Abstract
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.
Competing Interest Statement
ADM receives royalties from the publication of the Italian version of the Social Responsiveness Scale-Child Version by Organization Speciali, Italy. JKB has been a consultant to, advisory board member of, and a speaker for Takeda/Shire, Medice, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. CFB is director and shareholder in SBGneuro Ltd. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JT is a consultant to Roche. The remaining authors declare no competing interests.
Abbreviations
- ABIDE
- Autism Brain Imaging data exchange
- ADI-R
- Autism Diagnostic Interview-Revised
- ADOS-2
- Autism Diagnostic Observation Schedule-2
- ASD
- Autism Spectrum Disorder
- CSS
- Calibrated Severity Score
- F
- females
- IQ
- intellectual quotient
- M
- males
- Mean FD
- mean framewise displacement (Jenkinson et al., 2002)
- NT
- neurotypical
- RRB
- restricted repetitive behaviors.
