Hemodynamic basis for secondary cervical grey matter tissue loss after spinal cord injury

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Abstract Currently, there is no known treatment to limit and/or protect the injured spinal cord from secondary damage in patients with spinal cord injury (SCI). More than 60% of SCIs occur at the cervical spine, resulting in respiratory dysfunction, and quadriplegia, which is the paralysis of all four limbs, severely affecting patients' quality of life. A therapeutic strategy that can reduce grey matter tissue loss could have dramatic and meaningful functional outcomes for patients with cervical SCI. The overall objective of this proposal is to examine and evaluate critical blood flow parameters that can reduce grey matter loss for improved functional recovery after cervical SCI in a rodent model. Acutely after traumatic SCI, a complete loss of blood flow occurs at the injury center and is thought to be a major contributor of the injury expansion during the secondary phase. Improving blood flow to the lesion center and adjacent tissue has long been considered desirable to mitigate the loss of neural tissue. However, until recently, there were no techniques available to monitor spinal cord blood flow in vivo in real-time. Recently, we have developed a novel intravital ultrafast ultrasound imaging technique to visualize spinal blood flow in real-time with unprecedented spatial and temporal resolution. This new technology has created a unique opportunity to evaluate local spinal hemodynamic changes in real-time. Recent work from our group has shown that ultrafast ultrasound can 1) detect distinct areas of perfusion loss, in both the grey and white matter 2) evaluate quality of peri-lesional blood flow, and 3) visualize patent spinal vessel morphology (down to ~ 50 micrometer) in a rat thoracic SCI model. Excitingly, we have now extended this work to include non- invasive 3D image acquisitions, allowing us to monitor blood flow changes within the injured spinal cord in 4D (3D imaging with time). In addition to the loss of blood flow at the lesion center, injury areas often experience progressive hemorrhaging, resulting in an expanding hematoma. We hypothesize that reducing the propagation of intraparenchymal hemorrhage and reducing elevated intraspinal pressure after SCI can improve spinal tissue perfusion and mitigate secondary grey matter loss for improved functional outcomes. Importantly, because there are known sex differences in cerebral blood flow and response to spinal cord injury, we will examine the hemodynamic changes after cervical SCI in both males and females. By applying this innovative ultrasound imaging, we aim to (1) discover critical perfusion thresholds for grey matter tissue at risk, (2) monitor spatial and temporal development of the intraparenchymal hematoma, and (3) evaluate treatment effects of reducing raised intraspinal pressure in real-time. Overall, these studies will provide direct insights into the critical hemodynamic changes within the microcirculation of the spinal cord, as well as effective ways of limiting secondary grey matter damage for improved functional recovery after SCI.