CRCNS: Multiresolution Modeling of Human Thalamocortical Upstates and Downstates

CRCNS：人类丘脑皮质上部和下部的多分辨率建模

• 批准号: 8538511
• 负责人: Eric Halgren
• 金额: $ 33.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538511
• 关键词: Accounting; Affect; American; Anesthesia procedures; Animals; Area; Auditory; Biological Models; Boundary Elements; Brain; Cardiovascular Diseases; Cell Nucleus; Cells; Cerebrospinal Fluid; Characteristics; Collaborations; Complex; Computer Simulation; Computer software; Computing Methodologies; Cortical Column; Data; Diabetes Mellitus; Eastern Cooperative Oncology Group; Economics; Educational process of instructing; Electrocorticogram; Electroencephalography; Elements; Event; Excision; General Hospitals; General Population; Goals; Health; Healthcare; Hodgkin Disease; Human; Hybrids; In Vitro; Internet; Interneurons; Lead; Learning; Location; Magnetic Resonance Imaging; Magnetoencephalography; Massachusetts; Measures; Memory; Methods; Microelectrodes; Microscopic; Minority Groups; Modeling; Motivation; Neurocognitive; Neurons; New York; Outcome; Paris, France; Patients; Pattern; Physiological; Play; Policies; Population; Postdoctoral Fellow; Prefrontal Cortex; Process; Productivity; Property; Pyramidal Cells; Relative (related person); Research; Research Personnel; Research Proposals; Role; Running; Scalp structure; Science; Signal Transduction; Site; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleeplessness; Specific qualifier value; Speed; Stage II Sleep; Staging; Stereotyping; Stimulus; Surface; Synapses; System; Testing; Thalamic structure; Training; Travel; Universities; base; cell type; cranium; graduate student; in vivo; lectures; meetings; mortality; neocortical; neural circuit; neural model; non rapid eye movement; non-invasive system; prevent; relating to nervous system; sensory stimulus; somatosensory; teacher

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).

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。其中一种在清醒时占主导地位，由于神经元放电率和突触活动相对较高，因此被称为北部。另一个，与北部最深处一起振荡 非快速眼动睡眠阶段的特点是细胞放电受到严重抑制，被称为“下状态”。这种慢振荡（SO）已在具有细胞内记录的动物中进行了深入研究，特别是在麻醉下的体外和体内模型系统中。基本现象已从具有有限数量细胞的现实 Hodgkin-Huxley (H-H) 计算模型中的通道特性和突触连接重现4,6。最近的人类多微电极记录表明，SO 对应于第 3 阶段和第 4 阶段睡眠 EEG2 中突出的 0.5-2Hz δ 活动，而且，下行状态可以与第 2 阶段睡眠的 K 复合体 (KC) 相对隔离地发生。这些研究已经建立了上州和下州的基本局部机制，以及它们与在非侵入性记录中很容易观察到的突出脑电图现象的对应关系。然而，它们如何触发和同步的重要方面仍然未知且存在争议。 SO和KC是否存在于皮质的所有部分？如果是这样，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遍布整个皮层？如果它们传播，是否有特征速度或起源点？上州和下州的触发或同步方式是否有所不同？这些都是关于数十亿神经元如何协调的非常复杂的问题。尽管需要经验记录来提供线索，但必须用计算方法对这些记录进行处理和解释才能取得真正的进展。生物物理和统计正向和逆向计算对于将微电极数据与介观记录（ECOG-皮质电图）和非侵入性测量（MEG-脑磁图和EEG）相关联是必要的。神经模型对于测试北部和南部起源和传播的具体假设机制是否与微观和介观记录相对应是必要的。需要结合神经建模和正向计算来将假设的机制与脑电图和脑磁图记录联系起来。拟议的研究将深入了解人类皮层的这些基本状态，通过计算将动物与人类在通道、神经元、电路、系统和非侵入性全脑水平上的记录整合起来。 尽管这项研究提案的具体目标是了解基本的皮质功能状态，但基于模型的进一步研究可以应用于睡眠障碍患者的异常脑电图/脑磁图，以预测可能导致观察到的异常的机制。 KC 可能起到阻止觉醒的作用；了解其神经基础可以更好地治疗失眠。大多数证据表明，SO 是睡眠恢复过程的基本活动。 SO似乎在巩固前一天获得的记忆方面也发挥着核心作用。睡眠障碍与神经认知功能下降以及各种不良生理和长期健康结果（包括全因死亡率、糖尿病和心血管疾病）存在因果关系。超过 30% 的普通民众抱怨与睡眠相关的问题。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。除了医疗保健带来的显着经济效益外，教育效益还包括对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都将与其他研究人员共享，并将根据大学政策通过互联网提供。拟议研究将建立的新的跨学科合作将导致研究生和博士后研究员的跨学科培训，并将涉及代表性不足的群体和少数族裔。除了在会议和讲座上进行科学演示外，研究结果还将与 NSF 赞助的加州大学圣地亚哥分校学习科学中心（Sejnowski 共同领导）一起纳入 K-12 教师可以使用的教学模块中。 人类颅内记录在纽约大学马萨诸塞州总医院 (MGH-Cash) 进行。 （纽约大学-Thesen）、马赛（Chauvel）和布达佩斯（Ulbert）。 MEG/EEG 记录在 UCSD（哈尔格伦）进行。分析和建模在加州大学河滨分校 (UCR-Bazhenov)、巴黎分校 (Destexhe) 和加州大学圣地亚哥分校（中心站点 - Halgren、Sejnowski、Dale 和 Hagler）进行。