Brain-based sex differences in autism spectrum disorder across the lifespan: A systematic review of structural MRI, fMRI, and DTI findings

Females with autism spectrum disorder (ASD) have been long overlooked in neuroscience research, but emerging evidence suggests they show distinct phenotypic trajectories and age-related brain differences. Sex-related biological factors (e.g., hormones, genes) may play a role in ASD etiology and have been shown to influence neurodevelopmental trajectories. Thus, a lifespan approach is warranted to understand brain-based sex differences in ASD. This systematic review on MRI-based sex differences in ASD was conducted to elucidate variations across the lifespan and inform biomarker discovery of ASD in females We identified articles through two database searches. Fifty studies met criteria and underwent integrative review. We found that regions expressing replicable sex-by-diagnosis differences across studies overlapped with regions showing sex differences in neurotypical cohorts. Furthermore, studies investigating age-related brain differences across a broad age-span suggest distinct neurodevelopmental patterns in females with ASD. Qualitative comparison across youth and adult studies also supported this hypothesis. However, many studies collapsed across age, which may mask differences. Furthermore, accumulating evidence supports the female protective effect in ASD, although only one study examined brain circuits implicated in “protection.” When synthesized with the broader literature, brain-based sex differences in ASD may come from various sources, including genetic and endocrine processes involved in brain “masculinization” and “feminization” across early development, puberty, and other lifespan windows of hormonal transition. Furthermore, sex-related biology may interact with peripheral processes, in particular the stress axis and brain arousal system, to produce distinct neurodevelopmental patterns in males and females with ASD. Future research on neuroimaging-based sex differences in ASD would benefit from a lifespan approach in well-controlled and multivariate studies. Possible relationships between behavior, sex hormones, and brain development in ASD remain largely unexamined.