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Autism. Author manuscript; available in PMC 2020 November 01.
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Published in final edited form as:

Autism. 2020 November ; 24(8): 2190–2201. doi:10.1177/1362361320938194.

Sex-Related Patterns of Intrinsic Functional Connectivity in

Children and Adolescents with Autism Spectrum Disorders
Lindsay A. Olson, M.S., Lisa E. Mash, M.S.
Brain Development Imaging Laboratories, Dept. of Psychology, San Diego State University

San Diego State University / UC San Diego Joint Doctoral Program in Clinical Psychology

Annika Linke, Ph.D., Christopher H. Fong, M.A.

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Brain Development Imaging Laboratories, Dept. of Psychology, San Diego State University

Ralph-Axel Müller, Ph.D., Inna D. Fishman, Ph.D.

Brain Development Imaging Laboratories, Dept. of Psychology, San Diego State University

San Diego State University / UC San Diego Joint Doctoral Program in Clinical Psychology

Abstract
Background: Although a growing literature highlights sex differences in ASD clinical
presentation, less is known about female variants at the neural level. We investigated sex-related
patterns of functional connectivity (FC) within and between functional networks in children and
adolescents with ASDs, compared to typically developing (TD) peers.
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Method: Resting-state functional MRI data for 141 children and adolescents (7–17 years)
selected from an in-house sample and four sites contributing to the Autism Brain Imaging
Database Exchange (ABIDE I and II) were submitted to group independent component analysis
(ICA) to generate resting-state functional networks (RFNs). FC was estimated by generating RFN-
RFN correlation matrices, which were directly compared between males and females, and ASD
and TD groups.

Results: Results revealed greater connectivity within the default mode network (DMN) in TD
girls as compared to TD boys, while no such sex effect was observed in the ASD group.
Correlational analyses with clinical indices revealed a negative relationship between sensorimotor
connectivity and history of early autism symptoms in girls, but not in boys with ASD.

Conclusions: A lack of neurotypical sex differentiation in DMN functional connectivity

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observed in boys and girls with ASD suggests that sex-related differences in network integration
may be altered in ASD.
Lay Summary:

Corresponding Author: Lindsay Olson, M.S., Brain Development Imaging Laboratories, Department of Psychology, San Diego State
University, 6363 Alvarado Ct., Suite 200, San Diego, CA 92120, olsonlindsaya@gmail.com.
Conflicts of Interest: The authors have no financial disclosures or conflicts of interest to report.
Ethics Statement: For the in-house sample, informed assent and consent were obtained from all participants and their caregivers,
respectively, in accordance with the San Diego State University and University of California, San Diego Institutional Review Boards.
For ABIDE data, prior to data contribution, sites were required to confirm that their local Institutional Review Board or ethics
committee had approved both the initial data collection and the sharing of fully de-identified datasets.
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We investigated whether children and adolescents with autism spectrum disorders show sex-
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specific patterns of brain function (using fMRI) that are well documented in typically developing
males and females. We found, unexpectedly, that boys and girls with autism do not differ in their
brain functional connectivity, whereas typically developing boys and girls showed differences in a
brain network involved in thinking about self and others (the default mode network). Results
suggest that autism may be characterized by a lack of brain sex differentiation.

Introduction
Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders
characterized by social communication deficits and restrictive and repetitive behaviors and
interests, with symptom onset within the first years of life. While ASDs are symptomatically
heterogeneous, the sex imbalance in prevalence (approximately 3–4:1 male to female ratio)
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is a consistently striking characteristic of the disorder, dating back to its initial description
by Leo Kanner in 1943 (Baio et al., 2018; Constantino, 2017). Indeed, the male bias in ASD
is intrinsic to the features of the disorder itself, which may be associated with female
protective effects (biological mechanisms that reduce its incidence or severity in females), a
phenomenon that is observed, for instance, in Rett Syndrome, an X chromosome-linked
(XL) disorder with lethal consequences for males (Cauvet et al., 2019; Chahil & Bollu,
2018; Gockley et al., 2015).

Given the substantial sex dimorphism in ASD rates, most research studies have been
conducted with exclusively or predominantly male cohorts. As a result, less is known about
female variants of autism, although mounting evidence suggests that girls with ASDs may
be under-identified (Loomes, Hull, & Mandy, 2017) and that ASDs may affect girls
differently than boys (see Werling & Geschwind, 2013). Indeed, the sex imbalance in
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prevalence also biases our understanding of the diagnostic features of ASDs, which in turn
impacts the study of sex/gender-dependent and independent characteristics of the disorder,
and the investigation of etiology and distinct liability thresholds for genetic load and for
likelihood of developing the disorder in boys vs. girls (M. C. Lai, Lombardo, Auyeung,
Chakrabarti, & Baron-Cohen, 2015). For instance, sex-specific phenotypes may include
fewer restricted and repetitive behaviors (Szatmari et al., 2012), as well as fewer
externalizing behaviors (Hiller, Young, & Weber, 2014), in girls. Further, girls with ASDs
within the average-to-high IQ range are underrepresented (Hiller et al., 2014), which may
contribute to their lower participation rates in neuroimaging studies, as adherence to
instructions to remain still presents a barrier in those with lower IQ, thus biasing the current
understanding of the neural bases of ASDs. Finally, females may be more protected from
heritable and de novo ASD risk variants, as XL factors and sex hormones may modulate the
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effects of risk-conferring genetic variants on the presentation of ASD symptoms (Werling &
Geschwind, 2013). Altogether, these reports highlight the need to improve understanding of
sex-related neurobiological differences in ASDs, which will facilitate the development of
novel therapeutic interventions optimized for each sex (Constantino, 2017). However,
despite the growing evidence of sex-related phenotypic and genetic variability in ASDs, only
a few studies to date have focused on sex differences in brain organization in ASDs (Alaerts,

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Swinnen, & Wenderoth, 2016; Kovalev, Kruggel, & von Cramon, 2003; Kurth, Thompson,
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& Luders, 2018).

In neurotypical individuals, females generally have more symmetrical brains than males,
with respect to brain structure, function, network organization, and connectivity (Gong,
Gaolang, Yong, He, Evans, 2011), and such patterns are present well before adulthood. A
large study of neurotypical children, adolescents, and young adults (ages 9–22 years, N =
674) also demonstrated that males displayed greater between-network connectivity, whereas
females displayed greater within-module connectivity (Satterthwaite et al., 2015). By
contrast, others have failed to detect sex differences in functional connectivity (FC) among
typically developing (TD) children and adolescents (Solé-Padullés et al., 2016), though sex
differences in FC in adolescence may be age- and IQ-dependent (Schmithorst & Holland,
2006).
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While these findings demonstrate that sex plays a role in brain developmental trajectories
across the neurotypical lifespan, very few studies have examined differences in brain
organization between males and females with ASDs. The available evidence suggests that
boys and girls with ASDs have distinct patterns of early brain overgrowth, with enlargement
of brain volume observed more prominently, or even exclusively in boys (Courchesne,
Carper, & Akshoomoff, 2003; Nordahl et al., 2011). Atypical sex-related brain organization
appears to persist into adulthood, as typical patterns of sex differentiation in brain white
matter connectivity and volume (i.e., higher in neurotypical men than women) are absent
(Beacher et al., 2012), or attenuated (Cauvet et al., 2019; M.-C. Lai et al., 2017), in adults
with ASDs. Similarly, sex-related patterns of neurotypical cortical thickness may be absent
in adults with ASDs (Ecker, 2019; Ecker et al., 2017).
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Among theoretical explanations of sex effects in ASDs, including the higher incidence of
ASDs in males, Baron-Cohen’s “extreme male brain theory of autism” (EMBT), which links
ASD etiology to the effects of fetal testosterone (Baron-Cohen et al., 2015), is perhaps most
well-known. EMBT proposes that autism represents enhanced ‘systematizing’
neurocognition, which is predominant among neurotypical males versus females, in contrast
to ‘empathizing’ patterns prominently reflected in neurotypical females (although the author
allows that the degree of this dimorphism is somewhat distributed in the general population;
Baron-Cohen, 2002). However, the EMBT remains controversial (Alaerts et al., 2016;
Bejerot et al., 2012).

