Sex-dependent and sex-independent brain resting-state functional connectivity in children with autism spectrum disorder

Abstract

Background: Males are more likely to suffer from autism spectrum disorder (ASD) than females.As to whether females with ASD have similar brain alterations remain an open question. The current study aimed to examine sex-dependent as well as sex-independent alterations in restingstate functional connectivity in individuals with ASD compared with typically developing (TD) individuals. Method:Resting-state functional MRI data were acquired from the Autism Brain Imaging Data Exchange (ABIDE). Subjects between 6 to 20 years of age were included for analysis. After matching the intelligence quotient between groups for each dataset, and removing subjects due to excessive head motion, the resulting effective sample contained 28 females with ASD, 49 TD females, 129 males with ASD, and 141 TD males, with a two (diagnosis) by two (sex) design.Functional connectivity among 153 regions of interest (ROIs) comprising the whole brain was computed. Two by two analysis of variance was used to identify connectivity that showed diagnosis by sex interaction or main effects of diagnosis. Results:The main effects of diagnosis were found mainly between visual cortex and other brain regions, indicating sex-independent connectivity alterations. We also observed two connections whose connectivity showed diagnosis by sex interaction between the precuneus and medial cerebellum as well as the precunes and dorsal frontal cortex. While males with ASD showed higher connectivity in these connections compared with TD males, females with ASD had lower connectivity than their counterparts.Conclusions: Both sex-dependent and sex-independent functional connectivity alterations are present in ASD.

Enhancement of indirect functional connections with shortest path length in the adult autistic brain

“…The "-" symbol denotes a significantly negative linear relationship between SMP and age [Color figure can be viewed at wileyonlinelibrary.com] observed in autism, with sex-dependent differences only identified between the precuneus and medial cerebellum/dorsal frontal cortex (Di & Biswal, 2016). (a) Post-hoc analyses for main effect of sex on SMP.…”

“…The question arises whether the brain functional organization differs between autistic males and females after taking typical sex differences into account. To the best of our knowledge, only three studies have assessed resting-state functional connectivity in autistic males and females (Alaerts, Swinnen, & Wenderoth, 2016;Di & Biswal, 2016;Kozhemiako et al, 2019).…”

“…(d) Main effect of age at the network level. The "-" symbol denotes a significantly negative linear relationship between SMP and age [Color figure can be viewed at wileyonlinelibrary.com] observed in autism, with sex-dependent differences only identified between the precuneus and medial cerebellum/dorsal frontal cortex (Di & Biswal, 2016). Using seed-based and whole-brain functional connectivity analyses, Alaerts et al (2016) found that autistic males predominantly displayed hypo-connectivity while autistic females predominantly exhibited hyper-connectivity compared to sex-matched typical controls.…”

Imaging sex/gender and autism in the brain: Etiological implications

“…If risk mechanisms leading to autism in males and females are instead mostly qualitatively different , one would expect that males and females with autism differ in the kind of autism‐related atypical patterns of brain activity or structure they show (Lai et al, ). This has been increasingly shown in larger‐scale neuroimaging studies (with n = 13–53 females with autism) of brain anatomy (Nordahl et al, ; Beacher et al, ; Lai et al, ; Schaer et al, ; Retico et al, ) and functional activation patterns (Beacher et al, ; Schneider et al, ; Alaerts et al, ; Di and Biswal, ; Kirkovski et al, ). Findings indicative of substantial sex/gender differences in autism are also found in other levels including cognition (Bolte et al, ; Lemon et al, ; Lai et al, ; Goddard et al, ; Kauschke et al, ; Lehnhardt et al, ), early physical growth trajectory (Suren et al, ; Campbell et al, ), anthropometry (Bejerot et al, ), childhood genome‐wide gene expression (in transformed lymphoblastoid cell lines) (Tylee et al, ), and adulthood serum protein profiles (Schwarz et al, ; Kong et al, ; Ramsey et al, ; Steeb et al, ).…”

“…These suggest a strong sex/gender‐differential neural expression of autism in intrinsic functional organization of the resting‐state brain network (Alaerts et al, ). A preliminary study also using the ABIDE dataset (with n = 28 females with autism, aged 6–20 years; the autism groups scored slightly lower than the control groups on full‐scale IQ) further identified diagnosis‐by‐sex/gender interactions on the connectivity between precuneus and medial cerebellum/dorsal frontal cortex (Di and Biswal, ). Therefore, sex/gender‐differential neural characteristics of autism also seem to present in the intrinsic functional organization of the brain, and it is too early to conclude how age or IQ moderates these findings.…”