Brain Enlargement Persists through Adolescence in ASD, but Is Not Predicted By Clinical Severity

Background:  Converging evidence indicates that toddlers and early school age youth with Autism Spectrum Disorders (ASD) have larger brains than Typically Developing Controls (TDC). It remains unclear, however, if this enlargement persists beyond early development or whether there is later a period of arrested brain growth in ASD such that group differences disappear by adolescence or adulthood. Unfortunately, a majority of studies on this topic may be underpowered to detect the expected effects. Even well-powered studies are also often confounded by failure to match groups on characteristics correlated with brain volume (age, sex-ratio, and IQ). While toddlers with ASD have larger brains, there is limited evidence of a correlation between brain volume and ASD symptom severity. This is puzzling given reported group differences.

Objectives:  We seek to determine, using a large, well-characterized single-site sample: 1) whether there is a persistent brain enlargement in ASD from childhood through early adulthood, and 2) whether volume difference is related to ASD severity.

Methods:  A total of 477 individuals with (N=254) and without ASD (N=223) aged 6-25 (mean=13±3.79) completed a structural MRI study. The sample included a large number of females (N=102) and spanned a wide IQ range (47-158). This is perhaps the largest structural MRI study of ASD to date conducted with a single MRI scanner and sequence. High-resolution T1-weighted anatomical MRI images were examined for group differences in total brain, ventricular, gray, and white matter volumes. ASD severity was assessed with the Social Responsiveness Scale – 2 (SRS-2), the ADOS-2 calibrated severity score, and the Social Communication Questionnaire (SCQ).

Results:  Total brain, gray, white, and ventricular volumes were larger in the ASD group (effects of diagnosis partial η2=0.06, 0.07, 0.03, and 0.04, respectively, all ps<0.001, between-group percent differences=2.7, 2.9, 2.4, and 19.5%), with no interactions between diagnosis and age or sex. However, there were significant interactions between diagnosis and IQ, such that normative positive correlations of IQ and brain volume are absent in ASD. When controlling for age, sex, and IQ, neither ADOS severity score, the SRS, nor the SCQ significantly predicted brain volume within the ASD group.

Conclusions:  These results clarify our understanding of ASD brain size at different ages, showing that brain enlargement persists into adulthood. However, the magnitude of the ASD volumetric enlargements is greatest for those with lower IQs. The absence of volume by IQ correlations in ASD suggests that the cognitive advantages typically conferred by increased brain volume are absent in ASD. Importantly, the failure to find within-ASD correlations with disorder severity concurrent with the categorical between-group brain volume difference suggests that brain size enlargement might not be related to the core features of ASD per se, but rather is incidental to having ASD. This suggests that increased brain volume is not an underlying source of ASD phenotypic differences, which might instead be related to cortical microstructure or connectivity differences. Alternatively, the absence of a correlation between brain size and ASD severity might indicate that our putative severity metrics fail to capture important aspects of ASD heterogeneity.