An alternative theory, known as the sex incoherence theory, proposes that ASDs are
associated with neural androgyny or sex incoherence, rather than an amplification of
stereotypically male neurocognitive phenotypes (Bejerot et al., 2012). Indeed, a
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neuroimaging study (Alaerts et al., 2016), albeit in a sample spanning both childhood and
adulthood (ages 7–30 years), reported similar FC patterns between males with ASDs and TD
females, and between females with ASDs and TD males. In particular, males with ASDs
exhibited predominantly weaker connectivity relative to TD males between multiple regions
of interest (ROIs), reflecting neural feminization, while females with ASDs showed stronger
connectivity relative to TD females between the majority of ROI pairs with the whole-brain
coverage, reflecting a shift toward male phenotypes. On the other hand, hypoconnectivity

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within the default mode network (DMN) was recently reported in both males and females
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with ASDs (ages 12–18 years), as compared to TD males, who in turn had weaker DMN
connectivity than TD females (Ypma et al., 2016), consistent with previous evidence of
DMN hypoconnectivity as a male-dominant trait in neurotypical population (Biswal et al.,
2010; Tomasi and Volkow, 2012; Jung et al., 2015; Ritchie et al., 2018), and supportive of
the sex incoherence theory. Yet another study recently reported mixed results supportive of
both EMBT and sex incoherence theory, in a network-specific manner (Floris et al., 2018):
in their cohort, spanning a broad age range (6.5–58 years), an exaggerated neurotypical male
brain pattern (or ‘shift-toward-maleness’) was observed in the DMN, whereas a
predominantly female pattern (or ‘shift-toward-femaleness’) was detected in the
somatomotor network.

Taken together, sex-related patterns of functional brain connectivity in ASDs are equivocal,
with evidence supporting both sex incoherence or extreme male-like neural patterns.
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Disparate conclusions likely reflect methodological differences between studies, as well as

methodological shortcomings, such as inclusion of cohorts with broad age ranges spanning
in some cases 50 years, which effectively masks the unique neurodevelopmental trajectories
observed in ASDs. The lack of consensus also likely stems from the substantial etiological
and clinical heterogeneity, manifesting as diversity of deficits and associated features and
markers, characterizing ASDs (Jeste & Geschwind, 2014). Motivated by these challenges
and evidentiary ambiguities, the present study set out to examine sex-related patterns of
whole brain FC patterns and their relation to ASD symptoms, using a data-driven analytic
approach, Independent Component Analysis, applied to the aggregated MRI data from a
large data-sharing initiative, while restricting the sample age to childhood and adolescence.

Methods
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Participants
Resting-state functional MRI datasets for 141 children and adolescents (ages 7–17 years)
were selected from the publicly available Autism Brain Imaging Database Exchange
(ABIDE I and II; DiMartino et al., 2014 and 2017; n = 111) and an in-house sample (n =
31), with 69 datasets from children with ASDs (35 females and 34 males) and 72 datasets
from typically developing (TD) children (36 females and 36 males). Eligibility for the
inclusion of datasets was determined based on age (<18 years), eye-status during resting
state scans (eyes open), and fMRI data quality (low head motion: datasets in which > 80% of
volumes had <0.5mm frame-wise displacement). ABIDE datasets were included only from
sites that contributed at least 6 female datasets: New York University Langone Medical
Center (NYU_1 n = 32, NYU_2 n = 5), Georgetown University (GU n = 17), Kennedy
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Krieger Institute (KKI n = 32), Oregon Health and Science University (OHSU n = 24; see
Table 1 for details and participant characteristics and supplementary Tables S1 and S1a for
site-specific characteristic information).

ASD diagnoses were confirmed using the Autism Diagnostic Observation Schedule (Lord,
Rutter, Dilavore, Risi, Gotham, Bishop, 2012; Lord et al., 2000), Autism Diagnostic
Interview – Revised (Lord, Rutter, & Le Couteur, 1994), and expert clinical judgment based
on DSM-5 criteria (American Psychiatric Association, 2013). Inclusion in the TD group

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required absence of any developmental disorder (including ASD) or intellectual disability.

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Other specific exclusion criteria used for selecting TD participants (e.g., absence of
neurological or psychiatric history, or absence of family history of ASDs) varied across
ABIDE sites. Within each diagnostic group, boys and girls were matched, at the group level,
on age, handedness, overall cognitive functioning (using full scale IQ), in-scanner head
motion, and study site. Given the challenges involved in matching across all of these
variables, head motion in girls with ASDs (ASD-G) was marginally higher than in boys with
ASDs (ASD-B; p = 0.07). As such, motion was included as a covariate in comparisons
between these two groups. Boys and girls with ASDs were also matched on autism
symptoms (assessed with the ADOS Total Score), incidence of co-occurring psychiatric
conditions, and psychotropic medication usage, due to the documented effects of these
medications on brain function and connectivity (cf., Linke et al., 2017) (see Table 1 and
Table S3; for comparisons between TD and ASD groups combined across gender, see Table
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S2). ASD participants with co-occurring psychiatric diagnoses or those reporting

psychotropic medications usage were not excluded because of the high prevalence of
comorbid psychiatric conditions and psychiatric medication usage in ASDs (Spencer et al.,
2013). Overall cognitive ability was assessed by either the Wechsler Abbreviated Scale of
Intelligence, 2nd Edition (WASI-II; Wechsler, 2011) the Wechsler Intelligence Scales for
Children, 4th and 5th editions (WISC-4: Wechsler, 2006; WISC-5: Weiss & Saklofske,
2016), or the Differential Ability Scales, 2nd Edition (DAS-II—Elliot, 2007).

MRI Data Acquisition and Imaging Parameters

All MRI data were acquired using 3T MRI scanners, although imaging sequence parameters
for both anatomical T1 and functional T2* scans varied across sites (see details on scanning
parameters in Di Martino et al. (2014) and Di Martino et al. (2017). All fMRI data were
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collected during resting state (scan duration varied between 5:14 and 6:40 minutes), with
participants instructed to lie still with their eyes open.

