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

摘要： 脑性瘫痪（CP）是儿童期最常见的运动障碍，伴有其他认知功能障碍。 残疾，每1 000名儿童中有3名受到影响。由于子宫内或围产期损伤引起的 在发育中的脑中，CP导致白色病变，包括运动通路的损伤。 扩散MRI（例如扩散张量成像或DTI）可以帮助表征这些白色物质损伤， 以及治疗期间任何潜在的连通性改善。在过去的五年里，我们已经申请了 儿童慢性前列腺炎患者自体脐带血干细胞移植中高保真弥散MRI研究 治疗，并发展了对自体UCB干细胞的影响和益处的理解， 改善小儿CP患者的功能结果和大脑连接。具体来说，我们发现 相关脑网络的强有力证据表明：1）大脑连接障碍解释了运动 治疗前基线时CP儿童的认知异常，2）大脑连接增加 对UCB干细胞治疗期间的功能和行为改善有直接影响，3）脑 连接性的增加超出了典型的发育轨迹，与干细胞有直接的相关性。 剂量高于1.98 x 107个细胞/kg的潜在阈值，以及4）基线连接的严重程度 异常预测进一步下降的风险和细胞治疗的益处。还发现 脑连接性的增加可能与细胞治疗期间髓鞘形成的改善有关， 使用定量易感性绘图（QSM）进行额外的初步调查。在此基础上， 在此基础上，我们提出了这一更新的应用，以进一步发展高分辨率扩散MRI 和连通性成像方法来研究来自UCB的同种异体干细胞的积极作用 （储存在北卡罗来纳州脐带血银行），这两个可以达到必要的高剂量（相对于 有限的自体UCB干细胞），并应用于更多的CP患者（而不仅仅是那些 出生时保存的UCB）。具体而言，我们建议：1）实现前所未有的磁场均匀性， 我们最近在同步RF接收和Bo匀场技术方面的创新， 可能的空间分辨率和保真度，2）实现多波段多激发3D扩散MRI采集， 3）获得亚毫米空间分辨率、优化的SNR和高吞吐量; 高分辨率弥散MRI和脑连接体图，以及DTI引导的髓鞘敏感QSM 在儿童CP患者中，在治疗期间，沿着白色通路和整个脑连接体， 使用UCB衍生的同种异体干细胞的创新疗法。预计我们的持续和 协调一致的努力将大大推进我们对神经机制的理解， 基线时CP儿童的损伤以及干细胞治疗对连接的影响 最终提供令人信服的证据，以帮助计划最佳的治疗方案。

Abstract: Cerebral palsy (CP) is the most prevalent motor disorder of childhood with complications in other cognitive impairments, affecting 3 out of every 1,000 children. Largely due to in utero or perinatal injuries to the developing brain, CP results in white matter pathology including impairments to the motor pathway. Diffusion MRI (e.g. diffusion tensor imaging, or DTI) can help characterize these white matter impairments, as well as any potential connectivity improvement during treatment. Over the past five years, we have applied high-fidelity diffusion MRI in pediatric CP patients during autologous umbilical cord blood (UCB) stem cell therapies, and developed an understanding of the impact and benefit autologous UCB stem cells have on improving functional outcome and brain connectivity in pediatric CP patients. Specifically, we have found strong evidences in relevant brain networks that: 1) brain connectivity impairments account for the motor and cognitive abnormalities in children with CP at the pre-treatment baseline, 2) brain connectivity increases have a direct impact on functional and behavioral improvements during UCB stem cell therapy, 3) brain connectivity increases beyond that of typical development trajectory have a direct correlation with stem cell dosage above a potential threshold of 1.98 x 107 cells/kg, and 4) the severity of baseline connectivity abnormalities predicts the risk of further decline and the benefit of cell therapy. It was also found that the brain connectivity increase may be associated with improved myelination during cell therapy, through additional preliminary investigations using quantitative susceptibility mapping (QSM). Advancing from this solid foundation, we propose this renewal application to further develop ultrahigh resolution diffusion MRI and connectivity imaging methodologies to study the positive effect of allogenic stem cells derived from UCB (stored at the North Carolina Cord Blood Bank), which can both reach the necessary high dosage (as opposed to the limited autologous UCB stem cells) and be applied to more CP patients (rather than just the ones with UCB saved at birth). Specifically, we propose to: 1) achieve unprecedented magnetic field homogeneity based on our recent innovation on simultaneous RF reception and Bo shimming technology to enable the highest possible spatial resolution and fidelity, 2) achieve multi-band multi-shot 3D diffusion MRI acquisition with ultrahigh submillimeter spatial resolution, optimized SNR and high throughput, and 3) acquire and analyze ultrahigh resolution diffusion MRI and brain connectome maps, as well as DTI-guided myelin-sensitive QSM along white matter pathways and throughout the brain connectome, in pediatric CP patients during the course of innovative therapies using UCB-derived allogenic stem cells. It is expected that our continued and concerted efforts will greatly advance our understanding of the neural mechanisms on both connectivity impairments in children with CP at the baseline and on the impact of stem cell therapy on connectivity restorations, ultimately providing compelling evidence to help plan the best treatment options.