Accurate mapping of normal and abnormal patterns of brain development in fetuses and premature neonates is a key factor in early detection of developmental disorders as well as understanding how external factors can influence early brain growth. In our previous funding period we developed and applied novel fetal MRI motion correction and reconstruction techniques to produce the first 3D and 4D maps of normal human brain growth in-utero and to identify early cortical folding abnormalities in ventriculomegaly (VM), the most commonly identified fetal brain abnormality. These findings pose the question of whether measureable perturbations in tissue microstructure may be present along with these larger scale anatomical differences. Such changes could provide a clearer indicator of cortical damage than simply folding alone. In this renewal we therefore propose to develop new techniques that allow the general use diffusion MRI methods in un-sedated fetal studies. These methods, previously used in adults and children, can provide a unique new window into microstructural properties of fetal brain tissue. However, the technique has an important limitation for practical whole brain fetal imaging: it makes use of repeated acquisitions where subtle changes in MR signal provide the measure of interest. Fetal head motion within the scanner can perturb measurement location, orientation and signal level due to the changing relationship between the anatomy and scanner.
Our first aim i s to develop a novel unified framework that can make use of image acquisition physics for correction of both signal level and measurement geometry in diffusion weighted imaging. We will then develop complementary analysis tools that can account for the varying spatial and temporal sample density in the functional and diffusion data arising from fetal head motion. We will use these techniques to image a cross-section of normal fetuses and construct a normative spatio-temporal atlas of combined structural and micro-structural measurements in the fetal brain covering the critical age of first clinical MRI scan and the following period of cortical folding. Finally, we will use te same techniques to image and analyze data from a clinical group of fetuses with ventriculomegaly with the aim of detecting early micro-structural differences that are related to our previous cortical findings in fetuses exhibiting VM. The project as a whole has many wider applications beyond this common condition and would be a major step in understanding how functional specialization in the cortex relates to brain anatomy in both fetuses and premature neonates.

Public Health Relevance

Clinically, improved in-utero evaluation of the fetal brain is a key concern for obstetricians and pediatricians in managing complex pregnancies and there is also now an increasing public health awareness of the influence of the in-utero environment, in terms of factors such as stress and diet, on long-term health in later life. Diffusion imaging of te brain in childhood has revealed the presence of early markers of later cognitive and neuropsychological problems. The ability to map these same properties in-utero, promises to provide a rich set of very specific early markers that can be used to understand the impact of the in-utero environment on brain development and feasibly provide a route to the use of early neuro-protective agents and procedures early in childhood.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-V (82))
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Hirtz, Deborah G
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University of Washington
Schools of Medicine
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Fogtmann, Mads; Seshamani, Sharmishtaa; Kroenke, Christopher et al. (2014) A unified approach to diffusion direction sensitive slice registration and 3-D DTI reconstruction from moving fetal brain anatomy. IEEE Trans Med Imaging 33:272-89
Seshamani, Sharmishtaa; Cheng, Xi; Fogtmann, Mads et al. (2014) A method for handling intensity inhomogenieties in fMRI sequences of moving anatomy of the early developing brain. Med Image Anal 18:285-300
Studholme, Colin; Rousseau, Francois (2014) Quantifying and modelling tissue maturation in the living human fetal brain. Int J Dev Neurosci 32:3-10
Pontabry, J; Rousseau, F; Oubel, E et al. (2013) Probabilistic tractography using Q-ball imaging and particle filtering: application to adult and in-utero fetal brain studies. Med Image Anal 17:297-310
Rousseau, Francois; Oubel, Estanislao; Pontabry, Julien et al. (2013) BTK: an open-source toolkit for fetal brain MR image processing. Comput Methods Programs Biomed 109:65-73
Scott, Julia A; Habas, Piotr A; Rajagopalan, Vidya et al. (2013) Volumetric and surface-based 3D MRI analyses of fetal isolated mild ventriculomegaly: brain morphometry in ventriculomegaly. Brain Struct Funct 218:645-55
Thomason, Moriah E; Dassanayake, Maya T; Shen, Stephen et al. (2013) Cross-hemispheric functional connectivity in the human fetal brain. Sci Transl Med 5:173ra24
Rousseau, Francois; Gounot, Daniel; Studholme, Colin (2013) On high-resolution image estimation using low-resolution brain MRI. Conf Proc IEEE Eng Med Biol Soc 2013:1081-4
Habas, Piotr A; Scott, Julia A; Roosta, Ahmad et al. (2012) Early folding patterns and asymmetries of the normal human brain detected from in utero MRI. Cereb Cortex 22:13-25
Oubel, Estanislao; Koob, Meriam; Studholme, Colin et al. (2012) Reconstruction of scattered data in fetal diffusion MRI. Med Image Anal 16:28-37

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