Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity

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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.