Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity

我们有一个长期的兴趣在调查的时空演变的血流动力学反应功能（HRF）的重要途径，以了解功能性充血的作用，支持神经元的活动。HDR到局灶性脑活动的空间和时间特性的确定是一个非常相关的主题，因为它决定了功能神经成像技术在映射激活区域中的准确性，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。我们相信，这项工作将需要在良好控制的条件下提供极其短暂的刺激，以引发微小但可测量的血管事件，这些事件可能可以作为对更复杂刺激的综合CBF反应的基石。 在目前的审查周期，我们专注于研究的影响，刺激持续时间的时空特性的HRF在有意识的，清醒的绒猴。 为此，我们开发了一种简单而有效的适应方案，以调节和训练绒猴在数据采集期间耐受身体约束，并且我们设计了一种基于头盔的头部保护装置，该装置完全无创，能够在不牺牲舒适度的情况下保持头部静止。经过这样的训练后，绒猴在S1、S2和尾状核产生了强大且可重复的fMRI反应。我们能够可靠地检测BOLD和CBV对单个333-s长刺激的反应。我们观察到CBV-HRF的发作和峰值明显快于BOLD-HRF，表明动脉对CBV响应的显著贡献。通过改变刺激持续时间，我们观察到的快速增长和饱和的区域的激活和BOLD-HRF的峰值振幅的大小，这共同表明，功能性充血是一个快速和整合的过程，涉及整个皮层区域。 我们还一直在与我们的合作者合作，改善绒猴大脑的解剖和功能成像，以影响许多不同方向的研究。与Jeff Duyn和Danny赖希小组一起，我们一直在研究与脑组织结构和组成相关的T2* 和相位对比的性质。 我们已经能够确定，R弛豫在白色的问题是高度敏感的纤维取向相对于主要领域。我们通过在两个正交的大脑位置进行体内多梯度回波实验，直接证明了这种方向依赖性，揭示了近50%的变化的R弛豫速率常数的光学辐射，并归因于这种实质性的R各向异性的局部亚体素磁化率的影响所产生的高度有序和各向异性结构的髓鞘。 我们和大卫·利奥波德一起开发了对绒猴视觉皮层进行功能性磁共振成像的实验工具。超过25%的绒猴大脑皮层表面是专门用于视觉，迄今为止还没有绒猴视觉皮层的功能磁共振成像。推动在简明绒猴中进行视觉刺激的fMRI使我们进入了一条非常令人兴奋的研究神经血管耦合的途径，在这种情况下，动物需要积极关注任务，并可能带来新的结果，补充我们目前从被动体感刺激中获得的信息。我们也一直在帮助NIDA的Elliot Stein小组从强迫症（OCD）的绒猴模型中获得静息状态和功能磁共振成像数据。我们参与了由Steve Jacobson和Danny赖希小组在我们实验室进行的EAE工作。上述所有工作都在进行中，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.