TY - JOUR
T1 - Towards robust and replicable sex differences in the intrinsic brain function of autism
AU - Floris, Dorothea L
AU - Filho, José O A
AU - Lai, Meng-Chuan
AU - Giavasis, Steve
AU - Oldehinkel, Marianne
AU - Mennes, Maarten
AU - Charman, Tony
AU - Tillmann, Julian
AU - Dumas, Guillaume
AU - Ecker, Christine
AU - Dell'Acqua, Flavio
AU - Banaschewski, Tobias
AU - Moessnang, Carolin
AU - Baron-Cohen, Simon
AU - Durston, Sarah
AU - Loth, Eva
AU - Murphy, Declan G M
AU - Buitelaar, Jan K
AU - Beckmann, Christian F
AU - Milham, Michael P
AU - Di Martino, Adriana
N1 - Funding Information:
Work for this study has been partly supported by a Postdoctoral Training Award from the Autism Science Foundation (to DLF/ADM); by NIMH (R21MH107045, R01MH105506, R01MH115363 to ADM); by gifts to the Child Mind Institute from Phyllis Green, Randolph Cowen, and Joseph Healey, and by UO1 MH099059 (to MPM) and Dr. John and Consuela Phelan Scholarship (to ADM); by the Ontario Brain Institute via the Province of Ontario Neurodevelopmental Disorders Network (IDS-I l-02), the Slifka-Ritvo Award for Innovation in Autism Research from the International Society for Autism Research and the Alan B. Slifka Foundation, the Academic Scholars Award from the Department of Psychiatry, University of Toronto, the O’Brien Scholars Program in the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health (CAMH) and The Hospital for Sick Children, the Slaight Family Child and Youth Mental Health Innovation Fund from CAMH Foundation, and the Canadian Institutes of Health Research Sex and Gender Science Chair (GSB 171373) (to M-CL). We also acknowledge the contributions of all members of the EU-AIMS LEAP group. EU-AIMS LEAP has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115300 (for EU-AIMS) and No 777394 (for AIMS-2-TRIALS). This joint undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA and AUTISM SPEAKS, Autistica, SFARI. DM is also supported by the NIHR Maudsley Biomedical Research Centre. SBC was supported by the Autism Research Trust during the period of this work.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
KW - Autism spectrum disorder
KW - Replication
KW - Resting-state functional connectivity
KW - Robustness
KW - Sex differences
KW - Voxel-mirrored homotopic connectivity
UR - https://www.scopus.com/pages/publications/85101857861
U2 - 10.1186/s13229-021-00415-z
DO - 10.1186/s13229-021-00415-z
M3 - Article
C2 - 33648569
SN - 2040-2392
VL - 12
JO - Molecular Autism
JF - Molecular Autism
IS - 1
M1 - 19
ER -