Development of Contrast Enhanced Functional Ultrasound Imaging to Monitor Induced Neuroplasticity in Chronic Spinal Cord Injury

Functional ultrasound (fUS) imaging is a relatively new alternative to standard functional neuroimaging approaches (e.g., fMRI, PET) that utilizes ultrafast plane wave pulsing schemes to achieve improved signal-to-noise ratio and spatiotemporal resolution (1 msec, 100 µm). However, current fUS approaches isolate blood flow signal from tissue motion solely on the basis of relative velocity. This results in the exclusion of slow microcirculatory flows, a critical limitation given the recent implication of capillaries in the direct regulation of cerebral and spinal cord blood flow. The primary goal of this project is to develop a microcirculation-sensitive fUS modality by utilizing nonlinear excitation of circulating microbubble contrast agents. Cervical spinal cord injury (SCI) will be utilized as a model for the development of this new method and subsequent assessment of its utility. Specifically, intermittent hypoxia (IH), a promising method for the induction of neuroplasticity and restoration of healthy breathing function in chronic SCI, will be used to induce localized activation and long-term facilitation in the phrenic motor neuron pool. First, contrast-enhanced functional ultrasound (CE-fUS) imaging conducted in the intact spinal cord will be utilized to optimize transmit parameters (i.e., pulse repetition frequency, nonlinear pulsing schemes) and post-processing methods (i.e., motion correction, generalized linear modeling). Spatiotemporal filtering techniques will be utilized to isolate tissue perfusion and larger microvascular flow signals for independent analysis, heretofore impossible with existing fUS imaging techniques. CE-fUS imaging will then be applied to characterize the initial degeneration of neurovascular coupling in the perilesional region following controlled contusion SCI, and subsequent fundamental microvascular changes induced by repeated IH exposure during the chronic phase of injury. Successful completion of these studies will elucidate the fundamental microvascular changes that mediate IH-induced neuroplasticity following SCI. Moreover, CE-fUS imaging will enable further studies of differential hemodynamic response patterns at different levels of the vasculature, and will serve as a fundamental tool for the assessment of neurovascular pathologies and developmental therapies in future work.

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National Institutes of Health (NIH)