MRI Data Preprocessing

Data were preprocessed using AFNI (Cox, 1996) and FSL 5.0 (Smith et al., 2004). FSL was
used to normalize anatomical images to MNI152 template space and segment structural
images into white matter, grey matter, and cerebrospinal fluid. Functional data were slice-
time and motion-corrected, using the middle time point as the reference volume for re-
alignment; field map corrected (when field maps were available) to minimize magnetic field
inhomogeneity; aligned to anatomical data using FSL FLIRT with six degrees of freedom;
resampled to 3.0 mm isotropic voxels using sinc interpolation; and standardized to the
MNI152 template, using FSL nonlinear registration tool. Spatial smoothing with an isotropic
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Gaussian filter to an effective full-width at half-maximum of 6mm, and temporal filtering of

the signal with a high-pass Butterworth filter (0.008Hz < f) were applied. Six motion
parameters, mean white matter and CSF signals (extracted from participant-level masks
created with FSL and eroded by 1 voxel), and their first temporal derivatives (all equally
high-pass filtered) were modeled as nuisance regressors and removed from the data through
linear regression, in preparation for independent component analysis (ICA).

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Functional Connectivity Analyses

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Processed functional data from all ASD and TD participants, combined, were submitted to
group independent component analysis (ICA) using FSL’s Multivariate Exploratory Linear
Optimized Decomposition into Independent Components (MELODIC) to generate
maximally independent intrinsic functional networks (de Lacy, Doherty, King, Rachakonda,
& Calhoun, 2017). The Group ICA yielded 71 independent components. Components were
marked as artifacts if their spatial maps were confined to the boundaries of the brain or
cerebral ventricles, or were distributed irregularly (Griffanti et al., 2017). The remaining
components were labeled based on two criteria: 1) weighted spatial correlation (r>0.25) with
the ten primary networks derived by Smith and colleagues (Smith et al., 2009), and 2)
concordance with ICA-derived functional networks in previous literature. Ultimately, of the
71 independent components (ICs) derived from ICA, 17 were retained for further analyses
(see Figure S1 and Table S4).
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FSL MELODIC dual-regression was used to generate subject-specific resting functional

networks (RFNs) and associated time courses. Individual RFN spatial maps were
thresholded at 90% of z-score values to generate individualized RFN masks for all
participants. After extracting the mean time series for each RFN mask, FC was estimated by
generating intra-individual Pearson correlation coefficients across all RFN-RFN pairs (136
pairs: (17×16)/2). The resulting correlation coefficients were transformed into Fisher’s z
scores, and individual connectivity matrices were averaged within each group (ASD Boys
[ASD-B], ASD Girls [ASD-G], TD Boys [TD-B], and TD Girls [TD-G]). Connectivity for
all 136 RFN-RFN pairs were compared using linear mixed effects models with Group (ASD,
TD) and sex (Girls, Boys) as predictor variables, head motion, IQ, and age as nuisance
regressors, and site as a random effect nuisance variable. Type-I error inflation was
controlled using False Discovery Rate correction for multiple comparisons.
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In an effort to reduce the overall number of comparisons, RFNs were categorized into three
overarching domains: sensorimotor or unimodal (e.g., visual, auditory networks), default
mode network, and higher-order supramodal domains (e.g., language, executive networks—
see Figure S3 for domain maps across groups). FDR-correction was used for all network and
domain-level analyses (sensorimotor/unimodal, DMN, and higher-order/supramodal) to
control type-I error rate. T-scores for comparisons between boys and girls in each domain
were generated using MATLAB’s ttest2 function.

Results
Sex, Diagnosis, and Sex by Diagnosis Interaction Effects on Network FC
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Connectivity matrices of mean RFN-RFN connectivity (z values) within each diagnostic

group and sex are presented in Figure 1a,b. Linear mixed effects models with diagnosis, sex,
and sex by diagnosis interaction terms as predictor variables, age, motion, and IQ as
nuisance regressors, and site modeled as a random effect revealed the main effects of sex,
diagnosis, and sex by diagnosis interaction effects (all at uncorrected p < 0.05). For
descriptions of the effect sizes of simple comparisons, see Supplementary Materials,
Appendix S1 and Figure S2. Overall, with regard to the main effects of sex, boys displayed

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higher connectivity than girls between the following networks: lateral visual (VIS1), default
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mode (PCC; DMN4), and occipital visual (VIS4) networks; and between sensorimotor (SM1
and SM2) and default mode (DMN3 and DMN4; see Figure 2 and Table 2a).

Main effects of diagnosis were observed as greater connectivity (ASD>TD) between medial
visual (VIS2 and VIS3) and dorsal attention (DAN) networks, and between auditory (AUD)
and default mode (DMN4) networks. Weaker connectivity (ASD<TD) was observed
between medial (DMN1) and PCC (DMN2 and DMN4) nodes of the default mode network,
and between default mode PCC node (DMN2) and the right frontoparietal (rFP) network,
PCC (DMN4) and right frontoparietal (rFP), and between PCC (DMN4) and language
(Lang) networks (see Figure 2 and Table 2a).

Finally, sex by diagnosis interaction effects were identified between sensorimotor and
higher-order supramodal networks, with TD girls displaying greater connectivity than TD
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boys between the sensorimotor (SM1) and dorsal attention (DAN) networks, and
sensorimotor (SM2) and left executive (lFP) networks, while the opposite pattern (girls
showing weaker connectivity than boys) observed in participants with ASDs within the same
connections (see Figure 2 and Table 2a). Other interaction effects were observed within the
default mode network (DMN1 and DMN2), with TD girls displaying greater connectivity
than TD boys within the DMN; and between default mode and language networks (DMN3
and LANG), with TD girls displaying greater connectivity than TD boys, with no differences
observed between ASD boys and girls (see Figure 2 and Table 2a).

Domain-level Connectivity
In order to reduce the number of comparisons and to examine overarching connectivity
patterns, the dimensionality of the connectivity matrix was reduced by grouping the
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individual RFNs into functional domains, achieved by averaging all RFN-RFN z-values
within the unimodal sensorimotor, default mode, and higher-order supramodal domains. The
averaged within- and between-domain z-values were compared within sex and diagnostic
group using linear mixed effects models, with site modeled as a random effect, and motion,
age, and IQ as nuisance regressors (see Figure 3a,b). Analyses revealed a significant main
effect of sex on DMN connectivity, such that girls showed higher DMN connectivity than
boys (see Table 2b). The sex by diagnosis interaction was not significant, but there was a
trend such that the sex effect was present in the TD group, but absent in the ASD group (IQ
and site were included in the model as nuisance regressors, with site modeled as a random
effect). Further, there was a significant main effect of diagnosis on sensorimotor
connectivity, controlling for motion and site, such that TD participants showed higher
within-sensorimotor-domain connectivity than ASD participants.
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Although no significant sex by diagnosis interaction effects were detected, a secondary

analysis comparing connectivity within sex and diagnostic group was conducted within these
three overarching functional domains. This analysis revealed significantly greater within-
DMN connectivity in TD girls compared to TD boys, t(70) = −2.87, p = 0.01 (FDR-corrected
p-value), with effect size of Hedges’ G = −0.52. By contrast, no significant differences in FC
within DMN, or within or between any other functional domains were observed between

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girls and boys with ASDs (or between ASD and TD boys, or ASD and TD girls) (see Figure
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3c,d).

