High Fidelity Diffusion MRI for Children with Cerebral Palsy in Stem Cell Therapy

描述(申请人提供)：最近出现的扩散张量成像(DTI)提供了一种新的对比机制，通过水的扩散特性来研究人脑中白质的发育和完整性，以及它们对神经元功能的影响。鉴于其独特的敏感性，DTI最有价值和最合适的应用之一是研究儿童大脑发育，因为儿童中许多衰弱的疾病都是由白质异常和损伤引起的。例如，脑瘫(CP)是儿童时期最常见的运动障碍，每1000名活产儿中就有2至3人受到影响，它是由宫内或围产期运动通路损伤引起的。其明确的白色MattR病理将受益于DTI提供的独家白质表征。然而，目前的DTI实践缺乏足够的空间分辨率和随后的定量一致性来表征CP复杂运动通路的损害及其在治疗过程中的恢复。造成这一不足的因素很多，其中最主要的是在实现高空间分辨率方面的技术限制，DTI脉冲序列固有的系统性失真，这在张量估计中引入了失真和误差，以及由于大的扩散加权梯度而对全局和局部运动的高度敏感性，这进一步复杂化了在患者群体中的实际应用。这些缺点加剧，特别是在儿童等弱势群体中。在这份提案中，我们旨在通过开发创新的采集解决方案来解决这些当前的限制，以实现亟需的空间分辨率和保真度，并随后应用我们的创新DTI采集方法来更好地表征脑瘫儿童的脑连接，利用我们与长期成功的临床计划的强大合作伙伴关系，使用创新的、有希望的脐带血干细胞疗法。具体地说，我们建议：1)达到更好地描绘复杂白质纤维结构所需的高空间分辨率，2)达到高空间保真度，以改进张量估计和与神经解剖学的联合配准，3)大幅降低运动敏感度，以提高儿科患者群体的实用性，4)获取和开发CP中的儿科脑连接图，以研究在脐带血干细胞治疗期间儿童运动通路和功能的损害和恢复。我们预计，我们的创新采集方法将大大提高空间分辨率和量化 DTI措施的一致性，这可以提高我们对干细胞治疗前景的理解，并帮助设计儿童CP的最佳治疗方案。我们的新方法也有可能在基础和临床神经科学中得到更广泛的应用。 公共卫生相关性：扩散张量成像(DTI)对水的扩散特征敏感，为研究人员和临床医生提供了一个研究白质微观结构、发育和病理的新维度。然而，生成的大脑连接图往往缺乏足够的空间分辨率和随后的定量一致性，导致对脑白质变化的评估不足，对诊断大脑疾病和研究潜在疾病机制的临床意义指数较少。我们在这里提出了一种综合的DTI获取方法，解决了空间分辨率、空间保真度和运动敏感度方面的三个紧迫限制，这些限制阻碍了我们对大脑发育的研究。此外，我们将在高分辨率DTI中应用新的采集方法来绘制脑性瘫痪(CP)儿童的复杂脑连接图，利用我们正在进行的努力，通过脐带血(UCB)输注在CP儿童中使用创新和有前途的干细胞疗法。我们期待我们的项目将提供一个强大的技术基础，以更好地描述CP复杂运动通路中的连通性损害，并评估它们在干细胞治疗期间的恢复。DTI的空间分辨率大大提高，也将在翻译神经科学中得到更广泛的应用。

DESCRIPTION (provided by applicant): The recent emergence of diffusion tensor imaging (DTI) provides a new contrast mechanism through water diffusion characteristics to investigate the white matter development and integrity in the human brain, and their impact on neuronal functions. Given its unique sensitivity, one of the most valuable and fitting applications of DTI i the investigation of developing brains in children, as many debilitating diseases in children are originated from white matter abnormalities and injuries. For example, Cerebral Palsy (CP), which results from in utero or perinatal injuries to motor pathways, is the most prevalent motor disorder of childhood, affecting 2 to 3 out of every 1,000 live births. Its well-defined white mattr pathology would benefit from the exclusive white matter characterization provided by DTI. However, the current DTI practice lacks sufficient spatial resolvability and subsequent quantitative consistency to characterize the impairment of the complex motor pathway in CP and its recovery during treatment. There are many contributing factors to this inadequacy, chief among them are the technical limitations in achieving high spatial resolution, the systematic distortions inherent in the DTI pulse sequences that introduce distortions and errors in tensor estimation, and the heightened sensitivity to global and local motions due to large diffusion weighting gradients that further complicate the practical utility in patient populations. These drawbacks are exacerbated especially in vulnerable populations such as children. In this proposal, we aim to address these current limitations by developing innovative acquisition solutions to achieve the much needed spatial resolution and fidelity, and to subsequently apply our innovative DTI acquisition methodology to better characterize the brain connectivity in children with CP, leveraging our strong partnership with a long-standing and successful clinical program using an innovative and promising stem cell therapy through umbilical cord blood (UCB) infusion. Specifically, we propose to: 1) achieve high spatial resolution necessary to better delineate complex white matter fiber structure, 2) achieve high spatial fidelity to improve tensor estimation and co-registration with neuroanatomy, 3) achieve greatly reduced motion sensitivity to improve practical utility in pediatric patient populations, 4) acquire and develop pediatric brain connectivity maps in CP to investigate the impairment and recovery of motor pathway and functions in children during UCB stem cell therapy. We anticipate that our innovative acquisition methodology will greatly increase the spatial resolvability and quantitative consistency of DTI measures, which can improve our understanding on the promising effects of stem cell therapy and help design the best treatment plan for children with CP. It is also likely that our new methodology will find broader application in basic and clinical neurosciences at large. PUBLIC HEALTH RELEVANCE: Sensitive to water diffusion characteristics, diffusion tensor imaging (DTI) provides researchers and clinicians a new dimension to study white matter microstructure, development and pathology. However, the resultant maps on brain connectivity often lacks sufficient spatial resolvability and subsequent quantitative consistency, leading to inadequate assessment of white matter changes and less clinically meaningful indices to diagnose brain disorders and investigate underlying disease mechanisms. We propose here an integrated DTI acquisition methodology that addresses three pressing limitations in spatial resolution, spatial fidelity, and motion sensitivity that hamper our investigation in developing brains. Further, we will apply the new acquisition methodology in high-resolution DTI to map the complex brain connectivity in children with Cerebral Palsy (CP), taking advantage of our ongoing effort using an innovative and promising stem cell therapy through umbilical cord blood (UCB) infusion in children with CP. We anticipate that our project will provide a robust technical foundation to better characterize the connectivity impairment in complex motor pathways in CP, and assess their recovery during stem cell therapy. The greatly improved spatial resolvability for DTI will also find broader applicability in translational neuroscience.