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

Abstract

Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4-6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism.

Fig. 1.

Total cerebral volume (TCV) is enlarged in males with regressive autism (ASD-REG) relative to typical development (TD) (ANCOVA with group, age and Fisher post hoc corrections). TCV in the autism without regression group (ASD-nREG) did not differ from TD. There were no group differences for the females. Horizontal lines represent mean TCV for each group.

Fig. 2.

Cross-sectional analysis of head circumference measurements from birth through 18 mo of life. Groups do not differ from birth through 4 mo of age. The ASD-REG group diverges from the ASD-nREG and TD groups around 4–6 mo of age.

Fig. 3.

Longitudinal head circumference growth in males. Lighter lines represent the growth trajectories of the brains of individuals in this study. Bold lines indicate the piecewise linear longitudinal model fit to each clinical group separately. Results from the longitudinal analysis confirm that the ASD-REG group is larger than the TD and ASD-nREG groups.