Prenatal Cerebral Ischemia Disrupts MRI-Defined Cortical Microstructure Through Disturbances in Neuronal Arborization

Preterm ischemia disrupts MRI-defined maturation of the cerebral cortex by impairing the differentiation of cortical neurons in fetal lambs. Early Start for Better Brains Despite all of the recent advances in medical care for premature newborns, these infants still often experience complications. In particular, cognitive problems and developmental delays are common in this patient population and can be difficult to predict. Now, two sets of authors have obtained new data that approach this problem from different angles using diffusion tensor magnetic resonance imaging (MRI) in human infants and newborn lambs. Vinall and coauthors examined 95 premature newborn babies who were born at 24 to 32 weeks of gestation. The authors performed two sets of MRI scans on these infants: one scan was done about 2 months before their due dates and the other scan when they reached full term. The authors also tracked the infants’ growth parameters—weight, length, and head size—as well as data on other factors that could affect brain growth, including the presence of infections or other serious illnesses. A detailed analysis of the MRI scans showed that the development of normal brain structure correlated with postnatal growth (and presumably nutrition) even after accounting for any other illnesses the infants may have experienced early in life. Dean et al. took a different approach to studying premature brain development: they analyzed the brain structures of fetal lambs that had experienced ischemia in utero at a time that corresponded to about two-thirds of full gestation time. The lambs were analyzed both by MRI and by histological analysis of the brain at 1, 2, or 4 weeks after an in utero ischemic event, and these data were compared to those of age-matched animals that did not undergo ischemic episodes. Here, the authors also saw abnormalities in brain development by MRI and correlated them with histological and structural aberrations. The growth impairment seen in the animals’ brains by MRI corresponded to disturbances in the branching of neuronal dendrites and abnormal formation of synapse connections with other neurons. More studies are needed to understand how postnatal growth, nutrition, illness, and prenatal ischemia affect the developing brain to develop methods for preventing any resulting injury. In addition, long-term studies should help to determine how differences in brain anatomy and MRI data translate into developmental and cognitive outcomes. Children who survive preterm birth exhibit persistent unexplained disturbances in cerebral cortical growth with associated cognitive and learning disabilities. The mechanisms underlying these deficits remain elusive. We used ex vivo diffusion magnetic resonance imaging to demonstrate in a preterm large-animal model that cerebral ischemia impairs cortical growth and the normal maturational decline in cortical fractional anisotropy (FA). Analysis of pyramidal neurons revealed that cortical deficits were associated with impaired expansion of the dendritic arbor and reduced synaptic density. Together, these findings suggest a link between abnormal cortical FA and disturbances of neuronal morphological development. To experimentally investigate this possibility, we measured the orientation distribution of dendritic branches and observed that it corresponds with the theoretically predicted pattern of increased anisotropy within cases that exhibited elevated cortical FA after ischemia. We conclude that cortical growth impairments are associated with diffuse disturbances in the dendritic arbor and synapse formation of cortical neurons, which may underlie the cognitive and learning disabilities in survivors of preterm birth. Further, measurement of cortical FA may be useful for noninvasively detecting neurological disorders affecting cortical development.