CRCNS: Multiresolution Modeling of Human Thalamocortical Upstates and Downstates

描述(申请人提供)：哺乳动物的大脑皮质有两种根本不同的工作模式。一种在清醒时占主导地位，被称为北部，因为相对较高的神经元放电率和突触活动。另一种，在州北部最深的地方摇摆 非快速眼动睡眠的阶段，其特征是细胞放电受到严重抑制，被称为下州。这种慢振荡(SO)已经在有细胞内记录的动物中得到了深入的研究，特别是在体外和体内麻醉下的模型系统中。在细胞数量有限的现实Hodgkin-Huxley(H-H)计算模型中，从通道属性和突触连接中复制了基本现象4，6。最近在人类的多微电极记录表明，SO对应于在阶段3和4睡眠EEG2中突出的.5-2赫兹增量活动，进一步，下行状态可以相对孤立地发生，因为阶段2的K-复合体(KC)睡眠1。这些研究已经建立了州上和州下的基本局部机制，以及它们与在非侵入性记录中容易观察到的显著脑电现象的对应关系。然而，它们如何被触发和同步的重要方面仍然未知和有争议。大脑皮层的所有部分都会发生这种情况和KC吗？如果是这样，它们是否优先发生在某些地区？不同的SO和KC是否涉及不同的皮质区域？它们是同时出现在所有区域，还是扩散到大脑皮层？如果它们扩散，有没有一个特有的速度或起源点？北部和南部在触发或同步的方式上有区别吗？这些都是非常复杂的问题，涉及数十亿个神经元是如何协调的。尽管经验记录是提供线索所必需的，但这些线索必须用计算方法处理和解释，才能取得真正的进展。为了将微电极数据与介观记录(脑电地形图)和非侵入性测量(脑磁图和脑电)联系起来，有必要进行生物物理学和统计正反演计算。神经模型是必要的，以测试特定的假设机制的起源和扩散的上州和下州是否对应的微观和介观记录。需要结合神经建模和正向计算来将假设的机制与脑电和脑磁图记录联系起来。拟议的研究将产生对人类大脑皮层这些基本状态的深刻理解，通过计算将动物与人类在通道、神经元、回路、系统和非侵入性全脑水平上的记录整合在一起。 尽管这项研究计划的具体目标是了解基本的皮质功能状态，但基于这些模型的进一步研究可以应用于睡眠障碍患者的异常脑电/脑磁图，以预测可能导致观察到的异常的机制。KC可能起到防止觉醒的作用；了解它的神经基础可能会导致更好地治疗失眠。大多数证据表明，SO是睡眠恢复过程中的基本活动。在巩固前一天获得的记忆方面，SO似乎也发挥了核心作用。睡眠障碍与神经认知功能降低以及各种不利的生理和长期健康后果有因果关系，包括全因死亡、糖尿病和心血管疾病。超过30%的总人口抱怨与睡眠有关的问题。睡眠障碍--尤其是睡眠呼吸暂停、睡眠不足和嗜睡--影响着7000万美国人，导致每年160亿美元的医疗费用和500亿美元的生产力损失。除了从医疗保健中获得显著的经济利益外，教育方面的好处还包括将参与研究的研究生和本科生的培训。所有用于运行模型的软件将与其他研究人员共享，并将根据大学的政策通过互联网获得。拟议研究将建立的新的跨学科合作将导致对研究生和博士后研究员进行跨学科培训，并将涉及代表性不足的群体和少数群体。除了在会议和讲座上的科学陈述外，这项研究的成果将被纳入K-12教师可以使用的教学模块，并与由Sejnowski共同指导的加州大学圣地亚哥分校NSF赞助的学习科学中心一起使用。 来自人类的颅内记录在纽约大学的马萨诸塞州综合医院(MGH-Cash)进行。(纽约大学-提森)、马赛(肖维尔)和布达佩斯(乌尔伯特)。脑磁图/脑电记录在加州大学圣迭戈分校(哈尔格伦)进行。分析和建模在UC Riverside(UCR-Bazhenov)、Paris(Destexhe)和UCSD(中央站点-Halgren、Sejnowski、Dale和Hagler)进行。

DESCRIPTION (provided by applicant): Mammalian cortex operates in two fundamentally different modes. One, dominant during waking, is termed the upstate because of relatively high neuronal firing rates and synaptic activity. The other, oscillating with the upstate in the deepest stages of non-rapid eye-movement sleep, is characterized by a profound suppression of cell-firing and is termed the downstate. This slow oscillation (SO) has been intensively studied in animals with intracellular recordings, especially in model systems in vitro and in vivo under anesthesia. The basic phenomena have been reproduced from channel properties and synaptic connectivity in realistic Hodgkin-Huxley (H-H) computational models with limited numbers of cells4,6. Recent multi-microelectrode recordings in humans have demonstrated that the SO corresponds to .5-2Hz delta activity prominent in the stage 3 and 4 sleep EEG2, and further, that the downstate can occur in relative isolation as the K-Complex (KC) of stage 2 sleep1. These studies have established the basic local mechanisms of upstates and downstates, and their correspondence to prominent EEG phenomena that are easily observable in non-invasive recordings. However, important aspects of how they are triggered and synchronized remain unknown and controversial. Do SO and KC occur in all parts of the cortex? If so, do they preferentially occur in some areas? Do different SO and KC involve different cortical areas? Do they occur in all areas simultaneously or do they spread across the cortex? If they spread, is there a characteristic speed or point of origin? Do upstates and downstates differ in how they are triggered or synchronized? These are very complex questions