Biophysical Basis of Functional Connectivity by MRI

描述（由申请人提供）：本提案的总体目标是确定来自大脑的磁共振（MRI）信号的静息状态波动中的区域间相关性是否可靠地测量区域之间的功能连接。在静息状态下识别高度相关的低频MRI信号的模式可能提供了一种强有力的方法来描绘和描述神经回路。此外，在几种疾病中观察到的静息状态连接的改变表明，这些相关性反映了大脑组织的重要水平。然而，尽管静息状态相关性已经被广泛用于评估大脑功能结构，但其精确解释仍不清楚，它们是否是功能连接的直接指标也完全没有得到证实。为了研究连通性，我们将使用高场（9.4T）的超高分辨率MRI来描绘麻醉的非人类灵长类动物的皮质网络。猴的SI皮质亚区是一个很好的实验模型，因为该区域的功能和解剖结构已经用侵入性电生理和组织学方法进行了很好的研究。在9.4T，使用振动触觉刺激的fMRI采集识别SI皮质内功能不同的皮质区域（3a，3b和1），每个区域显示不同的精细尺度区域内和区域间以及更长范围的皮质-丘脑连接。我们将（a）使用刺激驱动的激活图来识别候选区域，然后在亚毫米分辨率下测量猴脑的静息状态空间连接模式;（B）测量静息状态BOLD、CBF的内在点扩散函数（脑血流量）和CBV（脑血容量）相关性;以及（c）确定区域间相关性如何随功能作用、空间分辨率以及BOLD、CBF和CBV信号之间的变化而变化。我们将使用简单的多变量模型，以减少数据的格式，他们可以直接比较电生理测量。然后，我们将通过与相同动物的定量电生理学和组织学直接比较来验证静息状态MRI信号的连接性测量。我们将（a）定量确定电生理定义的神经元反应图和静息状态fMRI相关图的空间重叠程度：（B）确定自发电记录的特征（多单位尖峰和局部场电位）显示了类似于BOLD的相关性模式：（c）确定似乎通过BOLD和电生理学功能连接的区域是否也表现出强烈的相互作用，通过将解剖示踪剂注射到通过电映射和功能磁共振成像识别的候选区域中，并在死后进行组织学评估，来建立区域解剖学连接。我们相信，拟议中的研究有相当重要的更好地了解静息状态的功能连接措施的神经基础，并将有直接的影响和影响的fMRI在基础和临床神经科学的应用。 公共卫生相关性：当受试者处于休息状态并且不从事任何特定的精神活动或任务时，对在几分钟内获得的大脑磁共振图像的系列分析揭示了基线的强烈区域间相关性 似乎反映了可识别的神经回路的MRI信号。有相当大的潜力，利用这种功能的连接，但迄今为止，还没有研究来验证这些信号的变化，揭示了实际的解剖连接或相关的变化，在神经电活动。这项研究将通过观察非人类灵长类动物大脑的高分辨率来建立这些联系。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to determine whether inter-regional correlations in resting state fluctuations of magnetic resonance (MRI) signals from the brain reliably measure functional connectivity between regions. The identification of patterns of highly correlated low frequency MRI signals in the resting state potentially provides a powerful approach to delineate and describe neural circuits. Moreover, observations of altered resting state connectivity in several disorders suggest these correlations reflect an important level of brain organization. However, although resting state correlations are already being widely used to assess brain functional architecture, their precise interpretation remains unclear, and whether they are direct indicators of functional connectivity is completely unsubstantiated. To investigate connectivity we will use very high- resolution MRI at high field (9.4T) to delineate cortical networks in anesthetized non-human primates. The sub- regions of SI cortex in monkeys are an excellent experimental model because the functional and anatomical structures of this region have previously been well investigated with invasive electrophysiological and histological methods. At 9.4T, fMRI acquisitions using vibrotactile stimuli identify functionally distinct cortical areas (3a, 3b and 1) within SI cortex, and each displays distinct fine-scale intra- and inter-regional, as well as longer range cortico-thalamic connectivity. We will (a) use stimulus-driven activation maps to identify candidate areas, and then measure resting state spatial connectivity patterns at sub-millimeter resolution in monkey brain; (b) measure the intrinsic point spread function of resting state BOLD, CBF (cerebral blood flow) and CBV (cerebral blood volume) correlations; and (c) determine how inter-regional correlations vary with functional role, spatial resolution and between BOLD, CBF and CBV signals. We will use simple multivariate models to reduce the data to a format by which they can be directly compared to electrophysiological measurements. We will then validate the measurements of connectivity from resting state MRI signals by direct comparisons with quantitative electrophysiology and histology in the same animals. We will (a) determine quantitatively the degree of spatial overlap of electrophysiologically defined neuronal response maps and resting state fMRI correlation maps: (b) determine what features of the spontaneous electrical recordings (multiple-unit spiking and local field potentials) from identified regions shw patterns of correlation similar to BOLD: (c) determine whether areas which appear to be functionally connected by BOLD and electrophysiology also exhibit strong inter-areal anatomical connections by injecting anatomical tracers into candidate regions identified by electrical mapping and fMRI and performing histological assessments post mortem. We believe that the proposed studies have considerable importance for better understanding the neural basis of resting state functional connectivity measures, and will have direct implications and impact on the applications of fMRI in both basic and clinical neuroscience. PUBLIC HEALTH RELEVANCE: The analysis of series of magnetic resonance images of the brain acquired over a period of minutes while the subject is in a resting state, and not engaged in any specific mental activity or task, reveals strong inter-regional correlations of the baseline MRI signal that appear to reflect identifiable neural circuits. There is considerable potential in exploiting this functional connectivity, but thus far there have been no studies to validate that these signal variations reveal actual anatomic connectivity or correlated variations in neural electrical activity. The studies proposed would establish these links by looking at very high resolution in the brains of non-human primates.