Sex Differences in Structural Brain Development Underlying a Female Protective Effect

Background: Autism Spectrum Disorders (ASD) disproportionately affect males over females. Our NIH Autism Center of Excellence Girls’ Neurogenetics Network has contributed to understanding this bias at the levels of gene structure and expression, neural dynamics, brain function, and connectivity. The skew may be explained in part via mechanisms that confer a Female Protective Effect (FPE), combined with normative sexually dimorphic brain development, environmental factors, and potential measurement biases. This work is important because characterizing the FPE may help illuminate and treat ASD in both sexes.

Objectives: We sought to model and evaluate cortical thickness in males and females with ASD and age-, sex-, and cognitive-ability matched typically-developing (TD) comparison participants.

Methods: The sample included 219 children and adolescents (age: M = 13.01y, SD = 2.91y, range = 8.03-17.99y; IQ: M = 107.50, SD = 17.87, range = 75-167) recruited from four research sites (Yale, Harvard, UCLA, Seattle). There were 54 ASD females, 52 TD females, 59 ASD males and 54 TD males. The four groups were well-matched on age and IQ. Females (F) and males (M) with ASD were well-matched on ASD symptom severity, language ability and adaptive behaviors. F-ASD and F-TD were well-matched on intracranial volume (ICV), so were M-ASD and M-TD. All participants underwent a T1-weighted structural scan. Cortical thickness was estimated using FreeSurfer v6.0.0 and fwhm=15mm. Quality of the structural MRI images were independently rated by two researchers, blind to group membership; 30 subjects (6 F-ASD, 5 F-TD, 17 M-ASD, 2 M-TD) exhibiting obvious head motion were discarded. Age was centered before entered into analysis. Results were thresholded at Z>1.96 (vertex-level) and p<.05 (cluster-level) (two-sided), while site, IQ, and ICV were included as covariates of no interest.

Results: The analysis showed that across all participants, as expected, there were widespread age-related reductions in cortical thickness during this developmental epoch. In males, the whole-brain analysis revealed a significant Age × Diagnosis interaction localized to the right pSTS and nearby regions as outlined in Figure 1. However, in girls, there were no surviving regions across the whole brain showing a significant Age × Diagnosis interaction, while the Age × Diagnosis interaction in the outlined region was not significant in girls, p=.21. Finally, the 3-way Age × Diagnosis × Sex interaction effect in the outlined region was significant, p=.04, partial η² = .024. The scatterplots are also presented for this region.

Conclusions: Consistent with prior, published reports, males with ASD relative to same-sex TD exhibit accelerated age-related cortical thinning specifically in the right pSTS region during late childhood and adolescence. However, this atypicality is not present in girls with ASD. These findings suggest evidence for one of the developmental brain differences underlying the FPE in ASD.