Correlations with Autism Symptoms

Relationships between FC and autism symptoms measured with ADOS and ADI-R were
examined in males and females with ASDs, separately, as an exploration into sex differences
in brain-behavior relationships. A total of 12 correlation tests were performed (correlations
between connectivity in unimodal sensorimotor, DMN, and higher-order supramodal
domains with ADI-R Total, and ADOS-Total scores). A negative correlation was observed
between sensorimotor domain connectivity (average of z-values of the 7 sensorimotor
RFNs) and early history of autism symptoms measured with the ADI-R Total in girls (r =
−0.53, uncorrected p = 0.003; Bonferroni corrected alpha = 0.004), but not boys with ASDs
(see Figure 4), when controlling for the effect of motion (see also Figure S4, for effects of
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motion on connectivity values). Associations between connectivity and autism symptoms

were not statistically significant for any other domains in boys or girls, after correcting for
multiple comparisons.

Discussion
This study investigated sex-related patterns of network connectivity in children and
adolescents with ASDs, using a data-driven method to characterize intrinsic whole brain
functional connectivity. The main and most striking finding was an absence of sex effects on
FC observed in the ASD group, compared to TD children and adolescents who displayed
sex-related connectivity differences within the default mode network, with TD girls showing
greater DMN connectivity than TD boys.
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First, our findings on neurotypical sex differentiation in the DMN observed in the TD group
align with those of previous studies of typical adults, showing higher DMN connectivity in
females compared to males (Biswal et al., 2010; Jung et al., 2015; Ritchie et al., 2018;
Tomasi & Volkow, 2012), suggesting that DMN network connectivity distinguishes
neurotypical male vs. female brains (Zhang et al., 2016). Notably, Lombardo et al. (2018)
showed that fetal testosterone levels predict DMN connectivity in adolescent males, but not
females, and linked their findings to specific genes that are expressed in DMN-relevant
circuitry, arguing that DMN connectivity is negatively associated with prenatal steroid
hormones, and may account, in part, for the observed DMN sex differences (Lombardo et
al., 2018).

While it is not completely understood how sex differences in DMN connectivity translate
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into differences in cognition or behavior, increased DMN connectivity in females aligns with
evidence of females’ greater prosocial orientation and stronger social-evaluative skills in
comparison to males (Gur et al., 2012; Rose & Rudolph, 2006). This is especially
noteworthy because, in addition to being spontaneously engaged during rest or active by
default, in the absence of overt or covert task, the DMN is also associated with social
inference and is said to play a central role in many aspects of social cognition (Kennedy &
Adolphs, 2012), including understanding others and mentalizing (Andrews-Hanna, Saxe, &
Yarkoni, 2014), as well as thinking about the self, in the past, present, and the future

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(Spreng, Mar, & Kim, 2009). Indeed, with task-activation data acquired in adults (ages 18–
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45) with and without ASDs, Lai et al. (2019) demonstrated hypoactivity in the ventral
medial prefrontal cortex (forming part of the DMN) in males with ASDs as compared to TD
males, during self-referential thinking, while no such sex difference was observed in females
with ASDs when compared to TD counterparts. Further, heightened activity in the ventral
medial prefrontal cortex was correlated with enhanced “camouflaging” in females – but not
males – with ASDs, suggesting that there may be sex-mediated links between the DMN /
social brain function in autism and the ability to blend in socially, despite autism-associated
social deficits.

Given its role in self- and other-cognition, it is unsurprising that alterations in DMN
connectivity have been implicated in several studies on the neurobiology of ASDs (Mars et
al., 2012; Spreng & Grady, 2010; Uddin, 2011). Alterations in DMN functional connectivity
are one of the few robust findings in ASDs (Assaf et al., 2010; Weng et al., 2010; Lynch et
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al., 2013; von dem Hagen et al., 2013; Ypma et al., 2016). Specifically, DMN
hypoconnectivity has been widely reported in people with ASDs, in both males and females
alike (Floris et al., 2018; Ypma et al., 2016). While this pattern is potentially supportive of
neural masculinization, it also may reflect neural gender incoherence. On the other hand,
there is evidence that diagnosis effects on DMN connectivity do not equally apply to boys
and girls with ASDs. Alaerts and colleagues (2016) observed DMN hyperconnectivity in
girls with ASDs (particularly within the PCC and superior temporal sulcus), while males
with ASDs showed reduced DMN connectivity compared to TD males. In light of their
findings, the authors argued that girls with ASDs showed a neural shift toward maleness
characterized by DMN hyperconnectivity (as TD boys in their sample showed greater
connectivity compared to TD girls), whereas a shift toward femaleness was observed in ASD
boys. Thus, the authors proposed that ASDs may be characterized by neural sex incoherence
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or androgynization, rather than neural masculinization (Alaerts et al., 2016).

In contrast to seed- and ROI-based connectivity analyses conducted by Alaerts and

colleagues (2016), the present study used a data-driven method to derive resting state
networks and to assess their functional connectivity. This critical difference in methodology
may partially explain the divergence of our findings from those put forth by Alaerts and
colleagues (despite the likely overlap in samples as both studies utilized data from ABIDE).
Independent Component Analysis (ICA) utilized in the present study yields individualized,
data-derived spatiotemporal maps of intrinsic functional networks, rather than one-size-fits
all atlas-derived ROIs, which create arbitrary spatial divisions between brain regions. As
such, ICA provides increased sensitivity to intra- and inter-subject differences not captured
by atlas-based ROI approaches (de Lacy et al., 2017).
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Findings from the present study cannot be fully explained by EMBT (shift toward maleness
in both genders), as our results did not reveal an exaggeration of the typical male neural
profile in either boys or girls with ASDs. However, the sex incoherence theory (shift toward
androgynous neural profiles) also does not fully account for the findings, as neural profiles
for ASD boys did not resemble those of TD girls. Our results did not reveal connectivity
patterns characterized by exaggerations of either male or female neurobiological profiles.
Rather, a neurotypical sex differentiation in DMN functional connectivity observed in our

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TD cohort was absent among ASD children and adolescents. The absence of sex effects in
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the ASD group suggests that autism may be characterized by a perturbation of the processes
that give rise to typical neural sex differentiation. These processes involve a complex
interplay between genes, gonadal hormones, and social and cognitive development as they
relate to sex identity (Hines, 2011). Indeed, perturbations to some of these processes (e.g.,
elevated fetal androgen exposure, elevated male hormone levels in females with ASDs) have
been observed in association with ASDs (Baron-Cohen et al., 2015; Bejerot et al., 2012)

Moreover, relationships between functional connectivity and autism symptoms were

detected in ASD girls, but not in boys, with weaker connectivity in the sensorimotor
networks associated with history of greater early autism symptomatology (measured with
the ADI-R) among girls with ASDs. This pattern suggests that in 7 – 17 years old girls with
ASDs, greater network integration is associated with decreased early symptomatology.
However, no such relationship between functional network integration and ASD symptoms
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was observed in boys. While these analyses do not reveal underlying causes for the differing
patterns of association between sensorimotor network integration and symptom presentation
in boys and girls with ASDs, the distinct relationships observed in boys compared to girls
highlight the importance of investigating these patterns separately in males and females on
the spectrum, as such patterns may go unnoticed in mixed-sex samples.

