Diffusion MRI of the developing cerebral cortical gray matter can be used to detect abnormalities in tissue microstructure associated with fetal ethanol exposure

Abstract

Fetal alcohol spectrum disorders (FASDs) comprise a wide range of neurological deficits that result from fetal exposure to ethanol (EtOH), and are the leading cause of environmentally related birth defects and mental retardation in the western world. One aspect of diagnostic and therapeutic intervention strategies that could substantially improve our ability to combat this significant problem would be to facilitate earlier detection of the disorders within individuals. Light microscopy-based investigations performed by several laboratories have previously shown that morphological development of neurons within the early-developing cerebral cortex is abnormal within the brains of animals exposed to EtOH during fetal development. We and others have recently demonstrated that diffusion MRI can be of utility for detecting abnormal cellular morphological development in the developing cerebral cortex. We therefore assessed whether diffusion tensor imaging (DTI) could be used to distinguish the developing cerebral cortices of ex vivo rat pup brains born from dams treated with EtOH (EtOH; 4.5 g/kg, 25%) or calorie-matched quantities of maltose/dextrin (M/D) throughout gestation. Water diffusion and tissue microstructure were investigated using DTI (fractional anisotropy, FA) and histology (anisotropy index, AI), respectively. Both FA and AI decreased with age, and were higher in the EtOH than the M/D group at postnatal ages (P)0, P3, and P6. Additionally, there was a significant correlation between FA and AI measurements. These findings provide evidence that disruptions in cerebral cortical development induced by EtOH exposure can be revealed by water diffusion anisotropy patterns, and that these disruptions are directly related to cerebral cortical differentiation.

Folding, But Not Surface Area Expansion, Is Associated with Cellular Morphological Maturation in the Fetal Cerebral Cortex

“…As shown previously, structural coherence over large ensembles of cell constituents can be quantified as a structure tensor, which is sensitive to the size scale of typical diffusion MRI (Budde and Frank, 2012;Budde et al, 2013;Khan et al, 2015). To quantify dispersion in axonal, dendritic, and radial glial cell process orientation distributions, 3D structure tensor calculations were performed (Khan et al, 2015).…”

“…Non-invasive magnetic resonance imaging (MRI) techniques can be used to characterize brain development in situ (i.e., without the need to section the brain) on both macroscopic and cellular-level scales (Thornton et al, 1997;Mori et al, 2001;McKinstry et al, 2002). Previously, it was shown that regional patterns in surface area expansion (Kroenke et al, 2007;Knutsen et al, 2013), folding (Smart and McSherry, 1986;van der Knaap et al, 1996;deIpolyi et al, 2005;Sawada et al, 2012;Knutsen et al, 2013), and water diffusion anisotropy (deIpolyi et al, 2005;Kroenke et al, 2007Kroenke et al, , 2009 can be found within the developing cerebral cortex.…”

“…Within cerebral cortical gray matter, water diffusion anisotropy can be interpreted in terms of the orientation distribution of axonal, dendritic, and glial cell processes (Bock et al, 2010;. Perturbed cellular morphological development has been identified through diffusion anisotropy measurements in animal studies (Bock et al, 2010;Dean et al, 2013;Leigland et al, 2013) and clinical populations (Dubois et al, 2008;Ball et al, 2013;Vinall et al, 2013) of individuals with neurological disorders that are characterized by macroscopically abnormal cerebral cortex at maturity. Similarities in regional patterns of microstructural and macroscopic characteristics of cerebral cortical development could provide evidence relating to the cellular mechanisms that influence cortical growth.…”

Radiological studies of fetal alcohol spectrum disorders in humans and animal models: An updated comprehensive review

“…There were variations in the local cortical thickness, suggesting unequal vulnerabilities to ethanol in different regions of the cerebral cortex [164]. Ex vivo DTI revealed higher FA in PAE animals in the cerebral cortex, with strongest effect in the superficial layers throughout age range from PD0-6, proposedly due to less complexity of axonal and dendritic organization [165].…”

“…In exact calculation, brain activation was more scattered and widespread. Higher FA in cerebral cortex, with strongest effect in the superficial layers [165] rsfMRI Chronic low dose (5% v/v), daily voluntarily…”