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: 8680375
• 负责人: Eric Halgren
• 金额: $ 34.87万
• 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/8680375
• 关键词: Accounting; Affect; American; Anesthesia procedures; Animals; Area; Auditory; Biological Models; Boundary Elements; Brain; Cardiovascular Diseases; Cell Nucleus; Cells; Cerebrospinal Fluid; Characteristics; Clinical; Cognitive; Collaborations; Complex; Computer Simulation; Computer software; Computing Methodologies; Cortical Column; Data; Diabetes Mellitus; Disease; Eastern Cooperative Oncology Group; Economics; Electrocorticogram; Electroencephalography; Elements; Emotional; Event; Excision; Functional Imaging; General Hospitals; General Population; Geometry; Goals; Health; Healthcare; Hodgkin Disease; Human; Hybrids; In Vitro; Internet; Interneurons; K-12 Faculty; Lead; Learning; Learning Module; Light; Location; Magnetic Resonance Imaging; Magnetoencephalography; Massachusetts; Measures; Memory; Mental Depression; Methods; Microelectrodes; Microscopic; Minority; Modeling; Motivation; Neurocognitive; Neurons; New York; Outcome; Paris, France; Patients; Pattern; Physiological; Play; Policies; Population; Postdoctoral Fellow; Prefrontal Cortex; Process; Productivity; Property; Pyramidal Cells; Regulation; 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; Underrepresented Minority; Universities; base; biophysical model; cell type; cranium; graduate student; in vivo; lectures; meetings; mortality; neocortical; neural circuit; neural model; neuropsychiatry; non rapid eye movement; non-invasive system; prevent; relating to nervous system; sensory stimulus; social; somatosensory

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）：哺乳动物皮质以两种根本不同的模式运行。其中一种是在醒来时占主导地位，被称为上州，因为神经元的发射速率和突触活动相对较高。另一种是在非拉比眼动睡眠的最深阶段与上州进行振荡的特征，其特征是对细胞射击的深刻抑制，并被称为下降。这种缓慢的振荡（SO）已在具有细胞内记录的动物中进行了深入研究，尤其是在麻醉下体外和体内模型系统中。基本现象已从逼真的Hodgkin-Huxley（H-H）计算模型中的通道性质和突触连通性复制，其细胞数量有限为4,6。人类中最近的多微电极记录表明，SO对应于第3阶段和第4阶段睡眠EEG2中突出的0.5-2Hz Delta活性，此外，下降可以相对隔离，就像第2期Sleep1的K-Complex（KC）一样。这些研究确定了上州和下国的基本局部机制，以及它们与突出的EEG现象的对应，在非侵入性记录中很容易观察到。但是，如何触发和同步的重要方面仍然未知和有争议。这样做，KC发生在皮层的所有部分吗？如果是这样，它们是否优先出现在某些地区？与众不同，KC是否涉及不同的皮质区域？它们是同时发生的，还是散布在皮质上？如果它们传播，是否存在特征速度或起源点？上州和下国的触发或同步如何有所不同？这些是关于数十亿个神经元如何协调的非常复杂的问题。尽管经验记录对于提供线索是必要的，但必须使用计算方法处理和解释这些线索，以实现真正的进展。为了将微电极数据与介观记录（Ecog-Ecog-Torticagraphy）和非侵入性测量（Meg-Magnetotophalography和EEG）相关联，必须进行生物物理和统计前进和逆计算。为了测试在上州和下州的起源和传播的特定假设机制是否对应于显微镜和介观记录的特定假设机制是必要的。需要结合的神经建模和正向计算，以将假设的机制与脑电图和MEG记录相关联。拟议的研究将对人类皮质的这些基本状态产生深入的了解，将动物与在通道，神经元，电路，系统和非侵入性全脑水平的通道中进行的记录相结合。 尽管该研究建议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患有睡眠障碍患者的异常脑电图/MEG，以预测可能导致观察到的异常情况的机制。 KC可能起作用以防止觉醒；知道其神经基础可能会导致更好地治疗失眠症。大多数证据表明，SO是睡眠恢复过程的基本活动。 SO在前一天获得的记忆的合并中似乎也起着核心作用。睡眠障碍与神经认知功能的降低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）具有因果关系。超过30％的普通人群抱怨与睡眠有关的问题。睡眠障碍 - 尤其是睡眠呼吸暂停，睡眠剥夺和嗜睡 - 影响了7,000万美国人，导致160亿美元的年度医疗保健费用和500亿美元的生产率损失。除了医疗保健的重大经济利益外，教育福利还包括对将参加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，并将根据大学政策通过Internet提供。拟议的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团体和少数群体。除了在会议和讲座上的科学演讲外，研究结果还将纳入教学模块中，K-12教师可以与Sejnowski共同指导的UCSD的NSF赞助的学习中心。 人类的颅内记录在纽约大学马萨诸塞州综合医院（MGH- CASH）进行。 （Nyuthesen），Marseille（Chauvel）和布达佩斯（Ulbert）。 MEG/EEG录音发生在UCSD（Halgren）。分析和建模发生在UC Riverside（UCR-Bazhenov），巴黎（Destexhe）和UCSD（中央站点 - Halgren，Sejnowski，Dale和Hagler）。