Early brain development in high risk children

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Despite the widespread belief that schizophrenia is a disorder of abnormal early brain development and numerous theories to that effect, there is little direct evidence to support this idea. This is in part due to the fact that until recently, the clinical study of human fetal and neonatal brain development was limited by a lack of appropriate tools with which to carry out such studies. Ultrasound and magnetic resonance imaging (MRI) are ideal techniques for the study of brain development in the human fetus, neonate, and child. Using ultrasound, it is possible to image the developing lateral cerebral ventricles in utero. Using high resolution MRI, it is possible to examine brain structure and its development from the neonatal period through childhood and into the period of risk for the onset of schizophrenia. The primary hypothesis of this research program is that abnormalities of brain structure and development, reflected in ventricle size and shape, along with abnormalities in total brain volume and white matter integrity in fetal and neonatal brain, are markers of abnormal development of thalamo-limbic-cortical circuits, associated abnormal GABA interneuron development, and ultimate susceptibility to schizophrenia. This will be the first study to use ultrasound to prospectively study prenatal and neonatal brain development in the offspring of women with schizophrenia. It will also prospectively study the development of fetuses with mild enlargement of the lateral ventricles, a structural abnormality that is hypothesized to represent an endophenotype of risk for schizophrenia. Subjects will have 2D ultrasounds in the second and third trimesters, and a 3D ultrasound and an MRI at 2 weeks after birth. Early childhood development will be followed prospectively at ages 1 and 2 years with the Mullen Scales of Early Learning and an assessment of working memory and attention, neurocognitive processes in which GABA interneurons play an important role. The identification of the timing of ventricle enlargement will provide a focus for studies of neurodevelopmental mechanisms that underlie schizophrenia. Understanding the causes of early abnormalities of ventricle structure will provide important information about genetic and environmental risk factors in schizophrenia. Finally, the study of lateral ventricle development will allow the early identification of children at high risk for schizophrenia and other neurodevelopmental disorders, ultimately making early intervention possible to prevent or mitigate this risk.