CRCNS: Advancing Computational Methods to Reveal Human Thalamocortical Dynamics

CRCNS：推进计算方法来揭示人类丘脑皮质动力学

• 批准号: 8927069
• 负责人: MATTI HAMALAINEN
• 金额: $ 29.18万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927069
• 关键词: Area; Basal Ganglia; Biology; Boston; Brain; Budgets; Characteristics; Computer Simulation; Computer software; Computing Methodologies; Data; Deep Brain Stimulation; Disease; Educational Curriculum; Electroencephalography; Essential Tremor; Event; Frequencies; Generations; Head; Health; High School Student; Human; Image; Investigation; Magnetic Resonance Imaging; Mathematics; Measures; Methods; Modeling; Motor; Neurosciences; Operative Surgical Procedures; Patients; Principal Investigator; Process; Signal Transduction; Source; Stimulus; Structure; Students; Synapses; Tactile; Testing; Thalamic structure; Time; Tremor; Work; base; experience; high school; insight; mathematical model; median nerve; millisecond; model development; neural model; novel; open source; outreach program; programs; relating to nervous system; response; sensorimotor system

DESCRIPTION (provided by applicant): Advancing methods to image and interpret neural activity in humans on fine temporal-spatial scales is critical to understanding how the brain works in health and disease. Magneto-/Electroencephalography (M/EEG) combined with structural MRI provides reliable recordings of cortical activity with millisecond precision. Recordings from subcortical structures, such as thalamus, have been limited due to low signal amplitudes and inherent difficulty in source localization. Further, our understanding of the generation of the macroscopic electrical currents producing these signals from cellular events is lacking. We will integrate M/EEG, computational modeling, and invasive electrophysiological recordings in human patients to optimize M/EEG inverse solvers to localize distributed thalamocortical (TC) sources and to interpret the underlying cellular events. To optimize our methods we will employ two paradigms known to robustly activate distinct thalamic and cortical sources in the sensorimotor system, including thalamus, SI, MI, SII: (1) median nerve (MN) evoked responses, & (2) motor evoked tremor activity in Essential Tremor (ET) patients. Our M/EEG inverse methods will take advantage of the fact low frequency (LF <100Hz) and high frequency (HF 100-800hz) evoked responses are disjoint in space and time and will combine this characteristic with precise anatomical head modeling constraints to localize concurrent cortical and thalamic activities. To interpret the cellular level events underlying the signals, we will expand a previously developed neural model of TC circuitry that accurately simulates LF SI tactile evoked source waveforms up to 125ms post-stimulus based on sequences of synaptic drive from thalamus and cortex. This model will be expanded to interpret the origin of observed LF and HF activity in the distributed TC network. Results will be validated and informed with invasive electrophysiological recording in ET patients undergoing deep brain stimulation (DBS) surgery. AIM 1: ADVANCE M/EEG TIME-FREQUENCY BASED INVERSE SOLVERS TO LOCALIZE TC EVOKED LF & HF ACTIVITY. We will establish that our advanced inverse methods can reliably localize sources in the thalamus, SI, MI, and SII, during (a) MN stimulation in healthy subjects & (b) MN and motor evoked tremor activity in ET patient, and that the responses from these sources are reflected in a sequence of LF and HF activities. AIM 2: INTERPRET CELLULAR LEVEL ORIGIN OF LF & HF SOURCE ACTIVITY WITH NEURAL MODELING. We will expand an existing computational model of a SI circuit that accurately simulates tactile evoked M/EEG measured source activity to an interconnected thalamic, SI, MI, and SII network. We will test the hypotheses that synaptic interactions between the networks can reproduce the sequences of activity measured Aim 1 and that the HF activity is created by burst firing, while the LF events represent initial synaptically driven slow dendriti processes and the envelope of the HF bursts. AIM 3: VALIDATE INVERSE METHODS AND MODEL PREDICTIONS WITH INVASIVE TC RECORDINGS. We will record LFP and spiking activity from the thalamus, and ECoG from the sensorimotor cortex, of ET patients undergoing DBS surgery during (a) MN stimulation & (b) motor evoked tremor activity. We will use the data to validate Aim 1 source localizations and Aim 2 model predictions. Data will also refine model development and hypotheses. Our integrated approach will provide novel insight into distributed TC activity that is not possible wih one method alone. We will develop free open source softwares that advance the ability to non-invasively (1) study TC interactions in humans with M/EEG & (2) interpret the cellular level origin of the activity. While our investigation is focused on the sensorimotor system, our methods will be broadly applicable to study activity in other brain networks, including deep structures like basal ganglia, and in many experimental paradigms. We will initiate a High School Neuroscience Outreach Program to educate Boston area High School students on human imaging and mathematical modeling in neuroscience. We will target local districts experiencing large budget cuts with elimination in extra-curricular enrichment. Our program will add a complimentary component to the math and biology curriculums.

