CRCNS: Integrated Empirical and Multiscale Modeling of Human Sleep Spindles

描述（由申请人提供）：拟议研究的总体目标是确定人类大脑生物物理水平上的大脑事件如何影响颅骨外的宏观记录。具体的重点是睡眠纺锤波，研究最好的睡眠节律，我们将获得同时的EEG， MEG和深度电极记录。这些经验数据将被分析，以确定皮层内与纺锤波相关的电流的层流来源，这些结果将与计算模型的预测相匹配。我们将开发三种相关的网络模型，以覆盖广泛的空间尺度。目前的假设是，首先，纺锤波是由多个松散耦合的皮层区域通过丘脑皮层传入事件的节律性激活产生的，从基质系统传到皮层表层，从核心系统传到中间层；其次，核心系统中受限制的丘脑皮层区域的纺锤波振荡通过基质系统传播。1)在睡眠纺锤波期间同时记录脑电和脑电。假设：脑磁图和脑电图将记录非常不同的活动模式在传感器水平和他们的推断来源。差的相关性将表现为主轴放电中相位和振幅关系的不恒定，以及主轴发生时间的松散相关性。2)睡眠纺锤波时颅内大电极记录，同时记录头皮脑电和脑磁图。假设：来自不同皮层发生器的记录只会彼此松散耦合，或与头皮脑电图松散耦合，从而支持MEG提出的一般观点。3)睡眠纺锤波时颅内微电极阵列的记录。假设：神经元发生器电流在每一个纺锤体的表层和中间层之间变化。4)重建人类联合皮层的核上和核下锥体细胞，确定它们的层状分布，并估计核心和基质丘脑皮质投影的可能终止区。假设：在人类的联想皮层和啮齿动物的感觉皮层之间会发现显著的解剖差异。1)基于结构MRI皮质重建构建准确、真实的脑电/脑磁图正演解。假设：颅外脑电/脑磁图的基本参数可以通过模拟多个区域之间不同同步的丘脑皮质区域来复制。EEG/MEG的拟合参数值将与颅内大电极记录推断的值相匹配。2)利用主成分分析法（PCA）分析皮质电流源密度（CSD）。通过重建核上和核下锥体细胞，它们的种群分布，以及基质和核传入事件的终止，来模拟从基质和核丘脑皮层传入事件中预期的CSD模式。假设：通过主成分分析确定的纺锤体的主要时空CSD成分将对应于由基质和核心丘脑皮层传入事件激活产生的CSD成分。3)构建基于霍奇金-赫胥黎离子电流的神经元模型，包括皮质细胞、丘脑网状核细胞、基质细胞和丘脑核心中继细胞，以及它们之间的相互联系。假设：在不同皮质层中预测的电流的时空模式将与使用建模目标2中描述的方法获得的结果相匹配。4)使用简化的神经模型将皮质小柱网络模型扩展为空间精确的皮质模型，并生成脑电/脑磁图。假设：从模型中预测的脑电图和脑磁图将与记录中观察到的相匹配，其中涉及到与建模目标1中导出的参数相对应的基质与核心丘脑皮质系统。5)建立与放大模型属性相匹配的统计模型，并用统计物理的方法进行分析。假设：矩阵系统控制皮层有效连通性，核心系统控制局部相关长度。来自人类的记录将在MGH （Cash）进行，并在UCSD （Halgren和Sejnowski）进行分析和建模。这三个团队的pi，学生和博士后研究员将在研究期间每天进行互动，每年至少举行一次正式会议，以评估进展并计划新的实验。

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to determine how brain events at the biophysical level in the human brain influence the macroscopic recordings outside the skull. The specific focus is on sleep spindles, the best studied sleep rhythm, for which we will obtain simultaneous EEG, MEG and depth electrode recordings. These empirical data will be analyzed to determine the laminar sources of the currents within the cortex associated with spindles and these results will be matched to predictions from computational models. We will develop three types of related network models to cover a wide range of spatial scales. The working hypotheses are, first, that spindles are generated by multiple loosely-coupled cortical regions through rhythmic activation of thalamocortical afferents, onto superficial cortical layers from the matrix system, and onto middle layers from the core system, and second, that spindle oscillations in restricted thalamocortical domains in the core system are spread via the matrix system. Empirical Specific Aims and Hypotheses 1) Record MEG and EEG simultaneously during sleep spindles. Hypothesis: MEG and EEG will record very different activity patterns at the sensor level and in their inferred sources. Poor correlation will be apparent as inconstant phase and amplitude relations within spindle discharges, as well as only loose correlations as to when spindles occur. 2) Record from intracranial EEG macro-electrodes during sleep spindles, with simultaneous scalp EEG and MEG recordings. Hypothesis: Recordings from different cortical generators will be only loosely coupled with each other, or with scalp EEG, thus supporting the general view suggested by MEG. 3) Record from intracranial microelectrode arrays during sleep spindles. Hypothesis: Neuronal generator currents vary during each spindle between superficial and middle layers. 4) Reconstruct supragranular and infragranular pyramidal cells from association cortex in humans, determine their laminar distribution, and estimate the likely termination zones of core and matrix thalamocortical projections. Hypothesis: Significant anatomical differences will be found between human association cortex and the rodent sensory cortex. Modeling Specific Aims and Hypotheses 1) Construct accurate, realistic EEG/MEG forward solutions based on cortical reconstruction from structural MRI. Hypothesis: Basic parameters of extracranial EEG/MEG can be replicated by modeling multiple thalamocortical domains with varying synchrony between domains. The values of the fit parameters to EEG/MEG will match those inferred from intracranial macroelectrode recordings. 2) Analyze the recorded cortical Current Source Density (CSD) using Principal Components Analysis (PCA). Model the CSD patterns expected from the matrix and core thalamocortical afferents using reconstructions of supragranular and infragranular pyramidal cells, their population distribution, and terminations of matrix and core afferents. Hypothesis: The main spatiotemporal CSD components contributing to the spindle identified with PCA will correspond to the CSD components modeled to result from activation of matrix and core thalamocortical afferents. 3) Construct neuronal models based on Hodgkin-Huxley ionic currents that include cortical cells, thalamic reticular nuclear cells, matrix and core thalamic relay cells, and their interconnections in a minicolumn. Hypothesis: The spatiotemporal patterns of currents predicted in different cortical layers will match those obtained using the methods described in modeling aim 2. 4) Scale up the cortical minicolumn network model using simplified neural models to a spatially accurate cortical model that can generate EEG/MEG patterns. Hypothesis: The predicted EEG and MEG from the model will match those observed in recordings, with the involvement of matrix vs core thalamocortical systems corresponding to the parameters derived in modeling aim 1. 5) Develop a statistical model that matches the properties of the scaled up model and analyze it with methods from statistical physics. Hypothesis: The matrix system controls the effective cortical connectivity and the core system controls the local correlation length. Collaborative research Recordings from humans will be performed at MGH (Cash), with analysis and modeling at UCSD (Halgren and Sejnowski). These 3 teams of PIs, students and postdoctoral fellows will interact on a daily basis during the research and will meet formally at least once a year to assess progress and plan new experiments.