While survival rates for premature infants have improved steadily over the last decade, the incidence of adverse neurodevelopmental outcomes has remained essentially unchanged. Approximately 50% of the half million very low birth-weight infants born each year in the United States will face motor, cognitive, and/or behavioral challenges. The principal neuropathology associated with prematurity occurs in the cerebral white matter (WM), with secondary impact on the developing cerebral cortex. The mortality rate in this cohort is very low, limiting the amount of pathological material available for study. Thus, methods for quantitative evaluation of cerebral WM in preterm infants are urgently required. Such methods could be used to define normal WM development, which would allow the monitoring of neonatal interventions aimed at optimizing cerebral development as well as identifying infants at risk for later cognitive impairment. MR diffusion measurements can provide information on WM microstructure and on neuronal fiber tracts. At present, it is not clear which parameters are the best indicators of white matter integrity or quality. Similarly, there is no consensus on the best means by which to identify or follow WM tracts. Currently, the diffusion tensor model is the most commonly used and is usually separately applied to individual voxels. White matter fiber bundles in the brain extend over many voxels and could be better modeled with extension of the diffusion tensor model to include local connectivity with neighboring voxels. Bayesian probability theory provides us with the tools for optimal model selection and parameter estimation that can better evaluate WM connectivity and provide a consistent probability theory basis for neuronal fiber tracts and their evaluation. The candidate's long-term goal is to develop diffusion MR imaging methods to provide an accurate evaluation of WM development and maturation using Bayesian probability theory. The central hypothesis is that Bayesian probability theory will provide a means for optimal parameter estimation that will provide accurate information on the status of WM connectivity. The objective in this application is to develop the software tools needed for Bayesian based analysis and to apply it initially to simulated data, followed by application to normal ex vivo baboon brain, followed by a study of normal human infants. The study will conclude with an evaluation of WM injury in ex vivo baboon brains with histological correlates. Bayesian probability theory has not been applied to the evaluation of WM development, and the candidate is able to compare human neonate results with normal and abnormal ex vivo baboon brains, which is a well-established model for human brain maturation.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Raju, Tonse N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Estep, Meredith E; Smyser, Christopher D; Anderson, Peter J et al. (2014) Diffusion tractography and neuromotor outcome in very preterm children with white matter abnormalities. Pediatr Res 76:86-92
Xu, Junqian; Shimony, Joshua S; Klawiter, Eric C et al. (2013) Improved in vivo diffusion tensor imaging of human cervical spinal cord. Neuroimage 67:64-76
Mac Donald, Christine; Johnson, Ann; Cooper, Dana et al. (2013) Cerebellar white matter abnormalities following primary blast injury in US military personnel. PLoS One 8:e55823
Ortinau, Cynthia; Beca, John; Lambeth, Jennifer et al. (2012) Regional alterations in cerebral growth exist preoperatively in infants with congenital heart disease. J Thorac Cardiovasc Surg 143:1264-70
Pizoli, Carolyn E; Shah, Manish N; Snyder, Abraham Z et al. (2011) Resting-state activity in development and maintenance of normal brain function. Proc Natl Acad Sci U S A 108:11638-43
Mac Donald, Christine L; Johnson, Ann M; Cooper, Dana et al. (2011) Detection of blast-related traumatic brain injury in U.S. military personnel. N Engl J Med 364:2091-100
Zhang, Dongyang; Snyder, Abraham Z; Shimony, Joshua S et al. (2010) Noninvasive functional and structural connectivity mapping of the human thalamocortical system. Cereb Cortex 20:1187-94
White, Desiree A; Connor, Lisa Tabor; Nardos, Binyam et al. (2010) Age-related decline in the microstructural integrity of white matter in children with early- and continuously-treated PKU: a DTI study of the corpus callosum. Mol Genet Metab 99 Suppl 1:S41-6
Lee, John J; Bretthorst, G Larry; Derdeyn, Colin P et al. (2010) Dynamic susceptibility contrast MRI with localized arterial input functions. Magn Reson Med 63:1305-14
Smyser, Christopher D; Inder, Terrie E; Shimony, Joshua S et al. (2010) Longitudinal analysis of neural network development in preterm infants. Cereb Cortex 20:2852-62

Showing the most recent 10 out of 16 publications