Towards robust and replicable sex differences in the intrinsic brain function of autism

Background: Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data. Methods: We addressed this gap by using the largest sample of male and female autistic and neurotypical (NT) control individuals, to date (ABIDE; Autism: 362 males, 82 females; NT: 410 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics. Secondary analyses assessed the robustness of primary results to different pre-processing approaches and their replicability in two independent samples, the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR). Results: Discovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical and subcortical regions. Sex-by-diagnosis interactions were confined to VMHC in dorsolateral occipital cortex with reduced VMHC in females with autism. Findings were highly robust to different pre-processing steps and replicable in another sample. Specifically, the sex-by-diagnosis interaction replicated in the larger of the two replication samples - EU-AIMS LEAP. Conclusions: Results emphasize that atypical cross-hemispheric interactions are neurobiologically relevant to autism. Systematic assessments of the factors contributing to their replicability are needed and necessitate coordinated large-scale data collection across studies.