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: 10459627
• 负责人: HAL BLUMENFELD
• 金额: $ 44.5万
• 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/10459627
• 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.

项目总结/摘要 失神发作最常见于儿童，持续5-10秒的凝视，伴随有节奏的 脑电图（EEG）上的“尖峰波”放电（SWD）。它们可以发生多达数百次， 在某些情况下，注意力和心理社会功能的缺陷持续到 成年后甚至癫痫发作抑制后。失神发作损害认知的机制是 不知道。失神发作的一个有趣但很少研究的方面是， 而另一些人甚至在同一个人身上也会有行为反应。变量之间的关系 缺席行为的严重程度和神经元活动可能提供基本的见解， 癫痫发作之前的人类研究和动物模型也显示了广泛的EEG和fMRI增加 在失神发作时降低我们最近在一个大的病人样本中发现， 在广泛的大脑网络中，受损越严重的行为具有更大的fMRI和EEG振幅。我们也 发现异常增强的功能磁共振成像同步持续之间的双边皮层区域，即使当 癫痫发作不存在于患者和动物缺席模型中。这些变化的神经基础 在休息和在SWD期间，我们还不知道，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fMRI信号的幅度与神经元总群体活动的变化有关。 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： 癫痫发作之前和期间广泛的大脑网络中涉及的神经元数量及其放电模式。 以前工作的一个重要局限是麻醉剂，它显著改变fMRI反应， 神经元的兴奋性。这可以解释为什么大多数动物模型显示皮层fMRI增加， SWD而人类研究显示持续的皮质功能磁共振成像下降占主导地位。因为如此 失神发作中生理学变化的神经元基础仍然不确定。我们最近 斯特拉斯堡的习惯性遗传失神癫痫大鼠（GAERS）进行清醒-头部固定实验。 在这个新模型中的初步测量显示，在SWD过程中，持续的皮层fMRI和CBF下降， 更接近人类。我们现在计划进行补充性的高时空分辨率实验， 这种清醒的模型包括功能磁共振成像，电生理学和行为，以充分了解神经元的基础， 失神发作的不同严重程度。我们的目标是首先对基线和期间涉及的网络进行成像， 重度与轻度SWD，并将神经影像学变化与EEG上的棘波和波幅相关联。 其次，我们将使用多单位和神经元系综记录，以确定严重的神经基础， 与轻度SWD相比。第三，我们将通过听觉检测将SWD的生理严重性与行为联系起来 和响应任务。跨这些层次的信息整合将增加我们对 失神癫痫的神经元变化可能导致新的治疗选择。