Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity

长期以来，我们一直有兴趣研究血流动力学反应功能(HRF)的时空演变，以此作为了解功能性充血在支持神经元活动中的作用的重要途径。确定HDR对局灶脑活动的空间和时间特征是一个非常相关的话题，因为它决定了功能神经成像技术在绘制激活区域图方面的准确性，建立了最终可实现的空间和时间分辨率，并影响了数据的解释。我们正在努力优化刺激参数，并在空间和时间上测量随后的HDR，长期目标是确定CBF控制的最终空间域及其相关的时间演变。我们认为，这项工作将需要极其短暂的刺激，在良好控制的条件下提供，以引发微小的、但可测量的血管事件，这可能是CBF对更复杂刺激的综合反应的基础。 在当前的综述周期中，我们重点研究了刺激持续时间对清醒的恒河猴HRF的时空特征的影响。为此，我们开发了一种简单而有效的驯化方案来调节和训练绒猴在数据采集过程中耐受身体束缚，并设计了一种基于头盔的头盔，它完全是非侵入性的，能够在不牺牲舒适性的情况下保持头部不动。在接受这样的训练后，绒猴在S1、S2和尾状核产生了健壮和可重复性的fMRI反应。我们能够可靠地检测到对S长刺激的大胆反应和CBV反应。我们观察到CBV-HRF的起始和峰值明显快于BOLD-HRF，表明动脉对CBV反应有显著贡献。通过改变刺激持续时间，我们观察到激活区的大小和BOLD-HRF峰值的快速增长和饱和，这共同表明功能性充血是一个涉及整个皮质区域的快速和综合的过程。 我们还一直在与我们的合作者合作，以一种在多个不同方向影响研究的方式来改进绒猴大脑的解剖和功能成像。与Jeff Duyn和Daniel Reich团队一起，我们一直在研究T2*的性质以及与脑组织结构和成分相关的相位差。我们已经能够确定白质中的R&8322；弛豫对相对于主野的纤维方向高度敏感。我们通过在两个相互垂直的脑位置进行体内多梯度回波实验，发现光辐射的松弛速率常数有近50%的变化，并将这种显著的R&各向异性归因于髓鞘高度有序和各向异性结构引起的局部亚体素敏感性效应，从而直接证明了这种方向依赖性。与David Leopold一起，我们一直在开发实验工具，以执行绒猴视觉皮质的功能磁共振成像。超过25%的绒猴大脑皮质表面专门用于视觉，到目前为止还没有对绒猴视觉皮质进行功能磁共振成像。推动在简洁的绒猴身上进行视觉刺激的功能磁共振成像，将使我们进入非常令人兴奋的途径，在动物需要主动关注任务的情况下研究神经血管耦合，并可能带来新的结果，这些结果将补充我们目前从被动体感刺激中获得的信息。我们还一直在帮助NIDA的Elliot Stein团队从强迫症(OCD)的绒猴模型中获得静息状态和功能磁共振数据。我们参与了史蒂夫·雅各布森和丹尼·赖克团队在我们实验室进行的EAE工作。以上都是正在进行的工作，其中一些手稿已经提交，但目前正在进行同行审查。

We have a long-standing interest in investigating the spatiotemporal evolution of the hemodynamic response function (HRF) as an important way to understand the role of functional hyperemia in supporting neuronal activity. The determination of both spatial and temporal characteristics of the HDR to focal brain activity is a topic of great relevance as it dictates the accuracy of functional neuroimaging techniques in mapping activation regions, establishes the ultimately achievable spatial and temporal resolution, and influences the interpretation of the data. We are working on optimizing stimulus parameters and measuring, in space and in time, the ensuing HDR, with the long-term goal of determining the ultimate spatial domain of CBF control and its associated temporal evolution. We believe such work will require extremely brief stimuli, delivered under well-controlled conditions, to elicit minute, yet measurable vascular events, which can presumably serve as the building blocks of the integrative CBF response to more complex stimuli. In the current review cycle, we focused on studying the influence of the stimulus duration on the spatiotemporal characteristics of the HRF in conscious, awake marmosets. For this, we developed a simple yet effective acclimatization protocol to condition and train the marmosets to tolerate physical restraint during the data acquisition, and we designed a helmet-based head restraint that is completely non-invasive and able to hold the head still without sacrificing comfort. After undergoing such training, the marmosets produced robust and reproducible fMRI responses in S1, S2, and caudate. We were able to reliably detect the BOLD and the CBV response to a single 333-μs-long stimulus. We observed that the CBV-HRF onsets and peaks significantly faster than the BOLD-HRF, indicating a significant arterial contribution to the CBV response. By varying the stimulus duration, we observed a quick growth and saturation of both the size of the regions of activation and the peak amplitude of the BOLD-HRFs, which collectively suggest that functional hyperemia is a fast and integrative process that involves the entire cortical region. We have also been working with our collaborators on improving both anatomical and functional imaging of the marmoset brain in a way to impact research in a number of different directions. With Jeff Duyn and Danny Reich groups, we have been investigating the nature of T2* and phase contrast as related to brain tissue structure and composition. We have been able to determine that R₂ relaxation in white matter is highly sensitive to the fiber orientation relative to the main field. We directly demonstrated this orientation dependence by performing in vivo multi-gradient-echo experiments in two orthogonal brain positions, uncovering a nearly 50% change in the R₂ relaxation rate constant of the optic radiations, and attributed this substantial R₂ anisotropy to local subvoxel susceptibility effects arising from the highly ordered and anisotropic structure of the myelin sheath. With David Leopold, weve been developing the experimental tools to perform fMRI of the marmoset visual cortex. More than 25% of the cortical surface of the marmoset brain is dedicated to vision, and there has been no fMRI of the marmoset visual cortex performed to date. Pushing to perform fMRI of visual stimulation in concisous marmosets puts us in the very exciting pathway of studying neurovascular coupling in conditions under which the animal needs to pay active attention to the task, and may bring in novel results that will complement the information we have been currently acquiring from passive somatosensory stimulation. We have also been helping the group of Elliot Stein at NIDA to obtain resting-state and fMRI data from a marmoset model of Obsessive-Compulsive Disorder (OCD). We have been involved with the EAE work performed in our lab by the groups of Steve Jacobson and Danny Reich. All of the above are works in progress, in which a few manuscripts have been submitted but are currently in peer review.