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: 8837196
• 负责人: MATTI HAMALAINEN
• 金额: $ 34.8万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837196
• 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; Simulate; 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)：提出在精细的时空尺度上成像和解释人类神经活动的方法，对于了解大脑在健康和疾病中的工作方式至关重要。脑磁图(M/EEG)与结构磁共振相结合，提供了可靠的、毫秒级精度的皮质活动记录。皮质下结构，如丘脑，由于低信号幅度和固有的源定位困难，记录一直受到限制。此外，我们对从细胞活动中产生这些信号的宏观电流的产生缺乏了解。我们将整合M/EEG、计算模型和人类患者的侵入性电生理记录，以优化M/EEG逆解算器，以定位分布的丘脑皮质(TC)源并解释潜在的细胞事件。为了优化我们的方法，我们将使用两种已知的范例来强有力地激活感觉运动系统中不同的丘脑和皮质来源，包括丘脑、SI、MI、SII：(1)正中神经(MN)诱发的反应，和(2)原发性震颤(ET)患者的运动诱发震颤活动。我们的M/EEG逆方法将利用低频(低频100赫兹)和高频(高频100-800赫兹)诱发的反应在空间和时间上是不相交的这一事实，并将这一特征与精确的解剖头部建模约束相结合来定位同时进行的皮质和丘脑活动。为了解释这些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，该模型基于丘脑和皮质的突触驱动序列，准确模拟刺激后长达125ms的LFSI触觉诱发源波形。该模式将被扩展以解释在分布的TC网络中观测到的低频和高频活动的来源。在接受脑深部刺激(DBS)手术的ET患者中，结果将通过有创电生理记录进行验证和通知。 目的1：改进基于M/EEG时频的逆解算器来定位TC诱发的低频和高频活动。我们将建立我们的先进的逆方法可以可靠地定位丘脑、SI、MI和SII的来源，在(A)刺激健康受试者的MN和(B)ET患者的MN和运动诱发的震颤活动期间，这些来源的反应反映在一系列的LF和HF活动中。 目的2：用神经模型解释低频和高频源活动的细胞水平来源。我们将把现有的SI电路的计算模型扩展到相互连接的丘脑、SI、MI和SII网络，该电路可以准确地模拟触觉诱发的M/EEG测量的源活动。我们将测试这样的假设，即网络之间的突触相互作用可以复制测量到的目标1的活动序列，并且HF活动是由爆发激发产生的，而LF事件代表最初突触驱动的缓慢树突过程和HF爆发的包络。 目的3：用侵入性TC记录验证逆方法和模型预测。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和棘波活动，以及感觉运动皮质的ECoG。我们将使用这些数据来验证AIM 1源本地化和AIM 2模型预测。数据还将完善模型开发和假设。我们的集成方法将提供对分布式TC活动的新见解，这是单一方法无法实现的。我们将开发免费的开源软件，以提高非侵入性的能力：(1)用M/EEG研究人类TC的相互作用；(2)解释细胞水平的起源 活动的一部分。虽然我们的研究集中在感觉运动系统上，但我们的方法将广泛适用于其他大脑网络中的活动研究，包括像基底节这样的深层结构，以及许多实验范式。我们将启动高中神经科学推广计划，向波士顿地区的高中生传授神经科学中的人体成像和数学建模。我们将以预算大幅削减的地方地区为目标，消除课外充实。我们的计划将在数学和生物课程中增加一个免费的部分。