These findings need to be interpreted in the context of several limitations. First, our dataset
lacked measures on pubertal status and did not control for menarche/menstruation in girls,
and therefore, we could not rule out the potential confound of these differential sex effects
on brain organization and functional connectivity (Klapwijk et al., 2013; Lisofsky et al.,
2015; Marceau, Ram, Houts, Grimm, & Susman, 2011; Tanner, 1962). Further, given that,
on average, boys begin puberty later than girls (Tanner, 1962), boys and girls in this study
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were likely not matched on pubertal status (as the groups were matched on chronological
age). Importantly, however, pubertal timing onset has been shown to be equivalent in
children and adolescents with and without ASDs (May, Pang, O’Connell, & Williams,
2017). Additionally, while allowing for greater sample sizes of girls and boys with ASDs,
the use of multisite data has inevitably contributed noise (due to distinct phenotypic
inclusion / exclusion criteria, variability between scanners, acquisition parameters, etc.),
although variability due to site was statistically controlled in analyses. Additionally, datasets
from ABIDE provide limited behavioral and phenotypic data, which restricted our ability to
examine whether the observed effects were related to clinical or phenotypic variability.

The current analyses of sex-related differences in resting-state functional connectivity in

children and adolescents with and without ASDs revealed a lack of typical sex
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differentiation in DMN functional connectivity in boys and girls on the spectrum. These
distinct brain-behavior relationships provide support for the notion that ASD may manifest
differently in girls than boys. As such, it remains critically important to include females in
studies of ASDs, as much of what is known about this heterogeneous set of disorders is
based on males. Rather than excluding females, studies should account for the effects of sex
in their analyses by testing and controlling for sex effects in their samples. Further, as female
ASD datasets are scarce, data-sharing initiatives (e.g., ABIDE I and II) remain a very useful
resource for learning about unique features of ASDs in girls and women on the spectrum,

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 Olson et al. Page 11

which, in turn, contributes to our understanding of ASDs as a complex set of

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neurodevelopmental disorders.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments:
Funding Sources: This work was supported by grants from the National Institutes of Health (K01 MH097972 to I.
Fishman and R01 MH081023 to R-A. Müller).

References
Alaerts K, Swinnen SP, & Wenderoth N (2016). Sex differences in autism: a resting-state fMRI
investigation of functional brain connectivity in males and females. Social Cognitive and Affective
Author Manuscript

Neuroscience, 11(6), 1002–1016. 10.1093/scan/nsw027 [PubMed: 26989195]

Andrews-Hanna JR, Saxe R, & Yarkoni T (2014). Contributions of episodic retrieval and mentalizing
to autobiographical thought: evidence from functional neuroimaging, resting-state connectivity, and
fMRI meta-analyses. NeuroImage, 91, 324–335. 10.1016/j.neuroimage.2014.01.032 [PubMed:
24486981]
Assaf M, Jagannathan K, Calhoun VD, Miller L, Stevens MC, Sahl R, … Pearlson GD (2010).
Abnormal functional connectivity of default mode sub-networks in autism spectrum disorder
patients. NeuroImage, 53(1), 247–256. 10.1016/j.neuroimage.2010.05.067 [PubMed: 20621638]
American Psychiatric Association (Ed.) (2013). Diagnostic and Statistical Manual of Mental Disorders
(5th ed.). Washington, DC: American Psychiatric Association.
Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, … Dowling NF (2018).
Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and
Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR.
Surveillance Summaries, 67(6), 1–23. 10.15585/mmwr.ss6706a1
Author Manuscript

Baron-Cohen S, Auyeung B, Nørgaard-Pedersen B, Hougaard DM, Abdallah MW, Melgaard L, …

Lombardo MV (2015). Elevated fetal steroidogenic activity in autism. Molecular Psychiatry, 20(3),
369–376. 10.1038/mp.2014.48 [PubMed: 24888361]
Beacher FD, Minati L, Baron-Cohen S, Lombardo MV, Lai M-C, Gray MA, … Critchley HD (2012).
Autism attenuates sex differences in brain structure: A combined voxel-based morphometry and
diffusion tensor imaging study. American Journal of Neuroradiology, (33), 83–89. 10.3174/
ajnr.A2880 [PubMed: 22173769]
Bejerot S, Eriksson JM, Bonde S, Carlström K, Humble MB, & Eriksson E (2012). The extreme male
brain revisited: gender coherence in adults with autism spectrum disorder. British Journal of
Psychiatry, 201(02), 116–123. 10.1192/bjp.bp.111.097899 [PubMed: 22500012]
Biswal BB, Mennes M, Zuo X-N, Gohel S, Kelly C, Smith SM, … Milham MP (2010). Toward
discovery science of human brain function. Proceedings of the National Academy of Sciences of the
United States of America, 107(10), 4734–4739. 10.1073/pnas.0911855107 [PubMed: 20176931]
Cauvet É, Van’t Westeinde A, Toro R, Kuja-Halkola R, Neufeld J, Mevel K, & Bölte S (2019). Sex
differences along the autism continuum: A twin study of brain structure. Cerebral Cortex (New
Author Manuscript

York, N.Y.: 1991), 29(3), 1342–1350. 10.1093/cercor/bhy303

Chahil G, & Bollu PC (2018). Rett Syndrome StatPearls Publishing Retrieved from http://
www.ncbi.nlm.nih.gov/pubmed/29489169
Constantino JN (2017). Taking stock of critical clues to understanding sex differences in the
prevalence and recurrence of autism. Autism, 136236131770441 10.1177/1362361317704414
Courchesne E, Carper R, & Akshoomoff N (2003). Evidence of brain overgrowth in the first year of
life in autism. JAMA, 290(3), 337 10.1001/jama.290.3.337 [PubMed: 12865374]

Autism. Author manuscript; available in PMC 2020 November 01.

 Olson et al. Page 12

Cox RW (1996). AFNI: software for analysis and visualization of functional magnetic resonance
neuroimages. Computers and Biomedical Research, an International Journal, 29(3), 162–173.
Author Manuscript

Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8812068

de Lacy N, Doherty D, King BH, Rachakonda S, & Calhoun VD (2017). Disruption to control network
function correlates with altered dynamic connectivity in the wider autism spectrum. NeuroImage:
Clinical, 15, 513–524. 10.1016/J.NICL.2017.05.024 [PubMed: 28652966]
Di Martino A, Yan C-G, Li Q, Denio E, Castellanos FX, Alaerts K, … Milham MP (2014). The autism
brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in
autism. Molecular Psychiatry, 19(6), 659–667. 10.1038/mp.2013.78 [PubMed: 23774715]
Di Martino A, Yan C-G, Li Q, Denio E, Castellanos FX, Alaerts K, … Milham MP (2017). Enhancing
studies of the connectome in autism using the autism brain imaging data exchange II. Scientific
Data, 4, 170010 10.1038/sdata.2017.10 [PubMed: 28291247]
Ecker C (2019). Notice of Retraction and Replacement: Ecker et al. Association between the
probability of autism spectrum disorder and normative sex-related phenotypic diversity in brain
structure. JAMA Psychiatry. 2017;74(4):329–338. JAMA Psychiatry, 76(5), 549. 10.1001/
jamapsychiatry.2018.4296
Author Manuscript

