Noninvasive Optical Imaging of the Human Brain

描述（由申请人提供）：为了增加功能性成像模式fMRI和漫射光学成像（DOI）的临床应用，我们需要确定它们测量的血流动力学变化与导致这些变化的潜在神经活动之间的关系。在我们上一个拨款周期中，我们使用DOI结合EEG/MEG来研究神经血管耦合。这些测量结果为不同突触活动成分在血流动力学反应中的作用提供了新的见解，揭示了血流动力学反应与晚期浅表皮质-皮层传递的相关性高于与第四层主要突触活动的相关性。考虑到迄今为止大多数侵入性动物研究尚未观察晚期突触活动，这些结果具有挑战性。鉴于我们的结果，有必要重新审视侵入性研究，并在神经血管耦合的建模中包括晚期突触活动。在这个新项目中，根据我们对大鼠的初步宏观EEG/DOI测量，我们建议使用广泛的显微技术来验证我们的总体假设：血流动力学反应不是由第四层的传入输入驱动的，而是由更浅层的晚期皮质-皮质传递驱动的。我们建议的关键特征是多模态方法，这将使我们能够在同一动物模型中从微观到宏观水平询问神经血管耦合，并将结果转化为人类功能神经成像。在目标1中，我们将在微观水平上确定单个SEP成分在血流动力学反应中的作用，解决我们的总体假设和神经科学中的几个悬而未决的问题：（1a）神经血管关系是线性的还是非线性的？（1b）血流动力学反应是从浅层还是中层开始的？（1c）浅表继发性或晚期突触活动与血流动力学反应的相关性更好吗？（1d）超极化会引起血管收缩吗？在目标2中，我们将把我们的微观发现与人类的宏观非侵入性结果联系起来。必要的步骤是：（2a）评估同一小动物模型中微观和宏观发现之间的对应关系。（2b）在清醒大鼠中验证神经血管耦合模型。（2c）评估基线血流量的影响。（2d）在EEG/DOI和MEG/DOI实验中验证人体被试的神经血管耦合模型。从临床角度来看，确定血流动力学反应是否由晚期皮质-皮质传递驱动，而不是由第四层的传入输入驱动，将对BOLD fMRI和DOI的临床作用产生深远影响。事实上，这种模型的开发和验证将允许扩展神经血管反应的使用，从功能定位到区域功能完整性的基本评估，参与网络处理和调节特征。

DESCRIPTION (provided by applicant): To increase the clinical utility of the functional imaging modalities fMRI and diffuse optical imaging (DOI), we need to determine the relationship between the hemodynamic changes they measure and the underlying neural activity that causes these changes. During our last grant cycle we used DOI in combination with EEG/MEG to study neurovascular coupling. The results of these measurements have provided new insight into the role of different synaptic activity components in the hemodynamic response revealing a higher correlation of the hemodynamic response to the late superficial cortico-cortical transmissions than to the principal synaptic activity in layer IV. These results are provocative considering that most invasive animal studies to date have not looked at the late synaptic activity. In light of our results, it is necessary to revisit the invasive studies and include the late synaptic activity in the modeling of the neurovascular coupling. In this new project, following our preliminary macroscopic EEG/DOI measurements in rats, we propose to use a broad range of microscopic techniques to validate our overall hypothesis that: The hemodynamic response is not driven by the afferent inputs in layer IV, but by the late cortico-cortical transmission in more superficial layers. The key feature of our proposal is the multimodal approach that will allow us to interrogate the neurovascular coupling from a microscopic to a macroscopic level in the same animal model and translate the results to human functional neuroimaging. In Aim 1 we will determine the role of the individual SEP components in the hemodynamic response at a microscopic level, addressing our overall hypothesis and several open questions in neuroscience: (1a) Is the neurovascular relationship linear or non-linear? (1b) Does the hemodynamic response start in superficial or middle layers? (1c) Does superficial secondary or late synaptic activity correlate better with the hemodynamic response? (1d) Does hyperpolarization cause vasoconstriction? In Aim 2 we will link our microscopic findings with the macroscopic noninvasive results in humans. The necessary steps are: (2a) Evaluate the correspondence between microscopic and macroscopic findings in the same small animal model. (2b) Validate the neurovascular coupling model in awake rats. (2c) Evaluate the effect of baseline blood flow. (2d) Validate the neurovascular coupling model in human subjects during EEG/DOI and MEG/DOI experiments. From a clinical perspective, determining whether the hemodynamic response is driven by late cortico- cortico transmission rather than by afferent inputs to layer IV would have a profound effect on the clinical role of BOLD fMRI and DOI. In fact the development and validation of such a model would allow expansion of the use of neurovascular responses from localization of function to fundamental assessment of regional functional integrity, involvement in network processing and character of modulation. PUBLIC HEALTH RELEVANCE: We will determine the relationship between electrical and vascular functional imaging signals during neuronal activity and their link with the underlying microscopic neurovascular physiology. This knowledge will benefit basic and clinical neuroscience applications of fMRI and DOI.