Altered Neural Connectivity in Females, But Not Males with Autism: Preliminary Evidence for the Female Protective Effect from a Quality-Controlled Diffusion Tensor Imaging Study

Previous studies using diffusion tensor imaging (DTI) to investigate white matter (WM) structural connectivity have suggested widespread, although inconsistent WM alterations in autism spectrum disorder (ASD), such as greater reductions in fractional anisotropy (FA). However, findings may lack generalizability because: (a) most have focused solely on the ASD male brain phenotype, and not sex-differences in WM integrity; (b) many lack stringent and transparent data quality control such as controlling for head motion in analysis. This study addressed both issues by using Tract-Based Spatial Statistics (TBSS) to separately compare WM differences in 81 ASD (56 male, 25 female; 4-21 years old) and 39 typically developing (TD; 23 males, 16 females; 5-18 years old) children and young people, carefully group-matched on sex, age, cognitive abilities, and head motion. ASD males and females were also matched on autism symptom severity. Two independent-raters completed a multistep scan quality assurance to remove images that were significantly distorted by motion artifacts before analysis. ASD females exhibited significant widespread reductions in FA compared to TD females, suggesting altered WM integrity. In contrast, no significant localized or widespread WM differences were found between ASD and TD males. This study highlights the importance of data quality control in DTI, and outlines important sex-differences in WM alterations in ASD females. Future studies can explore the extent to which neural structural differences might underlie sex-differences in ASD behavioral phenotype, and guide clinical interventions to be tailored toward the unique needs of ASD females and males. Autism Res 2019, 12: 1472-1483. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Previous Diffusion Tensor Imaging (DTI) studies have found atypical brain structural connectivity in males with autism, although findings are inconclusive in females with autism. To investigate potential sex-differences, we studied males and females with and without autism who showed a similar level of head movement during their brain scan. We found that females with autism had widespread atypical neural connectivity than females without autism, although not in males, highlighting sex-differences.