Ecker C, Andrews DS, Gudbrandsen CM, Marquand AF, Ginestet CE, Daly EM, … Murphy DGM
(2017). Association between the probability of autism spectrum disorder and normative sex-related
phenotypic diversity in brain structure. JAMA Psychiatry, 42(1), 48–59. 10.1001/
jamapsychiatry.2016.3990
Elliot C (2007). Differential Ability Scales (2nd ed.). San Antonio, TX: Harcourt Assessment.
Floris DL, Lai M-C, Nath T, Milham MP, Di Martino A, & Org AD (2018). Network-specific sex
differentiation of intrinsic brain function in males with autism. Molecular Autism, 9 10.1186/
s13229-018-0192-x
Gockley J, Willsey AJ, Dong S, Dougherty JD, Constantino JN, & Sanders SJ (2015). The female
protective effect in autism spectrum disorder is not mediated by a single genetic locus. Molecular
Autism, 6, 25 10.1186/s13229-015-0014-3 [PubMed: 25973162]
Gong Gaolang, Yong He, Evans A (2011). Brain connectivity: Gender makes a difference. The
Neuroscientist, 17(5), 575–591. Retrieved from http://journals.sagepub.com/doi/pdf/
10.1177/1073858410386492 [PubMed: 21527724]
Griffanti L, Douaud G, Bijsterbosch J, Evangelisti S, Alfaro-Almagro F, Glasser MF, … Smith SM
Author Manuscript

(2017). Hand classification of fMRI ICA noise components. NeuroImage, 154, 188–205. 10.1016/
J.NEUROIMAGE.2016.12.036 [PubMed: 27989777]
Gur RC, Richard J, Calkins ME, Chiavacci R, Hansen JA, Bilker WB, … Gur RE (2012). Age group
and sex differences in performance on a computerized neurocognitive battery in children age 8–21.
Neuropsychology, 26(2), 251–265. 10.1037/A0026712 [PubMed: 22251308]
Hiller RM, Young RL, & Weber N (2014). Sex differences in autism spectrum disorder based on
DSM-5 criteria: Evidence from clinician and teacher reporting. Journal of Abnormal Child
Psychology, 42(8), 1381–1393. 10.1007/s10802-014-9881-x [PubMed: 24882502]
Hines M (2011). Gender development and the human brain. Annual Review of Neuroscience, 34(1),
69–88. 10.1146/annurev-neuro-061010-113654
Jeste SS, & Geschwind DH (2014). Disentangling the heterogeneity of autism spectrum disorder
through genetic findings. Nature Reviews Neurology, 10(2), 74–81. 10.1038/nrneurol.2013.278
[PubMed: 24468882]
Jung M, Mody M, Saito DN, Tomoda A, Okazawa H, Wada Y, & Kosaka H (2015). Sex differences in
Author Manuscript

the default mode network with regard to autism spectrum traits: A resting state fMRI study. PloS
One, 10(11), e0143126 10.1371/journal.pone.0143126 [PubMed: 26600385]
Kennedy DP, & Adolphs R (2012). The social brain in psychiatric and neurological disorders. Trends
in Cognitive Sciences, 16(11), 559–572. 10.1016/j.tics.2012.09.006 [PubMed: 23047070]
Klapwijk ET, Goddings A-L, Burnett Heyes S, Bird G, Viner RM, & Blakemore S-J (2013). Increased
functional connectivity with puberty in the mentalising network involved in social emotion
processing. Hormones and Behavior, 64(2), 314–322. 10.1016/j.yhbeh.2013.03.012 [PubMed:
23998674]

Autism. Author manuscript; available in PMC 2020 November 01.

 Olson et al. Page 13

Kovalev VA, Kruggel F, & von Cramon DY (2003). Gender and age effects in structural brain
asymmetry as measured by MRI texture analysis. NeuroImage, 19(3), 895–905. 10.1016/
Author Manuscript

S1053-8119(03)00140-X [PubMed: 12880818]

Kurth F, Thompson PM, & Luders E (2018). Investigating the differential contributions of sex and
brain size to gray matter asymmetry. Cortex, 99, 235–242. 10.1016/J.CORTEX.2017.11.017
[PubMed: 29287244]
Lai M-C, Lerch JP, Floris DL, Ruigrok ANV, Pohl A, Lombardo MV, & Baron-Cohen S (2017).
Imaging sex/gender and autism in the brain: Etiological implications. Journal of Neuroscience
Research, 95(1–2), 380–397. 10.1002/jnr.23948 [PubMed: 27870420]
Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, & Baron-Cohen S (2015). Sex/gender differences
and autism: Setting the scene for future research. Journal of the American Academy of Child and
Adolescent Psychiatry. Elsevier Inc. 10.1016/j.jaac.2014.10.003
Laird AR, Lancaster JL, & Fox PT (2005). BrainMap: the social evolution of a human brain mapping
database. Neuroinformatics, 3(1), 65–78. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
15897617 [PubMed: 15897617]
Linke AC, Olson L, Gao Y, Fishman I, & Müller R-A (2017). Psychotropic medication use in autism
Author Manuscript

spectrum disorders may affect functional brain connectivity. Biological Psychiatry: Cognitive
Neuroscience and Neuroimaging, 2(6), 518–527. 10.1016/j.bpsc.2017.06.008 [PubMed:
29104944]
Lisofsky N, Mårtensson J, Eckert A, Lindenberger U, Gallinat J, & Kühn S (2015). Hippocampal
volume and functional connectivity changes during the female menstrual cycle. NeuroImage, 118,
154–162. 10.1016/J.NEUROIMAGE.2015.06.012 [PubMed: 26057590]
Lombardo MV, Auyeung B, Pramparo T, Quartier A, Courraud J, Holt RJ, … Baron-Cohen S (2018).
Sex-specific impact of prenatal androgens on social brain default mode subsystems. Molecular
Psychiatry, 1–14. 10.1038/s41380-018-0198-y
Loomes R, Hull L, & Mandy WPL (2017). What is the male-to-female ratio in autism spectrum
disorder? A systematic review and meta-analysis. Journal of the American Academy of Child &
Adolescent Psychiatry, 56(6), 466–474. 10.1016/J.JAAC.2017.03.013 [PubMed: 28545751]
Lord C, Rutter M, Dilavore P, Risi S Gotham K, Bishop S (2012). Autism Diagnostic Observation
Schedule, Second Edition (ADOS-2) Manual (Part I): Modules 1–4. Torrance, CA: Western
Psychological Services.
Author Manuscript

