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.

Public Health Relevance

Cerebral palsy (CP), the most prevalent motor disorder in childhood, is associated with lifelong disabilities. Finding effective therapies, rather than the largely supportive measures used in the current clinical practice, is of paramount importance. Recently, we have made noted progress in our understanding of functional improvement and brain connectivity increases during umbilical cord blood (UCB) stem cells therapy in pediatric CP patients. Taking advantage of our continued advance in UCB-derived allogenic stem cell therapy, we will further develop innovative diffusion MRI methodologies with greatly increased sensitivity and accuracy to investigate connectivity changes in relevant brain networks. It is thus anticipated that we will be able to gain greatly improved understanding on the neural mechanism of the initial brain impairment, and more importantly, on the neural mechanism of the potential brain repair and connectivity restoration in pediatric CP patients during innovative cell therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS075017-06A1
Application #
9445688
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Babcock, Debra J
Project Start
2012-02-15
Project End
2022-06-30
Budget Start
2017-09-30
Budget End
2018-06-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Duke University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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