Fetal exposure to alcohol leads to a wide range of neurological deficits collectively termed fetal alcohol spectrum disorders (FASD). The CDC estimates that FASD currently affects as many as 4.5 out of every 1000 births within the United States. Existing intervention strategies can improve the quality of life in affected individuals, provided they are initiated at the earliest age possible. Unfortunately, early FASD diagnosis is difficult, partly because behavioral manifestations of the disorder are not apparent until childhood. We propose to develop a magnetic resonance imaging (MRI)-based strategy to detect cellular-level morphological alterations in the developing cerebral cortex. Nonhuman primate research subjects will be bred after being trained to drink 1.5 g/kg/day of ethanol, or an isocaloric amount of maltose/dextrin solution. Animals will continue to drink throughout the first 60 days of pregnancy, after which access to ethanol will be terminated. Fetal brain T2-weighted and diffusion tensor imaging (DTI) data will be acquired on 3 groups of ethanol or maltose/dextrin animals: group 1 will be scanned on gestational day (G)85, group 2 on G110, and group 3 on G135. Immediately after MRI, fetuses will be delivered by cesarian section and brains will be prepared for histological processing.
The first aim for this experiment is to characterize the effects of early ethanol exposure on cerebral cortical thickness, surface area, and water diffusion anisotropy over the period ranging from G85 to G135.
The second aim i s to validate the cortical thickness effects of ethanol exposure using unbiased stereological techniques, and to characterize the biological source of the neuroimaging observations. The latter will be accomplished by determining cerebral cortical cell numbers, measuring the volume fraction of the neuropil, and quantifying morphological complexity of cortical neuronal axonal and dendritic arbors. This work will provide an objective strategy for characterizing the effects o early ethanol exposure on subsequent development of the cerebral cortex, which will facilitate earlier detection of FASD that is currently achievable.
Fetal exposure to alcohol results in the leading cause of environmentally related birth defects and mental retardation in the western world, and incurs such broad-reaching economic consequences that even prevention strategies deemed to be expensive (e.g. up to $850,000 per child) are deemed cost effective. A major obstacle to therapeutic intervention strategies for combating this neurodevelopmental disorder is the current inability to make a conclusive diagnosis until childhood. The objective of these experiments is to develop fetal MRI strategies for characterizing the biological effects associated with the development of subsequent behavioral impairments.
|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|
|Leigland, Lindsey A; Budde, Matthew D; Cornea, Anda et al. (2013) Diffusion MRI of the developing cerebral cortical gray matter can be used to detect abnormalities in tissue microstructure associated with fetal ethanol exposure. Neuroimage 83:1081-7|