Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Mar 6:9:17.
doi: 10.1186/s13229-018-0192-x. eCollection 2018.

Network-specific sex differentiation of intrinsic brain function in males with autism

Dorothea L Floris  1 , Meng-Chuan Lai  2   3 , Tanmay Nath  1 , Michael P Milham  4   5 , Adriana Di Martino  1
Affiliations

Network-specific sex differentiation of intrinsic brain function in males with autism

Dorothea L Floris et al. Mol Autism. .

Abstract

Background: The male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research on sex differentiation in ASD. Multiple sources of evidence have suggested a neurophenotypic convergence of ASD-related characteristics and typical sex differences. Two existing, albeit competing, models provide predictions on such neurophenotypic convergence. These two models are testable with neuroimaging. Specifically, the Extreme Male Brain (EMB) model predicts that ASD is associated with enhanced brain maleness in both males and females with ASD (i.e., a shift-towards-maleness). In contrast, the Gender Incoherence (GI) model predicts a shift-towards-maleness in females, yet a shift-towards-femaleness in males with ASD.

Methods: To clarify whether either model applies to the intrinsic functional properties of the brain in males with ASD, we measured the statistical overlap between typical sex differences and ASD-related atypicalities in resting-state fMRI (R-fMRI) datasets largely available in males. Main analyses focused on two large-scale R-fMRI samples: 357 neurotypical (NT) males and 471 NT females from the 1000 Functional Connectome Project and 360 males with ASD and 403 NT males from the Autism Brain Imaging Data Exchange.

Results: Across all R-fMRI metrics, results revealed coexisting, but network-specific, shift-towards-maleness and shift-towards-femaleness in males with ASD. A shift-towards-maleness mostly involved the default network, while a shift-towards-femaleness mostly occurred in the somatomotor network. Explorations of the associated cognitive processes using available cognitive ontology maps indicated that higher-order social cognitive functions corresponded to the shift-towards-maleness, while lower-order sensory motor processes corresponded to the shift-towards-femaleness.

Conclusions: The present findings suggest that atypical intrinsic brain properties in males with ASD partly reflect mechanisms involved in sexual differentiation. A model based on network-dependent atypical sex mosaicism can synthesize prior competing theories on factors involved in sex differentiation in ASD.

Keywords: Autism spectrum disorder; Extreme Male Brain; Gender Incoherence; Resting-state fMRI; Sex differentiation; Sex mosaicism.

