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/或保护受伤的脊髓免受继发性损伤。 脊髓损伤(SCI)患者的损伤。超过60%的脊髓损伤发生在颈椎，导致 呼吸功能障碍和四肢瘫痪，严重影响患者的 生活质量。一种可以减少灰质组织丢失的治疗策略可能会有戏剧性和 颈椎脊髓损伤患者的有意义的功能结果。这项提议的总体目标是 检查和评估可减少灰质丢失以改善功能的关键血流参数 啮齿动物模型颈脊髓损伤后的康复。 急性创伤性脊髓损伤后，损伤中心会发生完全的血流丧失，被认为是 在第二阶段是损伤扩大的主要因素。改善病变的血流量 长期以来，中心和邻近组织一直被认为是减轻神经组织丢失的理想选择。然而， 直到最近，还没有可用来实时监测活体脊髓血流的技术。 最近，我们开发了一种新的活体内超快超声成像技术来可视化脊柱 实时血流，具有前所未有的空间和时间分辨率。这项新技术创造了 这是一个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 研究表明，超快超声波可以检测出灰白色的不同区域的血流灌注损失。 物质2)评估病变周围血流的质量，以及3)显示脊髓血管未闭的形态(下至 ~50微米)建立大鼠胸段脊髓损伤模型。令人兴奋的是，我们现在已经将这项工作扩展到包括非 有创性的3D图像采集，使我们能够监测受伤脊髓内的血流变化 在4D(3D成像与时间)中。除了损伤中心的血流丧失外，损伤区域通常 进行性出血，导致血肿扩大。我们假设减少 脊髓损伤后实质内出血的扩散和降低升高的椎管内压力 可以改善脊髓组织的血流灌注，减轻继发性灰质丢失，从而改善功能 结果。重要的是，因为已知在脑血流和对脊髓的反应方面存在性别差异 对于脊髓损伤，我们将检测男性和女性颈椎脊髓损伤后的血流动力学变化。通过 应用这一创新的超声成像技术，我们的目标是：(1)发现灰质的临界灌注阈值 危险组织，(2)监测实质内血肿的空间和时间发展，以及(3) 实时评估降低椎管内升压的治疗效果。总体而言，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洞察，如 以及限制继发性灰质损伤以促进脊髓损伤后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.