We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4 -21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8 -10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse ''movies'' reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism.H uman brain development is structurally and functionally a nonlinear process (1-3), and understanding normal brain maturation is essential for understanding neurodevelopmental disorders (4, 5). The heteromodal nature of cognitive brain development is evident from studies of neurocognitive performance (6, 7), functional imaging (functional MRI or positronemission tomography) (8-10), and electroencephalogram coherence studies (1, 2, 10). Prior imaging studies show regional nonlinear changes in gray matter (GM) density during childhood and adolescence with prepubertal increase followed by postpubertal loss (11)(12)(13)(14). The GM density on MRI is an indirect measure of a complex architecture of glia, vasculature, and neurons with dendritic and synaptic processes. Studies of GM maturation show a loss in cortical GM density over time (15,16), which temporally correlates with postmortem findings of increased synaptic pruning during adolescence and early adulthood (17-19). Here we present a study of cortical GM development in children and adolescents by using a brain-mapping technique and a prospectively studied sample of 13 healthy children (4-21 years old), who were scanned with MRI every 2 years for 8-10 years. Because the scans were obtained repeatedly on the same subjects over time, statistical extrapolation of points in between scans enabled construction of an animated time-lapse sequence (''movie'') of pediatric brain development. We hypothesized that GM development in childhood through early adulthood would be nonlinear as described before and would progress in a localized, region-specific manner coinciding with the functional maturation. We also predicted that the regions associated with more primary functions (e.g., primary motor cortex) would develop earlier compared with the regions that are involved with more complex and integrative tasks (e.g., temporal lobe).The result is a dynamic map of GM maturation in the pre-and postpubertal period. Our results, while highlighting the remarkable heterogeneity, show that the cortical GM development appears to f...
Pediatric neuroimaging studies 1-5 , up to now exclusively cross sectional, identify linear decreases in cortical gray matter and increases in white matter across ages 4 to 20. In this large-scale longitudinal pediatric neuroimaging study, we confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20.The subjects for this study were healthy boys and girls participating in an ongoing longitudinal pediatric brain-MRI project at the Child Psychiatry Branch at the National Institute of Mental Health. Subjects were recruited from the community as previously described, using phone screening, questionnaires mailed to parents and teachers and face-to-face physical and psychological testing; approximately one in six volunteers were accepted 5 . At least 1 scan was obtained from each of 145 healthy subjects (89 male). Of these, 65 had at least 2 scans, 30 had at least 3 scans, 2 had at least 4 scans and 1 had 5 scans, acquired at approximately two-year intervals. The age range was from 4.2 to 21.6 years. There were no significant sex differences for age, Tanner stage, ethnicity, socioeconomic status, height, weight or handedness.All subjects were scanned on the same GE 1.5 Tesla Signa scanner using the same three-dimensional, spoiled-gradient, recalled echo in the steady state (3D SPGR) imaging protocol, with an axial-slice thickness of 1.5 mm, a time-to-echo of 5 ms, a repetition time of 24 ms, flip angle of 45°, a 192 ( 256 acquisition matrix, 1 excitation and a field of view of 24 cm. A clinical neuroradiologist evaluated all scans; no gross abnormalities were reported.Volumes of white and cortical gray matter were quantitatively analyzed by combining a technique using an artificial neural network to classify tissues based on voxel intensity with non-linear registration to a template brain for which these tissue regions had been manually defined 7 . This technique supplemented MRI signal-intensity information with predetermined brain anatomy and provides lobar (frontal, parietal, temporal and occipital) parcellation of cortical gray-and white-matter volumes.We used previously described statistical analysis techniques that combine cross-sectional and longitudinal data 8 . These longitudinal methods are more sensitive to detecting individual growth patterns, even in the presence of large interindividual variation 9 . We assessed if there was significant change with age, if developmental curves differed by sex and/or region and whether the developmental curves were linear or quadratic.The volume of white matter increased linearly with age ( Fig. 1; Table 1), increasing less in females than in males. The net increase across ages 4 to 22 w...
Understanding the organization of the cerebral cortex remains a central focus of neuroscience. Cortical maps have relied almost exclusively on the examination of postmortem tissue to construct structural, architectonic maps. These maps have invariably distinguished between areas with fewer discernable layers, which have a less complex overall pattern of lamination and lack an internal granular layer, and those with more complex laminar architecture. The former includes several agranular limbic areas, and the latter includes the homotypical and granular areas of association and sensory cortex. Here, we relate these traditional maps to developmental data from noninvasive neuroimaging. Changes in cortical thickness were determined in vivo from 764 neuroanatomic magnetic resonance images acquired longitudinally from 375 typically developing children and young adults. We find differing levels of complexity of cortical growth across the cerebrum, which align closely with established architectonic maps. Cortical regions with simple laminar architecture, including most limbic areas, predominantly show simpler growth trajectories. These areas have clearly identified homologues in all mammalian brains and thus likely evolved in early mammals. In contrast, polysensory and high-order association areas of cortex, the most complex areas in terms of their laminar architecture, also have the most complex developmental trajectories. Some of these areas are unique to, or dramatically expanded in primates, lending an evolutionary significance to the findings. Furthermore, by mapping a key characteristic of these development trajectories (the age of attaining peak cortical thickness) we document the dynamic, heterochronous maturation of the cerebral cortex through time lapse sequences ("movies").
Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.
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