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Multicenter Study
. 2021 Mar 1;12(1):19.
doi: 10.1186/s13229-021-00415-z.

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

Dorothea L Floris #  1   2 , José O A Filho #  3 , Meng-Chuan Lai  4   5   6   7   8 , Steve Giavasis  3 , Marianne Oldehinkel  2 , Maarten Mennes  1 , Tony Charman  9 , Julian Tillmann  9   10 , Guillaume Dumas  11   12 , Christine Ecker  13   14 , Flavio Dell'Acqua  13   15 , Tobias Banaschewski  16 , Carolin Moessnang  17 , Simon Baron-Cohen  7 , Sarah Durston  18 , Eva Loth  13   15 , Declan G M Murphy  13   15 , Jan K Buitelaar  1   2   19 , Christian F Beckmann  1   2   20 , Michael P Milham  3   21 , Adriana Di Martino  22
Affiliations
Multicenter Study

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

Dorothea L Floris et al. Mol Autism. .

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 > 3.1, cluster-level P < 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.

Keywords: Autism spectrum disorder; Replication; Resting-state functional connectivity; Robustness; Sex differences; Voxel-mirrored homotopic connectivity.

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Conflict of 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.

Figures

Fig. 1
Fig. 1
Overlap across R-fMRI metrics for main effects of diagnosis and sex. Upper panel: the surface inflated maps depict the extent of overlap across clusters showing significant main effects of diagnosis (left) and sex (right) across any of three resting state fMRI (R-fMRI) metrics showing statistically significant effects (Z > 3.1, P < 0.01). Purple clusters represent areas of significant group differences emerging for only one of any of the three R-fMRI measures, orange and yellow clusters indicate measures with overlap among 2 and 3 R-fMRI measures (see Additional file 1: Figure S2 for statistical maps of main effects for each R-fMRI metric). Cluster masks are overlaid on inflated brain maps generated by BrainNet Viewer. Lower panel: For each of the yellow and orange clusters in panel A, the table lists the cluster’s anatomical label based on the Harvard Oxford atlas, the specific R-fMRI metrics involved, and the group difference direction (ASD < NT or M < F in blue, ASD > NT or M > F in red). L left hemisphere, R right hemisphere, PCG/FP paracingulate cortex/frontal pole, ACC anterior cingulate cortex, PCC/Prec posterior cingulate cortex/precuneus, ASD autism spectrum disorder, NT neurotypical, M males, F females
Fig. 2
Fig. 2
Sex-by-diagnosis interaction effect, its robustness and replicability. (a) On the right, surface maps show the cluster with a significant (Z > 3.1, P < 0.01) sex-by-diagnosis interaction for voxel-mirrored homotopic connectivity (VMHC) resulting from discovery analyses in the ABIDE sample using the component-based noise reduction (CompCor) pipeline. The statistical Z maps are overlaid on inflated brain maps generated by BrainNet Viewer. (b) The upper panels show the pattern of VMHC group means in males and females by each diagnostic group (ASD and NT) extracted from the same cluster in data pre-processed following two alternative denoising pipelines, Global Signal Regression (GSR, left) and Independent Component Analysis-Automatic Removal of Motion Artifacts (ICA-AROMA, right). Results show a pattern similar to the those observed in discovery analyses with small to moderate effect sizes (ηp2 range = 0.01–0.07). (c) The lower graph shows replicability in two independent samples: the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR) and the EU-AIMS Longitudinal European Autism Project (LEAP). The pattern of results was replicable in the EU-AIMS LEAP (N = 309) with a small effect size (ηp2 = 0.01) and had a negligible effect size in GENDAAR (N = 196; ηp2 < 0.01). For all graphs VMHC data are shown as residuals obtained after regressing out mean framewise displacement and age effects. L left, R right, A anterior, P posterior
Fig. 3
Fig. 3
Functional relevance of sex-by-diagnosis interaction in VMHC. a The radar plot shows the percentage (0–80%) of overlap between the voxels in the dorsolateral occipital cluster showing a significant VMHC sex-by-diagnosis interaction in discovery analyses and the 12 Yeo cognitive ontology probability maps [63] (probability threshold at P = 1e−5) for cognitive components C1–C12. As in Floris et al. [2], we labelled each component based on the top five tasks reported to be most likely recruited by a given component. b Word cloud based on the top 27 terms showing correlations between r = 0.64 to r = 0.10 associated with the same VMHC cluster based on the Neurosynth Image Decoder. c Sex-differential association between each individual’s VMHC at the cluster showing a significant sex-by-diagnosis interaction in primary analyses and available ADOS social-affect uncalibrated sub-scores in males and females with ASD. VMHC data are shown as residuals obtained after regressing out mean framewise displacement and age effects. While males showed no significant associations at corrected and uncorrected thresholds, females with lower dorsolateral occipital VMHC showed more severe social-affect symptoms at a uncorrected statistical threshold (F(1,311) = 4.44, p = 0.036)
Fig. 4
Fig. 4
Robustness and replicability summary. a The histogram summarizes the percentage of clusters showing a robust and replicable pattern of results as that observed in discovery analyses in the ABIDE sample for main effects of diagnosis (Dx; green; N = 7 clusters), sex (yellow; N = 10 clusters) and their interaction (blue; N = 1 cluster) across three R-fMRI metrics. All findings were robust to different preprocessing pipelines. Across R-fMRI metrics, main sex effects were moderately (50%) to largely (80%) replicable across independent samples: Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR) and the EU-AIMS Longitudinal European Autism Project (LEAP), respectively. Replicability for main effects of diagnosis was largely replicable in GENDAAR (86%) and minimally replicable in EU-AIMS LEAP (29%). The VMHC pattern observed for sex-by-diagnosis interaction in discovery analyses was replicated in EU-AIMS LEAP only. b Surface conjunction maps show the clusters replicated in GENDAAR only (G, purple), EU-AIMS LEAP only (E, blue) and in both samples (G and E, red) for each effect separately
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