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 development by having them return for participation at approximately two-year intervals. During their visit to the NIH participants are assessed in three realms - Brain Imaging, Neuropsychology, and Genetics. (1) 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 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. (2) 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. (3) 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 blood drawn 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. Key Findings and Recent Results from Project 1 - Mapping Developmental Trajectories of Brain and Behavior in Health and Illness. Prior work from our group has shown that brain developmental is characterized by 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. Prior investigations have also elucidated deviations from typical developmental trajectories for several clinical populations. Several publications related to Project 1 in the past year utilized graph theory approaches to characterize the network properties of how different regions of the brain relate to each other (REFS 1, 2). Differences in brain anatomy and network properties were characterized for several clinical populations including Autism Spectrum Disorder (REFS 11), and Obsessive Compulsive Disorder (REF 5). Additional publications examined: (1) how cortical expansion relates to folding patterns on the surface of the brain (REF 9);(2) introduced a novel method of quantifying the corpus collosum the main connection between the left and right halves of the brain (REF 10);(3) reviewed the literature and methodology of early brain overgrowth in autism (REF 8);and (4) quantified improvement in social attribution skills in children with high functioning autism spectrum disorder (REF 3). Key Findings and Recent Results from Project 2 - 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 male/female differences with respect to age of onset, prevalence, and symptom patterns. Prior work from our lab characterizing male/female differences in typical pediatric brain development has been amongst the most cited in the field. Publications within the past year related to Project 2 characterized brain development differences in people with 49,XXXXY Syndrome (i.e. three extra X chromosomes) (REF 4) and used high resolution imaging to show similar brain changes in mice and humans with XO (missing an X chromosome) (REF 7). Key Findings and Recent Results from Project 3 - 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 300 twin pairs. Studies of specific genes and environmental factors allow exploration of the mechanisms and influences on brain development. 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. Prior work from our group established that: (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 percent 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. Publications in the past year related to Project 3 have characterized the impact on brain development of specific gene variants, specifically Autism Risk Gene MET Variation (REF 12), DUF1220-Domain Copy Number (REF 18), and Homeobox A1 (REF 24). Impact: The project has generated over 250 papers and 30,000 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 400 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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Raznahan, Armin; Shaw, Phillip W; Lerch, Jason P et al. (2014) Longitudinal four-dimensional mapping of subcortical anatomy in human development. Proc Natl Acad Sci U S A 111:1592-7
Goddings, Anne-Lise; Mills, Kathryn L; Clasen, Liv S et al. (2014) The influence of puberty on subcortical brain development. Neuroimage 88:242-51
Alexander-Bloch, Aaron F; Reiss, Philip T; Rapoport, Judith et al. (2014) Abnormal cortical growth in schizophrenia targets normative modules of synchronized development. Biol Psychiatry 76:438-46
Lee, Nancy Raitano; Wallace, Gregory L; Raznahan, Armin et al. (2014) Trail making test performance in youth varies as a function of anatomical coupling between the prefrontal cortex and distributed cortical regions. Front Psychol 5:496
Schmitt, J Eric; Neale, Michael C; Fassassi, Bilqis et al. (2014) The dynamic role of genetics on cortical patterning during childhood and adolescence. Proc Natl Acad Sci U S A 111:6774-9
Mills, Kathryn L; Goddings, Anne-Lise; Clasen, Liv S et al. (2014) The developmental mismatch in structural brain maturation during adolescence. Dev Neurosci 36:147-60
Wade, Benjamin Seavey Cutler; Stockman, Michael; McLaughlin, Michael Joseph et al. (2013) Improved corpus callosum area measurements by analysis of adjoining parasagittal slices. Psychiatry Res 211:221-5
Alexander-Bloch, Aaron; Giedd, Jay N; Bullmore, Ed (2013) Imaging structural co-variance between human brain regions. Nat Rev Neurosci 14:322-36
Lopez, Katherine C; Lalonde, Francois; Mattai, Anand et al. (2013) Quantitative morphology of the corpus callosum in obsessive-compulsive disorder. Psychiatry Res 212:1-6
Bal, Elgiz; Yerys, Benjamin E; Sokoloff, Jennifer L et al. (2013) Do Social Attribution Skills Improve with Age in Children with High Functioning Autism Spectrum Disorders? Res Autism Spectr Disord 7:9-16

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