title: The autism puzzle: Diffuse but not pervasive neuroanatomical abnormalities in children with ASD.
abstract: Autism Spectrum Disorder (ASD) is a clinically diagnosed, heterogeneous, neurodevelopmental condition, whose underlying causes have yet to be fully determined. A variety of studies have investigated either cortical, subcortical, or cerebellar anatomy in ASD, but none have conducted a complete examination of all neuroanatomical parameters on a single, large cohort. The current study provides a comprehensive examination of brain development of children with ASD between the ages of 4 and 18 years who are carefully matched for age and sex with typically developing controls at a ratio of one-to-two. Two hundred and ten magnetic resonance images were examined from 138 Control (116 males and 22 females) and 72 participants with ASD (61 males and 11 females). Cortical segmentation into 78 brain-regions and 81,924 vertices was conducted with CIVET which facilitated a region-of-interest- (ROI-) and vertex-based analysis, respectively. Volumes for the cerebellum, hippocampus, striatum, pallidum, and thalamus and many associated subregions were derived using the MAGeT Brain algorithm. The study reveals cortical, subcortical and cerebellar differences between ASD and Control group participants. Diagnosis, diagnosis-by-age, and diagnosis-by-sex interaction effects were found to significantly impact total brain volume but not total surface area or mean cortical thickness of the ASD participants. Localized (vertex-based) analysis of cortical thickness revealed no significant group differences, even when age, age-range, and sex were used as covariates. Nonetheless, the region-based cortical thickness analysis did reveal regional changes in the left orbitofrontal cortex and left posterior cingulate gyrus, both of which showed reduced age-related cortical thinning in ASD. Our finding of region-based differences without significant vertex-based results likely indicates non-focal effects spanning the entirety of these regions. The hippocampi, thalamus, and globus pallidus, were smaller in volume relative to total cerebrum in the ASD participants. Various sub-structures showed an interaction of diagnosis-by-age, diagnosis-by-sex, and diagnosis-by-age-range, in the case where age was divided into childhood (age < 12) and adolescence (12 < age < 18). This is the most comprehensive imaging-based neuro-anatomical pediatric and adolescent ASD study to date. These data highlight the neurodevelopmental differences between typically developing children and those with ASD, and support aspects of the hypothesis of abnormal neuro-developmental trajectory of the brain in ASD.
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Sussman
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: R C
authors.initials: RC
authors.lastname: Leung
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: V M
authors.initials: VM
authors.lastname: Vogan
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Lee
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Trelle
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Lin
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: D B
authors.initials: DB
authors.lastname: Cassel
authors.affiliation: Cerebral Imaging Centre, Douglas Mental Health University Institute, Verdun, QC, Canada ; Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, QC, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Chakravarty
authors.affiliation: Mouse Imaging Centre (MICe), The Hospital for Sick Children, 25 Orde Street, Toronto, ON M5T 3H7, Canada ; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Lerch
authors.affiliation: Bloorview Research Institute, University of Toronto, 150 Kilgour Road, Toronto, ON M4G 1R8, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Anagnostou
authors.affiliation: Diagnostic Imaging Research, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000473:pathology*; D002531:Cerebellum / Q000254:growth & development* / Q000473:pathology; D002540:Cerebral Cortex / Q000254:growth & development* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005917:Globus Pallidus / Q000254:growth & development* / Q000473:pathology; D006803:Human Development / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D013788:Thalamus / Q000254:growth & development* / Q000473:pathology
keywords: ASD, Autism Spectrum Disorder; Autism Spectrum Disorder (ASD); CT, cortical thickness; CV, cortical volume; Cerebellar hippocampal and basal ganglia volume; Cortical anatomy; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; FDR, False Discovery Rate; GP, globus pallidus; Magnetic resonance imaging (MRI); Pediatric neuroanatomical development; SA, surface area; Stdv, standard deviation