Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity

长期以来，我们一直对研究血流动力学反应功能（HRF）的时空演变感兴趣，这是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对局灶性大脑活动的空间和时间特征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绘制激活区域时的准确性，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，其长期目标是确定CBF控制的最终空间域及其相关的时间演变。我们认为，这样的工作需要极短的刺激，在良好的控制条件下传递，以引起微小的，但可测量的血管事件，这可能是作为对更复杂刺激的综合CBF反应的基石。

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.