A unifying theme emerging from our work is that in neuroimaging, as in life, the journey is often as important as the destination. 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. The scans are 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. Recent Results and Key Findings from Project 1 Mapping Developmental Trajectories of Brain and Behavior Prior work from our group has established age related increases in white matter volumes and inverted U shaped trajectories for cortical and subcortical gray matter structures with relatively late maturation of higher association areas such as superior temporal lobe and the prefrontal cortex (Ref 7). Recent findings show that cortical regions with simpler laminar architecture (i.e. allocortex), including most limbic areas, show less complex growth trajectories than 6-layered cortical regions (i.e. isocortex) (Ref 17). Publications in the past year have also explored the behavioral and policy implications of these findings (Ref 1, 18) and the relationship between typical adolescent brain changes and the emergence of psychopathology (Ref 11). For instance, in schizophrenia almost all of the reported gray matter anomalies are predicted from exaggerations of typical adolescent regressive changes. Recent Results and Key Findings from Project 1 Male/Female Differences in Brain Development Sexual dimorphism of the developing brain is especially pertinent for child psychiatry because nearly all neuropsychiatric disorders of childhood demonstrate striking male/female differences with respect to age of onset, prevalence, and symptom patterns. Our work indicates developmental trajectories generally peak earlier in females (Ref 7, 18). In order to assess the roles of the X and Y chromosomes on 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). In Klinefelter syndrome (XXY) regional cortical thickness differences are robust and consistent with observed cognitive/behavioral strengths and weaknesses. Dosage effects are seen across groups with total cerebral volume (and disproportionately cerebellar volumes) decreasing with each additional X chromosome. Recent Results and Key Findings from Project 1 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. Recent results indicate (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. Multivariate analyses indicate that 60% of cortical thickness variance is accounted for by a single genetic factor and that five distinct groups of brain measures are influenced by shared genetic and environmental factors (Ref 13, 14, 19, 20). 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. 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. We have also demonstrated the effects of the Val158Met catechol-O-methyltransferase polymorphism on cortical structure in children and adolescents (Ref 8). Impact: The Brain Imaging project has had a high impact relative to the resources allocated having generated over 200 papers and 10,000 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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