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

Disrupted network segregation of the default mode network in autism spectrum disorder

“…The exclusion criteria for subjects were as follows: 1) without functional or structural images; 2) without handedness information or with mixed handedness; 3) without full-scale intelligence quotient (FIQ) information or FIQ smaller than 70 22 ; 4) eye status, time of repetition (TR), slice number, or data matrix size different from those of most subjects within a site; we used 180 time points for all Stanford subjects; 5) time points different from those of most subjects within a site (at the Stanford site, there were 20 subjects with 240 time points (50%), 17 subjects had 180 time points (42.5%), one subject had 181 time points, two subjects had 238 time points, and we truncated all the functional data to 180 time points. ); 6) severe artefacts and signal losses in functional images (by visual inspection); 7) scan duration less than 100 time points 23 ; 8) head motion exceeding 3 mm or 3 degrees; 9) bad spatial normalization (by visual inspection); 10) scan cover less than 91% of the whole brain; 11) spatial correlation < 0.6 (a threshold defined by mean - 2SD) between each participant’s regional homogeneity (ReHo) map and the group mean ReHo map 24 ; 12) some subjects were excluded to ensure group matching for age, FIQ, mean framewise displacement (mFD) 25 ( p > 0.05, Two-sample t-test) and sex and handedness ( p > 0.05, Chi-square test) in each centre; 13) at each step, any sites (UCLA_2 after poor spatial normalization, Caltech after inadequate cover) with less than 20 individual datasets were excluded; 14) subjects were screened according to DCM-IV (sites with a DSM-IV score of -9999 and a certain invalid score were excluded) and age (7-25 years); ultimately, a total of 609 subjects, including 269 ASDs and 340 HCs at 13 sites, were included in our investigation.…”

Can Open Science be a Tool to Dismantle Claims of Hardwired Brain Sex Differences? Opportunities and Challenges for Feminist Researchers

“…In other words, while an open science movement with limited diversity may still provide theoretical access to open science tools (for some people), it will fail to challenge the more fundamental issue of hierarchies within the scientific process and as such limit the degree to which it is compatible with feminism. As noted above, it may also stifle efforts to improve female representation within neuroscience (Schrouff et al, 2019) which would be detrimental to scientific inquiry (Murphy et al, 2020). We therefore propose that open science groups consider diversity within the movement (as should feminist researchers; Westmarland & Bows, 2018) and this could be practically achieved through promoting the learning of and broad engagement with open science of any degree rather than exclusivity.…”

“…It has offered novel strategies to examine robustness of methodology, design, and data which may be particularly relevant for feminists seeking to scrutinize claims about innate sex differences and dominant cultural beliefs about binary biological essentialism. Open science also presents a credible language with which to articulate frustrations about the political bias of sex difference research (as per Wickham, 2020), which may be especially important given the longstanding history of critical women's voices being marginalized in the mainstream (Murphy et al, 2020;Whitaker & Guest, 2020). However, before exploring the different tools that may provide a useful opportunity to challenge the brain sex differences evidence, we first outline the main areas of scientific concern within the research on hardwired sex brain differences.…”

“…An intuitive software which requires little formal training to use such as JASP may be particularly useful here, both for journalists themselves and for members of the public. Finally, open and intuitive software also promotes a collaborative and inclusive research community which may be important in increasing the appeal of this type of research to groups traditionally underrepresented in this area (Murphy et al, 2020).…”

“…This will ultimately benefit the broader scientific community as well. There have been some recent successful sex differences replication attempts (e.g., in autism; Floris et al, 2020) which have provided useful standards for research more generally in this area. More broadly, however, most of the key claims about women and men's brains fail to replicate consistently across individual studies as outlined in a detailed meta-synthesis of three decades of human brain sex difference findings by Eliot et al (2021).…”