Neuroimaging, neuronal firing and behavior in spike-wave seizures

棘波癫痫发作的神经影像学、神经元放电和行为

• 批准号: 10403184
• 负责人: HAL BLUMENFELD
• 金额: $ 44.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403184
• 关键词: Absence Epilepsy; Adult; Anesthetics; Animal Model; Animals; Attention; Auditory; Behavior; Behavioral; Bilateral; Brain; Child; Cognition; Core-Binding Factor; Detection; Development; Electroencephalography; Electrophysiology (science); Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Head; Human; Image; Impaired cognition; Impairment; Individual; Laser-Doppler Flowmetry; Maintenance; Measurement; Measures; Modeling; Neurons; Patients; Pattern; Performance; Periodicity; Physiological; Physiology; Population; Rattus; Resolution; Rest; Rodent; Sampling; Seizures; Severities; Signal Transduction; Study models; Time; Work; awake; base; behavior test; behavioral impairment; behavioral response; cortex mapping; experimental study; human model; improved; insight; neuroimaging; novel; prevent; psychosocial; relating to nervous system; response; restraint; spatiotemporal; spelling

PROJECT SUMMARY / ABSTRACT Absence seizures occur most commonly in children as staring spells lasting 5-10 seconds, with rhythmic “spike-wave” discharge (SWD) on electroencephalography (EEG). They can occur up to hundreds of times per day and are not benign, with deficits in attention and psychosocial function in some cases persisting into adulthood or even after seizure suppression. The mechanisms by which absence seizures impair cognition are not known. One intriguing but little-studied aspect of absence seizures is the fact that some episodes impair and others spare behavioral responses even within the same individual. The relationship between variable absence behavioral severity and neuronal activity may provide fundamental insights into the pathophysiology of seizures. Prior human studies and animal models have shown widespread EEG and fMRI increases as well as decreases during absence seizures. We recently found in a large patient sample that absence seizures with more severely impaired behavior had larger fMRI and EEG amplitude in widespread brain networks. We also found that abnormally enhanced fMRI synchrony persists between bilateral cortical regions even when seizures are not present in patients and in animal absence models. The neuronal basis for these changes both at rest and during SWD is not known, but our recent work in rodent absence models and normal conditions suggests that the amplitude of fMRI signals is related to changes in the total population activity of neurons. Therefore our central hypothesis is that the severity of absence seizures is determined by a combination of the number of neurons involved and their firing pattern in widespread brain networks before and during seizures. An important limitation of previous work has been anesthetic agents, which markedly alter fMRI responses and the excitability of neurons. This may explain why most animal models show cortical fMRI increases during SWD whereas human studies show a predominance of sustained cortical fMRI decreases. Because of this discrepancy the neuronal basis of physiology changes in absence seizures remains uncertain. We recently habituated genetic absence epilepsy rats of Strasbourg (GAERS) to allow awake-head fixed experiments. Initial measurements in this new model show sustained cortical fMRI and CBF decreases during SWD much more closely resembling humans. We now plan complementary high spatiotemporal resolution experiments in this awake model including fMRI, electrophysiology and behavior to fully understand the neuronal basis of variable severity in absence seizures. Our aims are to first image the networks involved at baseline and during severe versus mild SWD, and to relate the neuroimaging changes to spike and wave amplitude on EEG. Second, we will use multiunit and neuronal ensemble recordings to determine the neuronal basis of severe versus mild SWD. Third, we will relate the physiological severity of SWD to behavior through auditory detection and response tasks. The integration of information across these levels will increase our understanding of neuronal changes in absence epilepsy potentially leading to new treatment options.

项目概要/摘要 失神发作最常见于儿童，表现为持续 5-10 秒的凝视，并有节奏 脑电图 (EEG) 上的“尖峰波”放电 (SWD) 每次可发生数百次。 日，并且不是良性的，在某些情况下注意力和心理社会功能的缺陷持续到 成年期甚至癫痫发作抑制后失神发作损害认知的机制是 失神发作的一个有趣但很少研究的方面是，某些发作会损害患者的健康。 即使在同一个人内，其他人也不会做出行为反应。 变量之间的关系。 缺勤行为严重程度和神经活动可能为病理生理学提供基本见解 先前的人体研究和动物模型表明脑电图和功能磁共振成像也普遍增加。 我们最近在大量患者样本中发现，失神发作期间会减少。 我们还发现，更严重的行为受损在广泛的大脑网络中具有更大的功能磁共振成像和脑电图振幅。 发现即使在双侧皮质区域之间异常增强的功能磁共振成像同步性仍然存在 癫痫发作在患者和动物缺席模型中均不存在，这些变化的神经基础都存在。 休息时和 SWD 期间尚不清楚，但我们最近在啮齿动物缺席模型和正常条件下的工作 表明功能磁共振成像信号的幅度与神经元总体活动的变化有关。 因此，我们的中心假设是失神发作的严重程度是由以下因素的组合决定的： 癫痫发作前和癫痫发作期间涉及的神经元数量及其在广泛的大脑网络中的放电模式。 先前工作的一个重要限制是麻醉剂，它会显着改变功能磁共振成像反应和 这可以解释为什么大多数动物模型显示皮层功能磁共振成像在 SWD 而人类研究表明，皮质功能磁共振成像的持续下降占主导地位。 我们最近仍不确定失神发作的生理学变化的神经基础。 斯特拉斯堡的习惯性遗传失神性癫痫大鼠（GAERS）允许进行清醒头部固定实验。 这个新模型的初步测量显示，SWD 期间皮质 fMRI 和 CBF 持续下降很多 我们现在计划进行补充性的高时空分辨率实验。 这个清醒模型包括功能磁共振成像、电生理学和行为学，以充分了解神经基础 我们的目标是首先对基线和期间涉及的网络进行成像。 严重与轻度 SWD，并将神经影像学变化与脑电图上的尖峰和波幅联系起来。 其次，我们将使用多单元和神经集成记录来确定严重的神经基础 第三，我们将通过审计员检测将 SWD 的生理严重性与行为联系起来。 跨这些级别的信息整合将增加我们对任务的理解。 失神性癫痫的神经元变化可能会带来新的治疗选择。