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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD078561-01
Application #
8613915
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Freund, Lisa S
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$379,162
Indirect Cost
$161,026
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Fame, Ryann M; MacDonald, Jessica L; Dunwoodie, Sally L et al. (2016) Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity. J Neurosci 36:6403-19
Dai, Guangping; Das, Avilash; Hayashi, Emiko et al. (2016) Regional variation of white matter development in the cat brain revealed by ex vivo diffusion MR tractography. Int J Dev Neurosci 54:32-38
Wilkinson, Molly; Wang, Rongpin; van der Kouwe, Andre et al. (2016) White and gray matter fiber pathways in autism spectrum disorder revealed by ex vivo diffusion MR tractography. Brain Behav 6:e00483
Miyazaki, Yuta; Song, Jae W; Takahashi, Emi (2016) Asymmetry of Radial and Symmetry of Tangential Neuronal Migration Pathways in Developing Human Fetal Brains. Front Neuroanat 10:2
Charvet, Christine J; Hof, Patrick R; Raghanti, Mary Ann et al. (2016) Combining diffusion MR tractography with stereology highlights increased cross-cortical integration in primates. J Comp Neurol :
Cohen, Andrew H; Wang, Rongpin; Wilkinson, Molly et al. (2016) Development of human white matter fiber pathways: From newborn to adult ages. Int J Dev Neurosci 50:26-38
Fame, Ryann M; Dehay, Colette; Kennedy, Henry et al. (2016) Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex. Cereb Cortex :
Wilkinson, Molly; Kane, Tara; Wang, Rongpin et al. (2016) Migration Pathways of Thalamic Neurons and Development of Thalamocortical Connections in Humans Revealed by Diffusion MR Tractography. Cereb Cortex :
Wang, Rongpin; Dai, Guangping; Takahashi, Emi (2015) High Resolution MRI Reveals Detailed Layer Structures in Early Human Fetal Stages: In Vitro Study with Histologic Correlation. Front Neuroanat 9:150
Levman, Jacob; Takahashi, Emi (2015) Multivariate analyses applied to fetal, neonatal and pediatric MRI of neurodevelopmental disorders. Neuroimage Clin 9:532-44

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