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 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. Publications Project 1 past year: Suggest that abnormal cortical development in schizophrenia may be modularized or constrained by the normal community structure of developmental modules of the human brain connectome (REF 1). Suggest a significant role for puberty in structural brain development (REF 3). Highlight the relevance of anatomical covariance within the cortex to vocabulary skills in typically developing youth, further elucidating the distributed nature of neural systems subserving word knowledge (REF 4). Highlight the importance of structural covariance in the prediction of individual differences in executive function skills in youth. Identifies neuroanatomic coupling as a biological substrate that may contribute to executive function and dysfunction in childhood (REF 5). Suggest that developmental mismatch in structural brain maturation is present in neurotypically developing individuals. Highlight the need for prospective studies combining anatomical and behavioral measures (REF 6). Key Findings and Recent Results 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 Project 2 past year: Provide direct evidence in humans about the critical spatiotemporal role played by appropriately timed pubertal sex steroids during normal brain development. (REF 2) Suggest an unexpected role for X-linked genes in shaping sexually dimorphic brain development, and an evolutionarily conserved influence of X-linked genes on both cortical and subcortical development in mammals. Integration of these data with existing genomic knowledge generates a set of novel, testable hypotheses regarding candidate mechanisms for each observed pattern of anatomical variation across XO, XX and XY groups (REF 7). Bring spatiotemporal understanding of subcortical development closer to that of the cortex--allowing evolutionary, basic, and clinical neuroscience to be conducted within a more comprehensive developmental framework by establishing the developmental dynamism, spatial heterochonicity, and sexual dimorphism of human subcortical maturation (REF 8). Key Findings and Recent Results 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 Project 3 past year: Demonstrated that the heritability of cortical thickness increases gradually throughout late childhood and adolescence, with sequential emergence of three large regions of high heritability in the temporal poles, the inferior parietal lobes, and the superior and dorsolateral frontal cortices (REF 9). 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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