Towards robust and replicable sex differences in the intrinsic brain function of autism
Creators: name: Floris, Dorothea L.
name: Filho, José O. A.
name: Lai, Meng-Chuan
name: Giavasis, Steve
name: Oldehinkel, Marianne
name: Mennes, Maarten
name: Charman, Tony
name: Tillmann, Julian
name: Dumas, Guillaume
name: Ecker, Christine
name: Dell’Acqua, Flavio
name: Banaschewski, Tobias
name: Moessnang, Carolin
name: Baron-Cohen, Simon
name: Durston, Sarah
name: Loth, Eva
name: Murphy, Declan G. M.
name: Buitelaar, Jan K.
name: Beckmann, Christian F.
name: Milham, Michael P.
name: Di Martino, Adriana
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Research
Autism spectrum disorder
Resting-state functional connectivity
Sex differences
Replication
Robustness
Voxel-mirrored homotopic connectivity

description: Funder: Slifka-Ritvo Award for Innovation in Autism Research from the International Society for Autism Research
description: Funder: Alan B. Slifka Foundation; doi: http://dx.doi.org/10.13039/100012640
description: Funder: Academic Scholars Award from the Department of Psychiatry (CA)
description: Funder: O’Brien Scholars Program in the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health (CA)
description: Funder: Hospital for Sick Children; doi: http://dx.doi.org/10.13039/501100006126
description: Funder: Slaight Family Child and Youth Mental Health Innovation Fund from Centre for Addiction and Mental Health Foundation (CA)
description: Funder: Phyllis Green, Randolph Cowen, and Joseph Healey
description: 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 a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 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 (voxel-level Z &gt; 3.1, cluster-level P &lt; 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the 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. Results: Discovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples—EU-AIMS LEAP. Limitations: Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability. Conclusions: Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.