There has been growing awareness of the fact that developmental disturbances of gyral folding can lead to developmental neurological disorders such as dyslexia, schizophrenia, and Rett syndrome, and a number of studies have shown subtle abnormal white matter development in such disorders suggesting altered brain connectivity. It is therefore essential to develop a clear picture of the normal patterns and timin of development of brain pathways, and to interpret the role of white matter pathways in order to more accurately diagnose subtle disorders of brain connectivity during development. In a previous stage of this project, funded as an R21, we optimized diffusion MR acquisition and tractography reconstruction parameters for the study of connectional development in the fetal/pediatric brain, and confirmed key tractography components against histology. We have reported the developmental orders of fiber pathways in relation with the regression of migration pathways in the cerebrum and cerebellum, and emerging hemispheric asymmetry of the pathways. We established in developing human fetal, newborn, and toddler brains that high-angular resolution magnetic resonance imaging / diffusion spectrum imaging (HARDI/DSI) with optimal parameters has the potential to define connectional anatomy of the developing cerebrum and cerebellum. The goal of this R01 is to further confirm the preliminary findings by increasing the number of brain areas compared with imaging and histology, as well as by increasing the numbers of specimens/subjects and developmental time-points, and to determine more precisely the time course of development of brain connectivity and morphometry in the human fetus, newborn, and toddler brains.
In Aim 1, we will create a comprehensive developmental atlas of human fetal, newborn, and toddler brain pathways and brain morphology ex vivo. Development of fiber pathways in the cortex and white matter of the cerebral and cerebellum will be reported. The spatio-temporal relationships between the formation/maturation of fiber pathways and gyral structures will also be examined.
In Aim 2, we will validate key findings in Aim 1 with histology.
In Aim 3, we will compare ex vivo tractography derived from Aims 1 to clinically normal in vivo tractography in postnatal newborn and toddler brains. Trajectories and volume of each pathway will be assessed by co-registering ex vivo and in vivo diffusion data as a group comparison. In addition, individual variations will also be assessed.

Public Health Relevance

The completion of the proposed research has potential for important clinical applications in perinatal brain injury or malformation as well as understanding of subtle abnormality of folding/connectivity that affect higher cognitive functions after birth PUBLIC HEALTH RELEVANCE: The primary goal of the proposed research is to precisely determine the normal time course of developing brain connectivity and morphometry in the human fetal, newborn, and toddler brains, with histological confirmation on key findings. Successful research results will become a basis of our understandings on developmental brain disorders and dysfunctions.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Freund, Lisa S
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Children's Hospital Boston
United States
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Song, Jae W; Mitchell, Paul D; Kolasinski, James et al. (2015) Asymmetry of White Matter Pathways in Developing Human Brains. Cereb Cortex 25:2883-93
Lodato, Simona; Molyneaux, Bradley J; Zuccaro, Emanuela et al. (2014) Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nat Neurosci 17:1046-54
Takahashi, Emi; Hayashi, Emiko; Schmahmann, Jeremy D et al. (2014) Development of cerebellar connectivity in human fetal brains revealed by high angular resolution diffusion tractography. Neuroimage 96:326-33