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。我们优化了刺激参数，并在空间和时间上测量了随后的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，这样的工作需要非常短暂的刺激，在良好的控制条件下，引起分钟，但可测量的血管事件，这可能是作为更复杂的刺激的综合CBF反应的基石。 在当前的审查周期中，我们扩大了我们的意识清醒的绒猴模型的使用，以获得多感官功能数据，使用功能磁共振成像。遵循一个简单而有效的适应协议，条件和训练绒猴在数据采集过程中耐受身体约束，我们能够获得功能地图，而动物接受体感，听觉或视觉刺激。头部被限制与定制的头盔约束，是完全非侵入性的，能够保持头部仍然没有牺牲舒适度。将具有4个或8个元件线圈的RF线圈阵列放置在头盔内以获得具有最佳灵敏度的皮质响应。经过这样的训练后，绒猴在所有感官上都产生了强大且可重复的fMRI反应。从体感皮层，S1，S2，和尾状产生可靠的BOLD和CBV反应，一个单一的333 s长的刺激。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。在听觉皮层，我们能够检测到激活的听觉皮层（A1）的主要核心，以及在带和parabelt地区的音调和宽带噪声在0.5 - 22 kHz的范围内播放。 使用传统的块设计范例和扫描的绒猴大脑的周期为3.6秒，我们能够引起强大的双边反应的沉默与声音。当对比低频高频音，tonotopic地图，显示BOLD响应的空间特异性是足够的，以解决基本功能的皮质柱。在视觉皮层中，动物必须接受训练，以注意放置在磁体外部的监视器中呈现的图像。我们使用了一种正强化液体输送系统，每当动物持续注视屏幕时，我们就会奖励它们。通过眼动追踪系统监测和记录眼睛注视。我们训练动物主动将目光投向面部、身体和物体的图像，并使用植入式皮质电图（ECoG）阵列和功能磁共振成像（fMRI）测量清醒绒猴的枕颞叶皮层（OT）和丘脑（LGN和枕丘）的功能反应。这两种技术都获得了强大的刺激诱发反应。 使用ECoG，我们发现在高伽马范围（50-150 Hz）内的反应是选择性的刺激类别，特别是对面孔。在整个OT中，在离散的斑块中观察到强烈的类别特异性fMRI激活。结合ECoG与功能磁共振成像映射，我们确定了至少六个面选择性补丁，似乎占据两个平行的通路内腹侧流，类似于以前的研究结果在猕猴和人类。对于fMRI和ECoG反应，对结构化刺激与杂乱刺激的偏好沿着从后到前的梯度逐渐增加。结果表明，绒猴OT具有一组面部处理区域，其组织与先前在人类和猕猴中描述的相似，这表明面部处理网络的核心元素已经存在于生活在3500万年前的共同灵长类祖先中。 我们还继续与我们的合作者合作，改善绒猴大脑的解剖和功能成像，以影响多个不同方向的研究。与Jeff Duyn和Danny赖希团队一起，我们一直在研究髓磷脂作为解剖学功能磁共振成像对比源的作用。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 have optimized stimulus parameters and measured, 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 requires 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 expanded the use of our conscious awake marmoset model to obtain multi-sensorial functional data using fMRI. Following a simple yet effective acclimatization protocol to condition and train the marmosets to tolerate physical restraint during the data acquisition, we were able to obtain functional maps while the animal underwent somatosensory, auditory, or visual stimulation. The head was restrained with a custom-built helmet restraint that is completely non-invasive and able to hold the head still without sacrificing comfort. RF coils arrays with either 4 or 8 element coils were placed inside the helmets to obtain cortical responses with optimal sensitivity. After undergoing such training, the marmosets produced robust and reproducible fMRI responses in all senses. From somatosensory cortex, S1, S2, and caudate produced reliable BOLD and CBV responses to a single 333 s-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. In auditory cortex, we were able to detect activation in the main core of the auditory cortex (A1), as well as in the belt and parabelt areas to tones and broadband noise played in the 0.5 22 kHz range. Using a conventional block design paradigm and scanning the marmoset brain with a period of 3.6 s, we were able to elicit robust bilateral responses of silence versus sound. When contrasting low frequency to high-frequency tones, tonotopic maps were obtained, showing that the spatial specificity of the BOLD response is sufficient to resolve fundamental functional cortical columns. In visual cortex, the animals had to be trained to attend to images being presented in a monitor placed outside the magnet. We used a positive reinforcement liquid delivery system to reward the animals whenever they sustained their gaze to the screens. Eye gaze was monitored and recorded sing an eye-tracking system. We trained animals to actively direct their gaze to images of faces, bodies and objects, and measured functional responses in occipitotemporal cortex (OT) and thalamus (LGN and Pulvinar) of awake marmosets using both implanted electrocorticography (ECoG) arrays and fMRI. Robust stimulus-evoked responses were obtained with both techniques. Using ECoG, we found that responses within the high gamma range (50-150 Hz) were selective for stimulus categories, particularly for faces. Strong category-specific fMRI activation was observed in discrete patches throughout OT. Combining ECoG with fMRI mapping, we identified at least six face-selective patches that appear to occupy two parallel pathways within the ventral stream, similar to previous findings in macaques and humans. For both fMRI and ECoG responses, the preference for structured versus scrambled stimuli increased gradually along a posterior to anterior gradient. The results demonstrate that the marmoset OT has a set of face-processing regions that bear similar organization to those previously described in humans and macaques, suggesting that core elements of the face processing network were already present in the common anthropoid primate ancestor living 35 million years ago. We have also continued to work 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 role of myelin as a source of contrast for anatomical fMRI. 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.