regarding how billions of neurons are coordinated. Although empirical recordings are necessary to provide clues, these must be processed and interpreted with computational methods to make real headway. Biophysical and statistical forward and inverse computations are necessary to relate the microelectrode data to mesoscopic recordings (ECOG- electrocorticography) and non-invasive measures (MEG- magnetoencephalography and EEG). Neural modeling is necessary to test if specific hypothesized mechanisms for the origin and spread of the upstate and downstate correspond to the microscopic and mesoscopic recordings. Combined neural modeling and forward computations are needed to relate hypothesized mechanisms to EEG and MEG recordings. The proposed studies will yield a deep understanding of these fundamental states of the human cortex, computationally integrating animal with human recordings made at the channel, neuronal, circuit, system, and non-invasive whole-brain levels. Although the specific goal of this research proposal is to understand fundamental cortical functional states, further research based on the models could be applied to abnormal EEG/MEG from patients with sleep disorders, to predict the mechanisms that may be responsible for the observed abnormalities. The KC may function to prevent awakening; knowing its neural basis could lead to better treatment of insomnia. Most evidence suggests that the SO is the essential activity underlying the restorative processes of sleep. The SO also appears to play a central role in the consolidation of memories acquired in the preceding day. Sleep disorders have a causal relationship with reduced neurocognitive functions as well as variety of adverse physiologic and long-term health outcomes including all-cause mortality, diabetes, and cardiovascular disease. Over 30% of the general population complains about sleep-related problems. Sleep disorders - notably sleep apnea, sleep deprivation and sleepiness - affect 70 million Americans, resulting in $16 billion in annual healthcare expenses and $50 billion in lost productivity. In addition to significant economic benefits from healthcare, educational benefits include the training of graduate students and undergraduates who will be participating in the research. All of the software for running the models will be shared with other researchers and will be available through the internet in accordance with University policies. The new cross-disciplinary collaborations that will be established by the proposed research will lead to cross-disciplinary training of graduate students and postdoctoral fellows and will involve underrepresented groups and minorities. In addition to scientific presentations at meetings and lectures, the results of th research will be incorporated into teaching modules that could be used by K-12 teachers, in conjunction with the NSF sponsored Science of Learning Center at UCSD co-directed by Sejnowski. Intracranial recordings from humans are performed at Massachusetts General Hospital (MGH- Cash), New York Univ. (NYU- Thesen), Marseille (Chauvel), and Budapest (Ulbert). MEG/EEG recordings occur at UCSD (Halgren). Analysis and modeling occur at UC Riverside (UCR- Bazhenov), Paris (Destexhe), and UCSD (the central site- Halgren, Sejnowski, Dale and Hagler).