Lord C, Risi S, Lambrecht L, Cook EH, Leventhal BL, DiLavore PC, … Rutter M (2000). The autism
diagnostic observation schedule-generic: a standard measure of social and communication deficits
associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3),
205–223. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11055457 [PubMed: 11055457]
Lord C, Rutter M, & Le Couteur A (1994). Autism Diagnostic Interview-Revised: a revised version of
a diagnostic interview for caregivers of individuals with possible pervasive developmental
disorders. Journal of Autism and Developmental Disorders, 24(5), 659–685. Retrieved from http://
www.ncbi.nlm.nih.gov/pubmed/7814313 [PubMed: 7814313]
Lynch CJ, Uddin LQ, Supekar K, Khouzam A, Phillips J, & Menon V (2013). Default mode network
in childhood autism: Posteromedial cortex heterogeneity and relationship with social deficits.
Biological Psychiatry, 74(3), 212–219. 10.1016/j.biopsych.2012.12.013 [PubMed: 23375976]
Marceau K, Ram N, Houts RM, Grimm KJ, & Susman EJ (2011). Individual differences in boys’ and
girls’ timing and tempo of puberty: modeling development with nonlinear growth models.
Developmental Psychology, 47(5), 1389–1409. 10.1037/a0023838 [PubMed: 21639623]
Author Manuscript

Mars RB, Neubert F-X, Noonan MP, Sallet J, Toni I, & Rushworth MFS (2012). On the relationship
between the default mode network and the social brain. Frontiers in Human Neuroscience, 6, 189
10.3389/fnhum.2012.00189 [PubMed: 22737119]
May T, Pang KC, O’Connell MA, & Williams K (2017). Typical pubertal timing in an Australian
population of girls and boys with autism spectrum disorder. Journal of Autism and Developmental
Disorders, 47(12), 3983–3993. 10.1007/s10803-017-3281-3 [PubMed: 28856494]
Nordahl CW, Lange N, Li DD, Barnett LA, Lee A, Buonocore MH, … Amaral DG (2011). Brain
enlargement is associated with regression in preschool-age boys with autism spectrum disorders.

Autism. Author manuscript; available in PMC 2020 November 01.

 Olson et al. Page 14

Proceedings of the National Academy of Sciences of the United States of America, 108(50),
20195–20200. 10.1073/pnas.1107560108 [PubMed: 22123952]
Author Manuscript

Ritchie SJ, Cox SR, Shen X, Lombardo MV, Reus LM, Alloza C, … Deary IJ (2018). Sex differences
in the adult human brain: Evidence from 5216 UK Biobank participants. Cerebral Cortex (New
York, N.Y. : 1991), 28(8), 2959–2975. 10.1093/cercor/bhy109
Rose AJ, & Rudolph KD (2006). A review of sex differences in peer relationship processes: potential
trade-offs for the emotional and behavioral development of girls and boys. Psychological Bulletin,
132(1), 98–131. 10.1037/0033-2909.132.1.98 [PubMed: 16435959]
Satterthwaite TD, Wolf DH, Roalf DR, Ruparel K, Erus G, Vandekar S, … Gur RC (2015). Linked sex
differences in cognition and functional connectivity in youth. Cerebral Cortex, 25(9), 2383–2394.
10.1093/cercor/bhu036 [PubMed: 24646613]
Schmithorst VJ, & Holland SK (2006). Functional MRI evidence for disparate developmental
processes underlying intelligence in boys and girls. NeuroImage, 31(3), 1366–1379. 10.1016/
j.neuroimage.2006.01.010 [PubMed: 16540350]
Baron-Cohen Simon (2002). The extreme male brain theory of autism. TRENDS in Cognitive
Sciences, 6(6). Retrieved from http://tics.trends.com
Author Manuscript

Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, … Beckmann CF (2009).
Correspondence of the brain’s functional architecture during activation and rest. Proceedings of
the National Academy of Sciences of the United States of America, 106(31), 13040–13045.
10.1073/pnas.0905267106 [PubMed: 19620724]
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, … Matthews
PM (2004). Advances in functional and structural MR image analysis and implementation as FSL.
NeuroImage, 23, S208–S219. 10.1016/j.neuroimage.2004.07.051 [PubMed: 15501092]
Solé-Padullés C, Castro-Fornieles J, de la Serna E, Calvo R, Baeza I, Moya J, … Sugranyes G (2016).
Intrinsic connectivity networks from childhood to late adolescence: Effects of age and sex.
Developmental Cognitive Neuroscience, 17, 35–44. 10.1016/j.dcn.2015.11.004 [PubMed:
26657414]
Spencer D, Marshall J, Post B, Kulakodlu M, Newschaffer C, Dennen T, … Jain A (2013).
Psychotropic medication use and polypharmacy in children with autism spectrum disorders.
Pediatrics, 132(5), 833–840. 10.1542/peds.2012-3774 [PubMed: 24144704]
Spreng RN, & Grady CL (2010). Patterns of brain activity supporting autobiographical memory,
Author Manuscript

prospection, and theory of mind, and their relationship to the Default Mode Network. Journal of
Cognitive Neuroscience, 22(6), 1112–1123. 10.1162/jocn.2009.21282 [PubMed: 19580387]
Spreng RN, Mar RA, & Kim ASN (2009). The common neural basis of autobiographical memory,
prospection, navigation, theory of mind, and the Default Mode: A quantitative meta-analysis.
Journal of Cognitive Neuroscience, 21(3), 489–510. 10.1162/jocn.2008.21029 [PubMed:
18510452]
Szatmari P, Liu X-Q, Goldberg J, Zwaigenbaum L, Paterson AD, Woodbury-Smith M, … Thompson A
(2012). Sex differences in repetitive stereotyped behaviors in autism: Implications for genetic
liability. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 159B(1), 5–12.
10.1002/ajmg.b.31238 [PubMed: 22095612]
Tanner J (1962). Growth and Development (2nd ed.). Oxford: Blackwell Scientific Publications.
Tomasi D, & Volkow ND (2012). Gender differences in brain functional connectivity density. Human
Brain Mapping, 33(4), 849–860. 10.1002/hbm.21252 [PubMed: 21425398]
Uddin LQ (2011). The self in autism: an emerging view from neuroimaging. Neurocase, 17(3), 201–
Author Manuscript

208. 10.1080/13554794.2010.509320 [PubMed: 21207316]

von dem Hagen EAH, Stoyanova RS, Baron-Cohen S, & Calder AJ (2013). Reduced functional
connectivity within and between ‘social’ resting state networks in autism spectrum conditions.
Social Cognitive and Affective Neuroscience, 8(6), 694–701. 10.1093/scan/nss053 [PubMed:
22563003]
Wechsler D (2006). Wechsler Intelligence Scale for Children (4th ed.). San Antonio, TX: The
Psychological Corporation.
Wechsler D (2011). Wechsler Abbreviated Scales of Intelligence, Second Edition. San Antonio, TX:
NCS Pearson.

Autism. Author manuscript; available in PMC 2020 November 01.

