Developmental Neurology and Maternal Fetal Physiology

Terrie Inder, MD, is an associate professor of pediatrics and the director of the Washington University Neonatal Development Research (WUNDER) team. This is a large multidisciplinary team that provides clinical care, teaching and research to improve the outcomes for infants born at risk for disability. The team combines multidisciplinary research initiatives in pediatrics, neurology, radiology, obstetrics and psychology based on studies at the bedside of newborn infants in the neonatal and pediatric intensive care units at St. Louis Children’s Hospital. These studies include brain monitoring with electroencephalography for silent seizures, which are very common in sick babies, early treatment with caffeine in preterm infants to prevent cerebral palsy, treatment of high-risk pregnancies with pomegranate juice and studying natural stem-cell regeneration in the immature brain. All infants are followed into childhood to monitor their progress. Inder specializes in newborn medicine, neurology and radiology at the School of Medicine and uses imaging studies on brains of premature, at-risk infants to help predict developmental outcomes, in particular the risk of severe cognitive delays, psychomotor delays, cerebral palsy or hearing or visual impairments. Using sophisticated analysis of magnetic resonance imaging (MRI), Inder can determine abnormalities in the brains of preterm infants born at 30 weeks gestation or less and assist in guiding families as to the risk for future disability. The outcomes of the MRI scans can also inform the physicians about the impact of treatment in the neonatal intensive care unit on brain development.

Inder currently has a P30 Intellectual and Developmental Disabilities Research Center grant under review. David C. Van Essen, PhD, and David M. Holtzman, MD, are investigators with her on this application, which would provide significant increase in services related to these projects.

David C. Van Essen, PhD, is professor and head of the Department of Anatomy and Neurobiology. His laboratory uses physiological, anatomical and computational approaches to study the cerebral cortex. One major focus is on information processing in the primate visual cortex in monkeys and humans. Another involves developing and using computerized brain-mapping software to analyze cortical structure and function in primates and rodents. His neurophysiological studies focus on the mechanisms of form processing and pattern recognition in the visual cortex of the macaque monkey. His lab is particularly interested in the transformations in neuronal receptive field characteristics that occur at early and intermediate stages of the visual hierarchy. On the brain-mapping front, he has developed freely available software tools for surface-based analyses of the cerebral cortex and has used these to generate atlases for the human, monkey, rat and mouse cortex that can be visualized online at  http://sumsdb.wustl.edu:8081/sums/. His lab has developed probabilistic surface-based atlases that accurately convey commonalities as well as differences between individuals. He uses these approaches (i) to analyze left-right asymmetries in the cerebral cortex of normal human subjects; (ii) to reveal localized shape differences associated with specific neurological disorders; and (iii) to objectively evaluate a variety of proposed homologies between monkey and human cortical areas. In collaboration with Inder and others, VanEssen also studies human cortical development in premature as well as term-born infants. Their objectives are to better understand normal cortical maturation and to characterize cortical abnormalities that correlate with abnormal childhood development.

David M. Holtzman, MD, is the Andrew B. and Gretchen P. Jones Professor of Neurology and professor of developmental biology. He is also head of the Department of Neurology, associate director of the Alzheimer’s Disease Research Center and a member of the Hope Center for Neurological Disorders. The two major interests in his lab are understanding the basic mechanisms underlying acute and chronic cell dysfunction in the CNS, particularly as these mechanisms may relate to Alzheimer's disease (AD) and injury to the developing brain. For purposes of this grant, this description will detail the latter. Hypoxic-ischemic (H-I) injury to the neonatal brain is a frequent cause of encephalopathy, seizure and motor impairment (cerebral palsy). Holtzman’s lab is interested in further understanding molecular mechanisms of brain injury following neonatal H-I as well as developing potential treatments to prevent or limit brain injury. A previous study from his lab had shown that polyphenol-rich pomegranate juice can protect the neonatal mouse brain against H-I injury when given to mothers in drinking water. To test the hypothesis that this protection is due to the polyphenols in the juice, they studied the effects of the pomegranate polyphenol extract in the same neonatal H-I model. To further explore the role of a specific polyphenol in neonatal H-I, they also investigated the effects of resveratrol. They showed that pomegranate polyphenols and resveratrol reduce caspase-3 activation following neonatal H-I (West T, Atzeva M, Holtzman DM: Pomegranate Polyphenols and Resveratrol Protect the Neonatal Brain against Hypoxic-Ischemic Injury. Dev Neurosci 2007;29:363-372). These and other recent findings suggest that polyphenols should be further investigated as a potential treatment to decrease brain injury due to neonatal H-I. He has published a recent novel finding that certain agents such as pomegranate juice are particularly protective against H-I induced injury in neonatal animals and is in the process of exploring the cellular and molecular pathways that underlie these effects.

SUMMARY
This group of investigators studies molecular mechanisms of cell injury and death in rodent models of neonatal hypoxic-ischemic brain injury and ties this in with magnetic resonance imaging. This approach both improves understanding of the brain injury sustained by rodents and is confirmed in prematurely born human infants. This understanding has the potential to improve clinical practices and assist in reducing injury in these babies, ultimately reducing disabilities. It may also help identify those infants who are at high risk for developing cerebral palsy or mental retardation so they can be provided early access to therapy services. Junior faculty interested in maternal-fetal physiology and neurodevelopmental outcomes will have outstanding mentors in this area. Two chairs (one clinical and one basic) combine with a neonatologist to collaborate on a neurologic and scientific approach to this problem.