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: 10624315
• 负责人: HAL BLUMENFELD
• 金额: $ 43.97万
• 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/10624315
• 关键词: Absence Epilepsy; Adult; Anesthetics; Animal Model; Animals; Attention; Auditory; Behavior; Behavioral; Bilateral; Brain; Calibration; 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; Work; awake; behavior test; behavioral impairment; behavioral response; cortex mapping; experimental study; habituation; human model; improved; insight; neural; neuroimaging; neuronal excitability; neuronal patterning; novel; prevent; psychosocial; 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.

项目摘要/摘要 失神发作在儿童中最常见，因为凝视持续5-10秒，有节律性 脑电“棘波”放电(SWD)。它们可能在一年内发生数百次 而且不是良性的，注意力和心理社会功能的缺陷在某些情况下会持续到 成年后，甚至在癫痫发作抑制之后。失神发作损害认知的机制是 不知道。失神发作一个耐人寻味但鲜有研究的方面是，有些发作会损害 而另一些人甚至在同一个人内部也不会有行为反应。变量之间的关系 失神、行为严重程度和神经元活动可能提供对病理生理学的基本见解。 癫痫发作的症状。先前的人体研究和动物模型也显示出脑电和功能磁共振成像的广泛增加。 在失神发作期间AS减少。我们最近在一个大的患者样本中发现，失神发作与 在广泛的脑网络中，行为损害越严重，fMRI和EEG幅度越大。我们也 发现异常增强的fMRI同步性在两侧皮质区域之间持续存在，即使当 在患者和动物缺席模型中不存在癫痫发作。这些变化的神经元基础 休息期和社署期间的情况不得而知，但我们最近在啮齿动物缺席模型和正常条件下的工作 提示fMRI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共同决定的 癫痫发作前和发作期间广泛大脑网络中涉及的神经元数量和它们的放电模式。 以前工作的一个重要限制是麻醉剂，它显著改变fMRI反应和 神经元的兴奋性。这可能解释了为什么大多数动物模型显示皮质功能磁共振成像在 SWD，而人类研究显示，持续的皮质功能磁共振成像优势减少。正因为如此 失神发作中生理学改变的神经基础仍不确定。我们最近 习惯性遗传缺失性癫痫大鼠(GAERS)，允许清醒头部固定实验。 这个新模型的初步测量显示，在SWD期间，持续的皮质fMRI和CBF减少了很多 更接近于人类。我们现在计划进行互补性的高时空分辨率实验 这种觉醒模型包括功能磁共振成像、电生理学和行为学，以充分了解神经元的基础 失神发作的严重程度不同。我们的目标是首先描绘出基线和期间涉及的网络 重度SWD与轻度SWD比较，并将神经影像改变与EEG上的棘波和波幅联系起来。 其次，我们将使用多单位和神经元集合记录来确定重症脑脊髓炎的神经元基础。 而不是轻度的社保。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。跨这些层次的信息集成将增加我们对 失神癫痫的神经元变化可能导致新的治疗选择。

项目成果

Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures.

• DOI: 10.1038/s41467-022-35535-4
• 发表时间: 2023-01-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: McCafferty, Cian;Gruenbaum, Benjamin F.;Tung, Renee;Li, Jing-Jing;Zheng, Xinyuan;Salvino, Peter;Vincent, Peter;Kratochvil, Zachary;Ryu, Jun Hwan;Khalaf, Aya;Swift, Kohl;Akbari, Rashid;Islam, Wasif;Antwi, Prince;Johnson, Emily A.;Vitkovskiy, Petr;Sampognaro, James;Freedman, Isaac G.;Kundishora, Adam;Depaulis, Antoine;David, Francois;Crunelli, Vincenzo;Sanganahalli, Basavaraju G.;Herman, Peter;Hyder, Fahmeed;Blumenfeld, Hal
• 通讯作者: Blumenfeld, Hal