CRCNS: Advancing Computational Methods to Reveal Human Thalamocortical Dynamics

描述（由申请人提供）：在精细的时空尺度上对人类神经活动进行成像和解释的先进方法对于理解大脑在健康和疾病中如何工作至关重要。磁/脑电图（M/EEG）结合结构MRI提供了精确到毫秒的皮层活动的可靠记录。来自皮层下结构（如丘脑）的记录由于低信号幅度和源定位的固有困难而受到限制。此外，我们对从细胞事件产生这些信号的宏观电流的产生的理解是缺乏的。我们将整合脑电/脑电图、计算建模和人类患者的侵入性电生理记录，以优化脑电/脑电图反求解器，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，我们将采用两种已知的模式来强大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，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（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，并将这一特征与精确的解剖头部建模约束相结合，以定位并发的皮层和丘脑活动。为了解释信号背后的细胞水平事件，我们

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.