Autism spectrum disorder (ASD) is diagnosed in females less often than males by a factor of 1 to 4. Emerging behavioral accounts suggest that females are rated to be less severely autistic than males on several measures of early social development. Remarkably, to date, there have been no systematic attempts to characterize potential brain structural differences underlying the distinct behavioral profiles observed in females and males with ASD. Such work is critical for understanding the etiology of this heterogeneous disorder, as well as for understanding why the prevalence is low in females.
To characterize and compare brain structure in girls and boys with ASD.
Behavioral and structural MRI data from 25 7-13y old girls with ASD (mean age: 10.3y, mean IQ: 103), and 25 IQ-matched boys with ASD (mean age: 10.3y, mean IQ: 102) was obtained from Autism Brain Imaging Data Exchange (ABIDE) – a public repository of behavioral and neuroimaging data.
Brain morphometry was assessed using the optimized voxel-based morphometry method. Structural images were resliced and spatially normalized to the stereotactic space. The normalized images were then segmented into gray matter (GM), white matter, and cerebrospinal fluid compartments. The GM images were modulated and smoothed. Group differences in GM volume were examined by comparing modulated smoothed GM images of girls with ASD with those of boys with ASD, using state-of-the-art multivariate pattern analysis (MVPA).
Females and males did not differ in overall severity of childhood autism. There were also no sex differences in social and communication deficits. However, females showed less severe restricted and repetitive behavior (p< 0.01).
To delineate neural markers that underlie the unique behavioral profile in female chidren with ASD, we compared brain structure in ASD girls with ASD boys. Using MVPA analysis, we found that GM in several cortical regions could discriminate female and male children with ASD. Notably, GM volume in the precentral gyrus, fusiform gyrus, angular gyrus, cerebellum, and the insula showed high accuracies (85-90%) for distinguishing girls from boys. Additionally, we found that the GM volume in the precentral gyrus and cerebellum was correlated with scores on the Repetitive/Restrictive Domain of the ADI-R (p < 0.001) such that the female children with the least impairment in the Repetitive/Restrictive domain showed greatest GM volume in regions involved in motor function. No such relationship was observed in boys.
Our findings not only provide evidence for distinct behavioral profiles in girls with ASD, compared to boys, but also show a link between these behavioral differences to brain structural differences demonstrating for the first time that at earlier ages closer to disorder onset, the brain in female children with ASD is structured in ways that may contribute to reduced behavioral impairments. These findings may reflect different developmental trajectories between females and males with ASD. More generally, brain-based gender-specific biomarkers of ASD developed here may eventually be used to aid in early and more accurate detection of the heterogeneous disorder in females, as well as targeted intervention strategies.
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