Mapping Early Brain Development in Autism

Department of Neurosciences, School of Medicine, University of California-San Diego, La Jolla, CA 92093, USA.
Neuron (Impact Factor: 15.05). 11/2007; 56(2):399-413. DOI: 10.1016/j.neuron.2007.10.016
Source: PubMed


Although the neurobiology of autism has been studied for more than two decades, the majority of these studies have examined brain structure 10, 20, or more years after the onset of clinical symptoms. The pathological biology that causes autism remains unknown, but its signature is likely to be most evident during the first years of life when clinical symptoms are emerging. This review highlights neurobiological findings during the first years of life and emphasizes early brain overgrowth as a key factor in the pathobiology of autism. We speculate that excess neuron numbers may be one possible cause of early brain overgrowth and produce defects in neural patterning and wiring, with exuberant local and short-distance cortical interactions impeding the function of large-scale, long-distance interactions between brain regions. Because large-scale networks underlie socio-emotional and communication functions, such alterations in brain architecture could relate to the early clinical manifestations of autism. As such, autism may additionally provide unique insight into genetic and developmental processes that shape early neural wiring patterns and make possible higher-order social, emotional, and communication functions.

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    • "Of particular interest is the right posterior superior temporal sulcus (pSTS), which is a central node in social information processing and is functionally disrupted in ASD[6]. On the other hand, the search for neuroanatomical abnormalities via non-diffusion-weighted, structural MRI (sMRI) has yielded less consistent findings, aside from a tendency towards early brain overgrowth during the first years of life13141516. The field has yet to identify reliable cortical neuroanatomical markers for ASD using sMRI171819. "
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    ABSTRACT: Individuals with autism spectrum disorder (ASD) have been characterized by altered cerebral cortical structures; however, the field has yet to identify consistent markers and prior studies have included mostly adolescents and adults. While there are multiple cortical morphological measures, including cortical thickness, surface area, cortical volume, and cortical gyrification, few single studies have examined all these measures. The current study analyzed all of the four measures and focused on pre-adolescent children with ASD. We employed the FreeSurfer pipeline to examine surface-based morphometry in 60 high-functioning boys with ASD (mean age = 8.35 years, range = 4–12 years) and 41 gender-, age-, and IQ-matched typically developing (TD) peers (mean age = 8.83 years), while testing for age-by-diagnosis interaction and between-group differences. During childhood and in specific regions, ASD participants exhibited a lack of normative age-related cortical thinning and volumetric reduction and an abnormal age-related increase in gyrification. Regarding surface area, ASD and TD exhibited statistically comparable age-related development during childhood. Across childhood, ASD relative to TD participants tended to have higher mean levels of gyrification in specific regions. Within ASD, those with higher Social Responsiveness Scale total raw scores tended to have greater age-related increase in gyrification in specific regions during childhood. ASD is characterized by cortical neuroanatomical abnormalities that are age-, measure-, statistical model-, and region-dependent. The current study is the first to examine the development of all four cortical measures in one of the largest pre-adolescent samples. Strikingly, Neurosynth-based quantitative reverse inference of the surviving clusters suggests that many of the regions identified above are related to social perception, language, self-referential, and action observation networks—those frequently found to be functionally altered in individuals with ASD. The comprehensive, multilevel analyses across a wide range of cortical measures help fill a knowledge gap and present a complex but rich picture of neuroanatomical developmental differences in children with ASD.
    Full-text · Article · Dec 2016 · Molecular Autism
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    • "Autism Spectrum Disorder (ASD) is a heritable disorder involving early brain maldevelopment (Courchesne et al, 2011a). The brain at young ages is abnormal in a myriad of ways including brain overgrowth with an anterior/frontal to posterior cortical gradient in the majority, but undergrowth in a minority, during the first years of life (Courchesne et al, 2007); this shift upward in brain size distribution is quantitative and not categorical. Brain weight at autopsy is also shifted upward with heavier than the normal mean for an estimated 80% of 2–16 year olds, but lighter for a minority (Redcay & Courchesne, 2005; Courchesne et al, 2011b). "
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    ABSTRACT: Genetic mechanisms underlying abnormal early neural develop- ment in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi-tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored rela- tionships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregu- lated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candi- date genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/ S and G2/M phase transition. Finally, analyses of the CHD8 subnet- work and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.
    Full-text · Article · Dec 2015 · Molecular Systems Biology
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    • "Early years of life including 2–7 years mark an important period for the formation of neural wiring patterns [Casey et al., 2005]. This period is critical for brain development and early intervention [Courchesne et al., 2007; Sowell and Bookheimer, 2012]. To date, there has been no analysis of WM based on parcellated tract or tract group for children with ASD of age 2–7 years. "
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    ABSTRACT: Atypical age-dependent changes of white matter (WM) microstructure play a central role in abnormal brain maturation of the children with autism spectrum disorder (ASD), but their early manifestations have not been systematically characterized. The entire brain core WM voxels were surveyed to detect differences in WM microstructural development between 31 children with ASD of 2-7 years and 19 age-matched children with typical development (TD), using measurements of fractional anisotropy (FA) and radial diffusivity (RD) from diffusion tensor imaging (DTI). The anatomical locations, distribution, and extent of the core WM voxels with atypical age-dependent changes in a specific tract or tract group were delineated and evaluated by integrating the skeletonized WM with a digital atlas. Exclusively, unidirectional FA increases and RD decreases in widespread WM tracts were revealed in children with ASD before 4 years, with bi-directional changes found for children with ASD of 2-7 years. Compared to progressive development that raised FA and lowered RD during 2-7 years in the TD group, flattened curves of WM maturation were found in multiple major WM tracts of all five tract groups, particularly associational and limbic tracts, in the ASD group with trend lines of ASD and TD crossed around 4 years. We found atypical age-dependent changes of FA and RD widely and heterogeneously distributed in WM tracts of children with ASD. The early higher WM microstructural integrity before 4 years reflects abnormal neural patterning, connectivity, and pruning that may contribute to aberrant behavioral and cognitive development in ASD. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2015 · Human Brain Mapping
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