Project 1 - Early Brain Development in High-Risk Children

John H. Gilmore, PI

Research Studies

Schizophrenia is associated with subtle abnormalities of brain structure, including enlarged lateral ventricles, reduced cortical gray matter volumes, reduced hippocampal volumes, as well as abnormal diffusion properties in white matter. While it has been hypothesized that these brain abnormalities arise during early brain development, there has been little direct evidence to support this idea. In the first funding period of this Conte Center project, we developed the magnetic resonance image (MRI) acquisition and image analysis tools to study very early brain development children at high risk for schizophrenia - the offspring of women with schizophrenia. Our study to date indicates that compared to normal controls, the offspring of mothers with schizophrenia have reduced cortical gray matter on neonatal MRI, while the lateral ventricles are not enlarged compared to controls. There is a suggestion of altered white matter development as well. This is the first concrete evidence that genetic risk for schizophrenia is associated with altered gray matter development around the time of birth. The perinatal and early postnatal period is one of the critical phases in the development of cortical connectivity - a time of rapid synapse growth – one that is a focus of this Conte Center. In addition, we have developed a large cohort of normal controls. In this normal cohort, we have found robust growth of gray matter compared to white matter, as well as cortical region specific differences in gray matter growth in the neonatal period, consistent with human and non-human primate studies of synapse development.

Our original grant proposed to use 1.5 T MRI and focused only on the study of ventricle volume and intracranial volume. After the Center was funded, UNC obtained a 3T research scanner that has greatly increased our ability to study brain structure in this difficult to study age. In collaboration with the Neuroimaging Core, novel state-of-the-art image analysis tools were developed for tissue segmentation, brain parcellation, atlas building, brain mapping, and quantitative tractography of diffusion tensor images, which can now be applied to longitudinal MRIs from birth to two years and beyond.

In the second funding period, we propose to continue our study of early brain development in normal and high risk children, applying our novel image analysis methodologies to study gray and white matter development in an expanding cohort, and to study longitudinal brain developmental as we follow our cohort into mid childhood. Specific Aims include:

Specific Aim 1. Children at high risk for schizophrenia will have structural differences in gray and white development matter in the first two years of life compared to controls.

We will continue recruiting high risk offspring and will follow our expanding cohort of high risk and normal controls with developmental assessments and MRIs after birth and at ages 1 and 2 years. We hypothesize that children at high risk for schizophrenia will have reduced cortical gray matter volumes and less “mature” or organized cortical white matter on DTI.

Specific Aim 2. Children at high risk for schizophrenia will have abnormal gray and white matter development at ages 4 and 6 years.

Prior studies of children at high risk for schizophrenia found abnormalities of neurocognitive function in childhood. We hypothesize that children at high risk for schizophrenia will exhibit abnormal gray and white matter development at ages 4 and 6 years.

Specific Aim 3. Children at high risk for schizophrenia will have unique brain structural abnormalities compared to the offspring of women with bipolar illness.

The structural brain abnormalities observed in the offspring of women with schizophrenia may be related to high rates of pre- and perinatal complications, or medication taken during pregnancy. We will use the offspring of women with bipolar illness as a comparison group to control for these factors and hypothesize that reduced gray matter volumes will be unique to the schizophrenia group.

Specific Aim 4. Specific risk genes will regulate gray and white matter development in normal children.

Studies in adults indicate that polymorphisms of genes with a role in schizophrenia and development, such as BDNF, DISC1 and GAD1 are associated with alterations in brain structure. We are currently collecting DNA on all our subjects and propose to study whether these genes, influence early gray and white matter development in normal subjects. We will also explore the contributions of polymorphisms of NCAM1, NRG1, and COMT.