Longitudinal Magnetic Resonance Imaging Study of Cortical Development through Early Childhood in Autism

Abstract

Cross-sectional magnetic resonance imaging (MRI) studies have long hypothesized that the brain in children with autism undergoes an abnormal growth trajectory that includes a period of early overgrowth; however, this has never been confirmed by a longitudinal study. We performed the first longitudinal study of brain growth in toddlers at the time symptoms of autism are becoming clinically apparent using structural MRI scans at multiple time points beginning at 1.5 years up to 5 years of age. We collected 193 scans on 41 toddlers who received a confirmed diagnosis of autistic disorder at ϳ48 months of age and 44 typically developing controls. By 2.5 years of age, both cerebral gray and white matter were significantly enlarged in toddlers with autistic disorder, with the most severe enlargement occurring in frontal, temporal, and cingulate cortices. In the longitudinal analyses, which we accounted for age and gender effect, we found that all regions (cerebral gray, cerebral white, frontal gray, temporal gray, cingulate gray, and parietal gray) except occipital gray developed at an abnormal growth rate in toddlers with autistic disorder that was mainly characterized by a quadratic age effect. Females with autistic disorder displayed a more pronounced abnormal growth profile in more brain regions than males with the disorder. Given that overgrowth clearly begins before 2 years of age, future longitudinal studies would benefit from inclusion of even younger populations as well as further characterization of genetic and other biomarkers to determine the underlying neuropathological processes causing the onset of autistic symptoms.

Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders

“…Very little is known about the neuropathology of autism in females. There is some preliminary evidence suggesting that girls have similar (23) and possibly even more pronounced volumetric differences than boys (13,24,25). However, sample sizes in these studies are quite small, with fewer than 10 girls with autism in each study.…”

“…Studies using retrospective head circumference measurements as a proxy for brain size suggest that whereas children with autism are born with normal or slightly smaller brain size, the trajectory of growth accelerates during the first year of life (8)(9)(10). Several MRI studies of very young children with autism report a 5-10% abnormal enlargement in total brain volume that persists into early childhood (11)(12)(13).…”

Effects of age and symptomatology on cortical thickness in autism spectrum disorders

“…Across these studies, grey matter volumes within frontal and temporal lobes were significantly increased in children and adolescents with ASD compared to typically developing individuals (Bloss & Courchesne, 2007;Carper, Moses, Tigue, & Courchesne, 2002;Courchesne, Campbell, & Solso, 2011;Hazlett, Poe, Gerig, Smith, & Piven, 2006;Kates et al, 2004;Palmen et al, 2005;Schumann et al, 2010). However, volumetric measurements of lobular regions do not provide spatially localized information on grey matter abnormalities.…”

Autism Spectrum Disorder

“…Longitudinal MRI studies indicate that altered grey and white matter development in early childhood ASD localises prominently to frontal and temporal cortical regions (6). Genetic risk loci for ASD often localise to genes involved in regulating synapse structure (38).…”

“…Socio-emotional processing structures include ventral (i.e., amygdala, orbito-frontal cortex) and dorsal (i.e., anterior/posterior cingulate cortex, precuneus) limbic structures within frontal and temporal lobes, which are linked by long-range white matter tracts facilitating broad network synchronisation (3). Post-mortem and magnetic resonance imaging (MRI) findings in ASD include: altered expression of genes involved in regulating synapse structure in frontal and temporal cortex (4), reduced functional connectivity between limbic regions during socio-emotional performance (5), abnormal frontal and temporal white matter growth (6), and altered axonal density within anterior cingulate white matter (7), which collectively implicate the presence of disrupted connectivity within the limbic network in the disorder. Further examination of the microstructural properties of impaired limbic connectivity in ASD is central to gaining insight into the biology of characteristic socio-emotional deficits in this disorder.…”