描述（由申请人提供）：改进在精细时空尺度上对人类神经活动进行成像和解释的方法对于理解大脑在健康和疾病中的工作方式至关重要。磁磁/脑电图 (M/EEG) 与结构 MRI 相结合，可以以毫秒精度可靠地记录皮质活动。由于信号幅度低和源定位固有的困难，来自皮层下结构（例如丘脑）的记录受到限制。此外，我们对从细胞事件中产生这些信号的宏观电流的产生缺乏了解。我们将整合人类患者的 M/EEG、计算模型和侵入性电生理记录，以优化 M/EEG 逆解算器，定位分布式丘脑皮质 (TC) 源并解释潜在的细胞事件。为了优化我们的方法，我们将采用两种已知的范式，以稳健地激活感觉运动系统中不同的丘脑和皮质源，包括丘脑、SI、MI、SII：(1) 正中神经 (MN) 诱发反应，以及 (2) 运动诱发震颤特发性震颤（ET）患者的活动。我们的 M/EEG 逆方法将利用低频 (LF <100Hz) 和高频 (HF 100-800hz) 诱发反应在空间和时间上不相交的事实，并将这一特性与精确的解剖头部建模约束相结合，以定位并发皮质和丘脑活动。为了解释信号背后的细胞水平事件，我们 将扩展先前开发的 TC 电路神经模型，该模型根据丘脑和皮层的突触驱动序列，准确模拟刺激后长达 125 毫秒的 LF SI 触觉诱发源波形。该模型将被扩展以解释分布式 TC 网络中观察到的 LF 和 HF 活动的起源。结果将通过接受深部脑刺激 (DBS) 手术的 ET 患者的侵入性电生理记录进行验证和告知。 目标 1：先进的基于 M/EEG 时频的逆求解器来定位 TC 诱发的低频和高频活动。我们将确定，在 (a) 健康受试者的 MN 刺激和 (b) ET 患者的 MN 和运动诱发震颤活动期间，我们的先进逆向方法可以可靠地定位丘脑、SI、MI 和 SII 中的源，并且响应这些来源反映在一系列低频和高频活动中。 目标 2：通过神经建模解释低频和高频源活动的细胞水平起源。我们将扩展 SI 电路的现有计算模型，该模型可准确模拟触觉诱发 M/EEG 测量的源活动到互连的丘脑、SI、MI 和 SII 网络。我们将测试以下假设：网络之间的突触相互作用可以重现目标 1 测量的活动序列，并且 HF 活动是由爆发放电产生的，而 LF 事件代表初始突触驱动的缓慢树突过程和 HF 爆发的包络。 目标 3：利用侵入式 TC 记录验证反演方法和模型预测。我们将记录接受 DBS 手术的 ET 患者在 (a) MN 刺激和 (b) 运动诱发震颤活动期间丘脑的 LFP 和尖峰活动，以及感觉运动皮层的 ECoG。我们将使用这些数据来验证 Aim 1 源定位和 Aim 2 模型预测。数据还将完善模型开发和假设。我们的集成方法将为分布式 TC 活动提供新颖的见解，这是单独使用一种方法无法实现的。我们将开发免费的开源软件，以提高非侵入性 (1) 通过 M/EEG 研究人类 TC 相互作用的能力 & (2) 解释细胞水平起源 的活动。虽然我们的研究重点是感觉运动系统，但我们的方法将广泛适用于其他大脑网络的研究活动，包括基底神经节等深层结构，以及许多实验范式。我们将启动一项高中神经科学外展计划，向波士顿地区的高中生进行神经科学中的人体成像和数学建模方面的教育。我们将针对经历大幅预算削减的地方地区，取消课外活动。我们的计划将为数学和生物课程添加免费内容。