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 缺席癫痫发作最常见于儿童中，因为持续5-10秒的咒语是有节奏的 脑电图（EEG）上的“尖峰波”排放（SWD）。他们可以每次发生数百次 一天，不是良性的，在某些情况下，注意力和心理社会功能的防御能力持续到 成年，甚至在癫痫发作后。缺席癫痫发作损害认知的机制是 不知道。缺席癫痫发作的一个有趣但鲜为人知的方面是某些情节损害的事实 以及其他人，即使在同一个人中也浪费了行为反应。变量之间的关系 缺乏行为严重程度和神经元活动可能会提供对病理生理学的基本见解 癫痫发作。先前的人类研究和动物模型也显示出宽度的脑电图和fMRI也增加了 在缺席期间下降。我们最近在一个大型患者样本中发现，缺乏 更严重的行为具有较大的fMRI和脑电图放大器在宽度大脑网络中。我们也是 发现即使 患者和动物吸收模型中不存在癫痫发作。这些变化的神经元基础 在静止和SWD期间，我们最近在啮齿动物吸光度模型和正常情况下的工作尚不清楚 表明fMRI信号的放大器与神经元总体活性的变化有关。 因此，我们的核心假设是，癫痫发作的严重程度取决于 癫痫发作之前和期间，涉及的神经元数量及其发射模式。 先前工作的一个重要局限性是麻醉剂，它显着改变了fMRI的反应和 神经元的兴奋。这可能解释了为什么大多数动物模型在期间显示皮质fMRI的增加 SWD的人类研究表明，持续的皮质功能磁共振成像的占主导地位。因为这 差异在缺席时生理变化的神经元基础仍然不确定。我们最近 Strasbourg（Gaers）习惯的遗传缺失大鼠允许清醒的固定实验。 该新模型中的初始测量显示SWD期间持续的皮质fMRI和CBF降低了 更像人类。现在，我们计划完整的高时空分辨率实验 这种清醒模型在内，包括fMRI，电生理学和行为，以充分了解 在缺席的情况下，严重程度可变。我们的目的是首先对基线和期间涉及的网络进行图像 严重与轻度SWD，并将神经影像学变化与脑峰值放大器的尖峰变化相关联。 其次，我们将使用多单位和神经元集合记录来确定严重的神经元基础 与温和的SWD相比。第三，我们将通过听觉检测将SWD的身体严重程度与行为联系起来 和响应任务。在这些层面上的信息集成将增加我们对 缺席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