中神经心理缺陷的治疗策略。 严重的证据线，包括我们的预后结果，表明丘脑皮层电路功能障碍 驱动电动机和VECT的认知异常。 VECT。 NREM睡眠期间的合并，并通过丘脑皮质回路产生和传播。 在Chith Centroral的尖峰中，感觉门控受损，就像在 VECT。 尽管有这些证据，但丘脑皮层之间的关系 BECT中的电生理学，连通性和认知症状尚未长期研究 该项目的目标是检验局灶性丘脑皮层电路cirsfunction介导的假设 VECT中的运动和认知症状。 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 收集和分析多模式数据的范式和计算工具链接丘脑皮质电路 首先，我们将确定是否与儿童一起进行认知缺陷。 Vects显示出异常的睡眠睡眠睡眠睡眠纺锤体活性活动活动活动，与睡眠依赖性记忆巩固有关。 其次，我们将确定感官收集受损受损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的影响 thalamoportical的纺锤体，门控和认知功能在VECT中完成。 代表着了解认知基础的病理生理机制的重大进展 VECT的功能障碍，并识别用于治疗认知缺陷的新目标和方法 Vect和相关的癫痫症。 。