A unifying theme emerging from our body of work is that in neuroimaging, as in life, the journey is often as important as the destination. In our studies, trajectories of brain morphometry, as opposed to snapshots in time, are more highly correlated with cognitive parameters, are better predictors of clinical outcome, and more robustly distinguish groups classified by genotype. To capture the path of development we follow people throughout their maturation by having them return for participation at approximately two-year intervals. During their visit to the NIH participants are assessed in three realms: (1) Brain Imaging, (2) Neuropsychology, and (3) Genetics.? ? Brain imaging. Magnetic resonance imaging (MRI) combines a powerful magnet, radio waves, and sophisticated computer technology to create exquisitely accurate pictures of the anatomy and physiology of the brain. It does this without the use of ionizing radiation making it safe for scans of people of all ages. In our project acquiring the scans takes between 15 and 40 minutes depending on the particular study. The scans are then processed through a series of ever improving image analysis tools developed by collaborators throughout the world. The output of the analytic tools allows us to compare the anatomy and physiology of brains between groups or within an individual over time. By morphing between images acquired at different ages we can create movies of brain development as can be seen at www.nimh.nih.gov/videos/press/prbrainmaturing.mpeg. ? ? Neuropsychology. For our studies of typical development we begin with an initial phone screening followed by questionnaires mailed to parents and teachers and then the in-person visit to the NIH. Once accepted into the study participants undergo a collection of psychological tests, including a standard IQ test. The specifics of the testing vary by diagnostic group but in general cover domains of language, executive, and social functions. ? ? Genetics. We request that participants provide a DNA sample via a blood draw (in which lymphoblasts can be immortalized to provide genetic testing for ongoing future analysis) or if they prefer not to have a blood draw via saliva. ? ? By combining data from these three realms we hope to gain insight into the dynamic interplay between brains, genes, and behavior in the developing brain. ? ? Male/Female Differences: Whether an organism is male or female is the single greatest discriminating morphometric factor in biology. Overall brain size in humans is robustly dimorphic with males having an approximately 10% greater volume, but the consensus on regionally specific differences is much less solid. Many of the findings or non-findings rest upon whether or how to account for the overall size difference in total cerebral volume when comparing the volumes of substructures. ? ? There is a particular paucity of data on sexual dimorphism of human brain anatomy between 4 and 18 years of age, a time of emerging differences in behavior and the sexually specific hormonal changes of adrenarche (the predominantly androgenic augmentation of adrenal cortex function occurring around age 8) and puberty. Sexual dimorphism of the developing brain is especially pertinent for child psychiatry, given that nearly all neuropsychiatric disorders of childhood demonstrate striking sex differences with respect to age of onset, prevalence, and symptom patterns. These findings indicate that the factors giving rise to sexual dimorphism also act as risk or protective agents for neurodevelopmental disorders. The observation that ages of increased risk of onset of disorders is different between disorders suggests that these effects may be specific to particular periods of development which are different in the two sexes. Understanding the development of sexual dimorphism may thus provide insights into the pathogenesis of neurodevelopmental disorders. ? ? The study of the etiology of sex differences in brain development is extremely complex due to the direct and indirect contributions of socialization and biological differences for males and females. Biological causes include sex differences in gonadal secretions that affect the brain and direct effects of the sex chromosome genes. The relative ease of manipulating hormone levels in animal models has led to a preponderance of literature and discussion about the effects of hormones on the brain. However, a growing body of literature suggests that differences in the neural expression of X and Y genes may have a larger role than previously appreciated. The X chromosome has many more genes than the Y chromosome. A species-specific complex process of X-inactivation occurs early in development in order to maintain dosage equivalence of most X chromosome genes. However, approximately 15% of X chromosome genes escape inactivation raising the question of whether dosage effects may contribute to sex differences. ? ? In order to assess the relative roles of these effects, we are studying naturally occurring populations with sex chromosome aneuploidies. We have recruited what we believe to be the worlds largest neuroimaging samples of people with XXY (N = 73), XYY (N = 32), XXYY (N = 32), XXXY (N = 6), XXXXY (N = 16), and XXX (N = 37).? ? Genetic and Environmental Influences on Brain Development: By comparing how alike identical twins (monozygotic) are to how alike fraternal twins (dizygotic) are we can begin to quantify the extent to which differences are due to genetic or environmental factors. Current sample size from the ongoing longitudinal study is approximately 200 twin pairs. Consistent themes are: (1) heritability is high and shared environmental effects low for most brain morphometric measures; (2) the cerebellum has a distinct heritability profile; (3) genetic and environmental factors contribute to the development of the cortex in a regional and age specific manner; and (4) shared genetic effects account for more of the variance than structure specific effects. Understanding influences on trajectories of brain development may shed light on the emergence of psychopathology during childhood and adolescence and ultimately may guide therapeutic interventions.? ? Another approach we are using to discern influences on brain development is to examine the effects of genetic variation. Just as groups can be classified by diagnosis or as male or female so to can they be classified according to their genetic makeup. A recent finding from our group indicates that the ApoE e4 allele, a significant risk factor for Alzheimers disease, affects cortical thickness in pediatric subjects in a pattern similar to that reported for geriatric subjects although the pediatric subjects do not have any cognitive deficits. This suggests that brain effects of susceptibility genes may be detectable long before the onset of symptomatology.? ? Impact: The Brain Imaging project has had a high impact relative to the resources allocated having generated over 200 papers and 8,000 citations since its inception in 1989. Results of the studies, particularly regarding adolescent brain development, have generated wide spread public interest and discussion affecting social, educational, and judicial realms. The findings have helped spawn other research initiatives, both nationally and internationally, to replicate and extend the findings. Data from the typically developing children and adolescents have been widely used as a comparison group for clinical populations. Collaborative studies have been published with over 300 different investigators representing over 50 universities. The long term nature of the study, the emphasis on typical development, and extensive data sharing/collaboration make the Brain Imaging projects well-suited for the Intramural program.
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