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

描述（申请人提供）：最近出现的弥散张量成像（diffusion tensor imaging， DTI）提供了一种新的对比机制，通过水扩散特征来研究人脑白质的发育和完整性及其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对儿童大脑发育的研究，因为许多儿童的衰弱性疾病都源于白质异常和损伤。例如，脑瘫（CP）是由子宫内或围产期运动通路损伤引起的，是儿童时期最常见的运动障碍，每1,000个活产婴儿中就有2至3个受到影响。其明确的白质病理将受益于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可分辨性和随后的定量一致性来表征CP中复杂运动通路的损伤及其在治疗期间的恢复。造成这种不足的因素有很多，其中主要是实现高空间分辨率的技术限制，DTI脉冲序列固有的系统畸变会在张量估计中引入畸变和误差，以及由于大的扩散加权梯度而对全局和局部运动的灵敏度提高，这进一步使患者群体的实际效用复杂化。这些弊端在儿童等弱势群体中尤为突出。在本提案中，我们的目标是通过开发创新的采集解决方案来解决这些当前的限制，以实现急需的空间分辨率和保真度，并随后应用我们创新的DTI采集方法来更好地表征CP儿童的大脑连接，利用我们与长期和成功的临床项目的强大合作伙伴关系，使用创新的和有前途的干细胞治疗通过脐带血（UCB）输注。具体而言，我们建议：1)实现高空间分辨率，以更好地描绘复杂的白质纤维结构；2)实现高空间保真度，以改善张量估计和与神经解剖学的共同配准；3)实现大幅降低的运动敏感性，以提高在儿科患者群体中的实用性；4)获取和开发CP中的儿科脑连接图，以研究UCB干细胞治疗期间儿童运动通路和功能的损伤和恢复。我们预计，我们的创新采集方法将大大提高空间可分辨性和定量

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.