 Olson et al. Page 15

Weiss LG, & Saklofske DH (2016). WISC-V Assessment and Interpretation Scientist – Practitioner
Perspectives. (Weiss A, Saklofske LG, Holdnack DH, Prifitera JA, Ed.). San Diego, CA: Elsevier
Author Manuscript

Academic Press.
Weng S-J, Wiggins JL, Peltier SJ, Carrasco M, Risi S, Lord C, & Monk CS (2010). Alterations of
resting state functional connectivity in the default network in adolescents with autism spectrum
disorders. Brain Research, 1313, 202–214. 10.1016/j.brainres.2009.11.057 [PubMed: 20004180]
Werling DMDM, & Geschwind DHDH (2013). Sex differences in autism spectrum disorders. Current
Opinion in Neurology, 26(2), 146–153. 10.1097/WCO.0b013e32835ee548.Sex [PubMed:
23406909]
Ypma RJF, Moseley RL, Holt RJ, Rughooputh N, Floris DL, Chura LR, … Rubinov M (2016). Default
mode hypoconnectivity underlies a sex-related autism spectrum. Biological Psychiatry. Cognitive
Neuroscience and Neuroimaging, 1(4), 364–371. 10.1016/j.bpsc.2016.04.006 [PubMed:
27430030]
Zhang C, Cahill ND, Arbabshirani MR, White T, Baum SA, & Michael AM (2016). Sex and age
effects of functional connectivity in early adulthood. Brain Connectivity, 6(9), 700–713. 10.1089/
brain.2016.0429 [PubMed: 27527561]
Author Manuscript
Author Manuscript
Author Manuscript

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Figure 1.
Connectivity Matrices (z-values) for RFN-RFN connectivity for a) ASD-B (lower left
triangle) and ASD-G (upper right triangle), and b) TD-B (lower left triangle) and TD-G
(upper right triangle).
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Figure 2.
Upper triangles depict beta values, and red cells in lower triangles depict p-values < 0.05
(uncorrected) showing RFN-RFN connectivity for a) main effects of diagnosis b) main
effects of sex, and c) sex by diagnosis interactions.
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Figure 3.
Top panel: Domain-level connectivity matrices (averaged z-values within- and between-
domains) for a) ASD-B (lower left triangle) and ASD-G (upper right triangle), and b) TD-B
(lower left triangle) and TD-G (upper right triangle). Bottom panel: DMN within-network
connectivity (averaged z-values for all DMN RFN components) plotted for c) ASD-B vs.
ASD-G, and d) TD-B vs. TD-G. TD-G showed significantly higher within-DMN
connectivity than TD-B (t(1, 70) = −2.87, p = 0.005, FDR corrected p = 0.01). ASD-B and
ASD-G did not differ in their within-DMN connectivity.
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Figure 4.
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Correlation between sensorimotor domain connectivity (averaged z-values for all 7

sensorimotor RFNs) and early history of symptoms as measured with the ADI-R (Total
Score), for ASD-B (blue) and ASD-G (red). The zero-order correlation is plotted with
(uncorrected p-value).
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Table 1.

Participant Characteristics
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Characteristic ASD-B, n = 34 ASD-G, n = 35 Boys vs. Girls, p

Handedness (R/L) 30/4 30/5 0.76
Age (years), mean ± SD (range) 11.5 ± 2.1 (7.2–17.7) 11.6 ± 2.9 (7.0–17.9) 0.72

Verbal IQ*, mean ± SD (range) 106.2 ± 17.8 (79–143) 103.0 ± 14.5 (79–139) 0.44

Nonverbal IQ*, mean ± SD (range) 105.0 ± 17.1 (81–142) 100.1 ± 19.9 (53–140) 0.34
Full-scale IQ, mean ± SD (range) 104.3 ± 17.9 (81–142) 101.2 ± 17.8 (66–132) 0.48
ADOS (total), mean ± SD (range) 11.7 ± 4.3 (3–23) 10.6 ± 2.7 (6–17) 0.45
ADI-R (total), mean ± SD (range) 40.7 ± 10.6 (20–61) 35.6 ± 12.8 (13–64) 0.09
RMSD, FC head motion, mean ± SD (range) 0.074 ± 0.04 (0.03–0.14) 0.086 ± 0.04 (0.03–0.16) 0.07
Proportion on Psychiatric Medication 10/34 12/35 0.67
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Characteristic TD-B, n = 36 TD-G, n = 36 Boys vs. Girls, p

Handedness (R/L) 31/5 32/3 0.48
Age (years), mean ± SD (range) 11.8 ± 2.3 (7.0–17.9) 11.4 ± 2.0 (8.7–17.3) 0.45

Verbal IQ*, mean ± SD (range) 112.4 ± 13.4 (86–141) 112.2 ± 12.8 (85–146) 0.37

Nonverbal IQ*, mean ± SD (range) 109.6 ± 16.5 (83–137) 108.4 ± 11.8 (79–126) 0.99
Full-scale IQ, mean ± SD (range) 112.4 ± 9.3 (91–137) 113.1 ± 11.6 (80–132) 0.58
RMSD, FC head motion, mean ± SD (range) 0.06 ± 0.02 (0.02–0.09) 0.06 ± 0.02 (0.02–0.11) 0.54

Notes. ASD-B: ASD Boys, ASD-G: ASD Girls, TD-B: TD Boys, TD-G: TD Girls, ADOS: Autism Diagnostic Observation Schedule, ADI-R:
Autism Diagnostic Interview-Revised, RMSD: Root mean squared displacement.

P-values reflect results from independent samples t-tests or chi-square tests of independence; ASD vs. TD comparisons are presented in Table S2.
Details on the participants’ psychotropic medication status and incidence of co-occurring psychiatric diagnoses in the ASD group are presented in
Table S3.
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*
Nonverbal and Verbal IQ data do not include data from OHSU, as this information was not available for the ABIDE OHSU collection.
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Table 2a.

LME Results for RFN-RFN Connectivity

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Effect Beta P-Value RFN 1 RFN 2

Diagnosis Effect ASD > TD −0.09 0.03 VIS2 DAN

−0.13 0.03 VIS3 DAN
−0.12 0.04 AUD DMN4

TD > ASD 0.02 0.02 DMN1 DMN2

0.20 <0.001 DMN1 DMN4
0.04 0.01 DMN2 rFP
0.11 0.02 DMN4 rFP
0.17 0.01 DMN4 Lang

Sex Effect Boys > Girls 0.08 0.02 VIS1 DMN4

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0.06 0.02 VIS2 VIS4

0.13 0.02 SM1 DMN4
0.05 0.02 SM2 DMN3

Diagnosis by Sex Interaction TD-G > TD-B, ASD-G = ASD-B 0.27 0.04 SM2 lFP
0.47 0.02 SM1 DAN
0.49 0.03 DMN1 DMN3
0.33 0.03 DMN2 Lang

Note: Results are shown for uncorrected p< 0.05 for completeness. Results did not survive FDR correction for multiple comparisons. Analyses
included motion, age, and IQ as nuisance regressors, and site as a random effect.
Author Manuscript
Author Manuscript

Autism. Author manuscript; available in PMC 2020 November 01.

 Olson et al. Page 22

Table 2b.

LME Results for Domain-Level Connectivity

Author Manuscript

Functional Domain Effect Beta P-Value

Sensorimotor Diagnosis: ASD > TD −0.13 0.04

DMN Sex: Girls > Boys −0.33 0.003
Sex X Diagnosis 0.26 0.10

*
Note: showing results for uncorrected p< 0.05 for completeness. Only main effect of gender on DMN connectivity survived FDR correction for
multiple comparisons.
Author Manuscript
Author Manuscript
Author Manuscript

Autism. Author manuscript; available in PMC 2020 November 01.