CRCNS: Multiresolution Modeling of Human Thalamocortical Upstates and Downstates

描述（由申请人提供）：哺乳动物皮层以两种根本不同的模式运作。一种在清醒时占主导地位，由于相对较高的神经元放电率和突触活动而被称为上状态。另一个在非快速眼动睡眠的最深阶段与上状态一起振荡，其特征是细胞放电受到严重抑制，被称为下状态。这种慢振荡（SO）已经在细胞内记录的动物中得到了深入的研究，特别是在体外和麻醉下的体内模型系统中。这些基本现象已经在具有有限细胞数量的现实霍奇金-赫胥黎（H-H）计算模型中从通道特性和突触连通性中重现了4,6。最近的人体多微电极记录表明，SO对应于。5-2Hz的δ活动在睡眠第3和第4阶段的EEG2中突出，进一步说，下行状态可以相对孤立地发生在睡眠第2阶段的k复合体（KC）中1。这些研究建立了上状态和下状态的基本局部机制，并与非侵入性记录中容易观察到的突出脑电图现象相对应。然而，它们如何被触发和同步的重要方面仍然是未知和有争议的。SO和KC是否出现在皮质的所有部位？如果有，它们是否优先发生在某些地区？不同的SO和KC涉及不同的皮质区域吗？它们是同时发生在所有区域还是在大脑皮层中扩散？如果它们传播，是否有特定的速度或起源点？上州和下州在触发或同步的方式上有不同吗？这些是关于数十亿神经元如何协调的非常复杂的问题。虽然经验记录对于提供线索是必要的，但这些必须用计算方法进行处理和解释，才能取得真正的进展。为了将微电极数据与介观记录（ECOG-皮质电图）和非侵入性测量（MEG-脑电图和脑电图）联系起来，需要进行生物物理和统计的正向和反向计算。神经模型是必要的，以测试是否特定的假设机制的起源和传播的上状态和下状态对应于微观和介观记录。需要结合神经建模和正演计算将假设的机制与脑电图和MEG记录联系起来。拟议的研究将产生对人类皮层这些基本状态的深刻理解，通过计算整合动物与人类在通道、神经元、电路、系统和非侵入性全脑水平上的记录。

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).