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

项目总结/摘要 功能超声（fUS）成像是标准功能神经成像的一种相对较新的替代方法 方法（例如，fMRI，PET），其利用超快平面波脉冲方案来实现改善的信号- 噪声比和时空分辨率（1毫秒，100 µm）。然而，目前的fUS方法隔离了血流， 仅基于相对速度从组织运动中提取信号。这导致了对慢的排斥 微循环流动，一个关键的限制，考虑到最近的影响毛细血管的直接调节， 大脑和脊髓的血流该项目的主要目标是开发一种对微循环敏感的 通过利用循环微泡造影剂的非线性激发的fUS模态。颈髓 损伤（SCI）将被用作开发这种新方法和随后评估的模型， 它的效用。特别是，间歇性缺氧（IH），一种有前途的方法，用于诱导神经可塑性和 在慢性SCI中恢复健康的呼吸功能，将用于诱导局部激活和长期 膈运动神经元池中的易化。首先，对比增强功能超声（CE-fUS）成像 将利用在完整脊髓中进行的发射来优化发射参数（即，脉冲重复频率， 非线性脉冲方案）和后处理方法（即，运动校正、广义线性建模）。 将利用时空滤波技术来分离组织灌注和较大的微血管血流信号 用于独立分析，这在现有的fUS成像技术中是不可能的。CE-fUS成像将 应用于表征病变周围区域神经血管耦合的初始变性， 控制挫伤SCI，以及随后重复IH暴露诱导的基本微血管变化 在受伤的慢性阶段。成功完成这些研究将阐明基本的 微血管变化介导脊髓损伤后IH诱导的神经可塑性。此外，CE-fUS成像将 能够进一步研究血管系统不同水平的不同血液动力学反应模式， 将作为评估神经血管病理和发育疗法的基本工具 在今后的工作中。

Project Summary/Abstract 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.