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

摘要 目前，还没有已知的治疗方法来限制和/或保护受损的脊髓免受继发性损伤。 脊髓损伤（SCI）患者的损伤。超过60%的SCI发生在颈椎，导致 呼吸功能障碍和四肢瘫痪，这是所有四肢瘫痪，严重影响病人的生活。 生活质量一种可以减少灰质组织损失的治疗策略可能具有显著的， 对颈椎脊髓损伤患者的功能结果有意义。本建议的总体目标是 检查和评估关键的血流参数，可以减少灰质损失，改善功能 在啮齿动物模型中的颈脊髓损伤后恢复。 急性创伤性脊髓损伤后，损伤中心的血流完全丧失， 是第二阶段损伤扩大的主要原因。改善病变的血流 中心和邻近组织长期以来被认为是减轻神经组织损失的理想选择。然而，在这方面， 直到最近，还没有可用于实时监测体内脊髓血流的技术。 最近，我们开发了一种新的活体超快超声成像技术， 以前所未有的空间和时间分辨率实时监测血流。这项新技术创造了 实时评估局部脊髓血流动力学变化的独特机会。我们小组最近的工作 已经表明超快超声可以1）在灰色和白色中检测灌注损失的不同区域 问题2）评估病变周围血流的质量，以及3）可视化开放的脊髓血管形态（下至 ~ 50微米）。令人兴奋的是，我们现在已经将这项工作扩展到包括非- 侵入性3D图像采集，使我们能够监测受伤脊髓内的血流变化 4D（3D成像与时间）。除了损伤中心的血流损失外，损伤区域通常 经历进行性血肿扩大，导致血肿扩大。我们假设减少 脊髓损伤后脑实质内出血的扩散和降低椎管内压力升高 可改善脊髓组织灌注并减轻继发性灰质损失， 成果。重要的是，由于已知脑血流量和脊髓反应存在性别差异， 脊髓损伤后，我们将检查血液动力学的变化，在男性和女性的颈部脊髓损伤。通过 应用这种创新的超声成像，我们的目标是（1）发现灰质的临界灌注阈值 危险组织，（2）监测脑实质内血肿的空间和时间发展，以及（3） 实时评估降低升高的椎管内压的治疗效果。总的来说，这些研究将 提供对脊髓微循环内关键血流动力学变化的直接见解， 以及限制脊髓损伤后继发性灰质损伤以改善功能恢复的有效方法。

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.