PubMed Disclaimer

Conflict of interest statement

All data included in this study were selected from publically available resources as fully de-identified removing all 18 HIPAA (Health Insurance Portability and Accountability)-protected health information identifiers. As such, they do not meet the criteria for human subject data requiring formal IRB approval.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Spatial overlap scenarios. Depending on the combination of statistical contrasts being overlapped, four different scenarios can emerge. Decreases or increases of R-fMRI metrics in males with autism spectrum disorder (ASD) relative to neurotypical males (NT M) lead to different scenarios depending on whether they overlap with increases or decreases in NT M relative to NT females (F) (gray boxes). Following the predictions of the Extreme Male Brain (EMB) theory and Gender Incoherence (GI) theory, two scenarios fit the EMB model predicting a shift-towards-maleness (STM) in males with ASD (see blue and turquois boxes) and two scenarios fit the GI model predicting a shift-towards-femaleness (STF) in males with ASD (see orange and yellow boxes)
Fig. 2
Fig. 2
Conjunction analyses. Plots (one per each resting-state fMRI metric [R-fMRI]) show the spatial overlap percentages across 500 successive statistical voxel-level thresholds for the four possible overlap scenarios (turquoise: shift-towards-maleness (STM) ASD-related increases (EMB 1; as indicated by the upward arrow) = ASD♂ > NT♂ and NT♂ > NT♀; blue: STM ASD-related decreases (EMB 2; as indicated by the downward arrow) = ASD♂ < NT♂ and NT♂ < NT♀; orange: shift-towards-femaleness (STF) ASD-related increases (GI 1; as indicated by the upward arrow) = ASD♂ > NT♂ and NT♂ < NT♀; yellow: STF ASD-related decreases (GI 2; as indicated by the downward arrow) = ASD♂ < NT♂ and NT♂ > NT♀). The black solid line represents the median of the null distribution of the random spatial overlap generated by 5000 Monte Carlo simulations for each threshold. The dotted lines mark the 0.5th and 99.5th percentiles of the null distribution of random spatial overlap. Only spatial overlaps consistently above the 99.5th percentile of the null distribution for at least 70% of the 500 tested thresholds were utilized for subsequent results’ characterization. R-fMRI abbreviations: DC degree centrality, fALFF fractional amplitude of low frequency fluctuations, ReHo regional homogeneity, VMHC voxel-mirrored homotopic connectivity, PCC-iFC posterior cingulate cortex intrinsic functional connectivity
Fig. 3
Fig. 3
Overlaps consistent with a shift-towards-maleness and a shift-towards-femaleness. For each panel, a and b, the left columns illustrate on inflated surface maps (BrainNet Viewer; https://www.nitrc.org/projects/bnv) the regions of significant spatial overlap based on the conjunction of statistical Z-maps resulting from the ABIDE I and FCP studies (voxel-level thresholded at Z ≥ 2.58) for each resting-state fMRI (R-fMRI) metric. The histograms in the right column of each panel describe the percentage of voxels within the above clusters included in the seven functional cortical networks described by Yeo et al. [40]. R-fMRI abbreviations: DC degree centrality, fALFF fractional amplitude of low frequency fluctuations, ReHo regional homogeneity, VMHC voxel-mirrored homotopic connectivity, PCC-iFC posterior cingulate cortex intrinsic functional connectivity. Seven functional Yeo networks: VS visual network, SM somatomotor network, DA dorsal attention network, VA ventral attention network, LB limbic network, FP fronto-parietal network, DN default network. a Overlaps consistent with the Extreme Male Brain (EMB) theory: Hyper-connectivity consistent with a shift-towards-maleness (STM) was mainly present in the FP network for ReHo, whereas an STM hypo-connectivity for ReHo, VMHC, and PCC-iFC and decreased fALFF were mainly centered around the DN. Color codes: turquoise = STM ASD-related increases (EMB 1); blue = STM ASD-related decreases (EMB 2). b Overlaps consistent with the Gender Incoherence (GI) theory: Hyper-connectivity consistent with a shift-towards-femaleness (STF) was mainly in DN for DC and ReHo, whereas an STF hypo-connectivity across DC, ReHo, VMHC, and PCC-iFC was mainly centered around the SM network. Color codes: orange = STF ASD-related increases (GI 1); yellow = STF ASD-related decreases (GI 2)
Fig. 4
Fig. 4
Cognitive ontology maps. The polar plot shows the percentage (0–100%) of overlap between the significant conjunctions of statistical Z-maps (voxel-level thresholded at Z ≥ 2.58) and the 12 Yeo cognitive ontology probability maps [41] (probability thresholded at p = 1e−5) for cognitive components C1–C12. We labeled each component based on the top five tasks reported to be most likely recruited by a given component. Results are summarized according to their consistency with the Extreme Male Brain (EMB) or Gender Incoherence (GI) models, regardless of the resting-state fMRI metric. Color codes: turquoise = shift-towards-maleness (STM) ASD-related increases (EMB 1); blue = STM ASD-related decreases (EMB 2); orange = shift-towards-femaleness (STF) ASD-related increases (GI 1); yellow = STF ASD-related decreases (GI 2)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Di Martino A, Yan CG, Li Q, Denio E, Castellanos FX, Alaerts K, Anderson JS, Assaf M, Bookheimer SY, Dapretto M, et al. The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Mol Psychiatry. 2014;19:659–667. doi: 10.1038/mp.2013.78. - DOI - PMC - PubMed
    1. Picci G, Gotts SJ, Scherf KS. A theoretical rut: revisiting and critically evaluating the generalized under/over-connectivity hypothesis of autism. Dev Sci. 2016;19:524–549. doi: 10.1111/desc.12467. - DOI - PubMed
    1. Lai MC, Lombardo MV, Suckling J, Ruigrok AN, Chakrabarti B, Ecker C, Deoni SC, Craig MC, Murphy DG, Bullmore ET, et al. Biological sex affects the neurobiology of autism. Brain. 2013;136:2799–2815. doi: 10.1093/brain/awt216. - DOI - PMC - PubMed
    1. Lai MC, Lombardo MV, Ruigrok AN, Chakrabarti B, Wheelwright SJ, Auyeung B, Allison C, Baron-Cohen S, Consortium MA. Cognition in males and females with autism: similarities and differences. PLoS One. 2012;7:e47198. doi: 10.1371/journal.pone.0047198. - DOI - PMC - PubMed
    1. Christensen DL, Baio J, Van Naarden BK, Bilder D, Charles J, Constantino JN, Daniels J, Durkin MS, Fitzgerald RT, Kurzius-Spencer M, et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR Surveill Summ. 2016;65:1–23. doi: 10.15585/mmwr.ss6503a1. - DOI - PubMed

Publication types