Table 4.
Significant findings of investigations of sex/gender-by-diagnosis interactions and sex/gender-stratified analysis of autism-control differences in resting-state functional connectivity (rs-fMRI).
| Study | Country of origin for study sample | Method (‘sex’ or ‘gender’ is based on the term used in the study) | Metrics/Outcome measure | Sample size (M:F) | Age range | Covariates in analysis | Notable results (‘sex’ or ‘gender’ is based on the term used in the study) |
|---|---|---|---|---|---|---|---|
| Alaerts et al., 2016 (ABIDE) | International | rs-fMRI (whole-brain region-to-region functional connectivity explored with whole-brain parcellated network of 200 ROIs) sex*dx |
resting-state functional connectivity (seed-to-voxel, whole-brain region-to-region) |
84 autism (42:42) 150 TD (75:75) |
all female participants 7–30 yr all male participants matched pair-wise for age and IQ |
frame-wise displacement scores, site, FSIQ, age |
seed-to-voxel significant sex*dx effects for right STS-seed, left STS-seed and PCC-seed whole-brain ROI-to-ROI significant sex*dx effects for right SFG-left MTG connection and right SFG-precuneus/PCC connection males (ASD < TD) females (ASD > TD) |
|
Ypma et al., 2016 (CFSA - primary; ABIDE - replication) |
United Kingdom; International |
rs-fMRI (ROIs: DMN defined as 58 8 mm-radius spherical ROIs derived from meta-analysis of fMRI studies) sex stratified |
a functional DMN intra-connectivity (density of all binary intra-DMN edges minus a constant number of such edges expected in a random network) |
CFSA 51 autism (35:16) 40 TD (20:20) ABIDE 463 autism (408:55) 517 TD (428:89) |
CFSA all participants 12–18 yr ABIDE all participants 6–58 yr (47% in 12–18 yr range) |
site, age, IQ, mean frame-wise displacement |
significant reduction in DMN intra-connectivity in both males and females with ASD compared to same-sex controls (significant reduction in DMN intra-connectivity was replicated in ABIDE sample) |
|
Subbaraju et al., 2017 (ABIDE) |
International |
rs-fMRI (ROIs: 90 regions of the brain based on AAL atlas) gender stratified |
temporal signals and spatial distribution weights from projection matrix of BOLD time-series signals |
505 autism (443:62) 530 TD (435:95) |
all participants 6.5–58 yr |
none reported |
regional differences in resting state activities: autistic males showed a clear shift in activities to PFC; diminished activities in other parts of the brain compared to TD males autistic females showed diminished activities in posterior and medial portions compared to TD females |
|
Yang and Lee, 2018 (ABIDE) |
International |
rs-fMRI (ROIs: four mentalizing regions – mPFC, bilateral TPJ, precuneus) sex*dx |
intrinsic functional connectivity (average BOLD time course extracted from each seed region correlated with time courses of all voxels in the rest of the brain) |
48 autism (24:24) 48 TD (24:24) |
no range; autism (M) 14.5 ± 4.7 yr autism (F) 14.4 ± 4.6 yr TD (M) 14.9 ± 4.3 yr TD (F) 14.5 ± 4.7 yr |
age, IQ scores, eye status during scanning, site information (TR, voxel size, length of scan) |
sex*dx interaction was found in both short- and long- distance functional connectivity effects autistic males showed overconnectivity (ASD > TD) in the bilateral TPJ autistic females showed underconnectivity (ASD < TD) in mPFC, precuneus, right temporo-parietal region |
| Tomasi and Volkow (2019) (ABIDE) | International | rs-fMRI (whole-brain + whole thalamic partition as seed region for seed-voxel correlation analyses) sex stratified |
lFCD, LI, ALFF, seed-voxel correlation maps | 656 autism (565:91) 835 TD (602:233) |
all participants 7–40 yr |
age, FSIQ, mean frame-wise displacement | autistic males showed lower lFCD in the anterior thalamus compared to TD males; group differences in thalamic lFCD between autistic females and typically developing females were not statistically significant |
| Smith et al., 2019 | United States | rs-fMRI (whole-brain) sex*dx | global functional connectivity in cortico-cerebellar organization | 79 autism (56:23) 89 TD (65:24) |
autism 11–62 yr TD 10–54 yr |
age, frame-wise displacement, global correlation level (GCOR) | two clusters in bilateral cerebellum with sex*dx interaction in global connectivity males showed cortico-cerebellar hypoconnectivity (ASD < TD) females showed cortico-cerebellar hyperconnectivity (ASD > TD) |
|
Lee et al., 2020 |
United States |
rs-fMRI (ROIs: amygdala connectomes) sex*dx sex*dx*age |
amygdala resting-state functional connectivity map (multivariate distance matrix regression; univariate analysis) |
116 autism (80:36) 58 TD (31:27) |
all participants 2–7 yr |
none reported |
significant sex*dx interaction observed for left amygdala for multivariate distance matrix regression model; four sex*dx interaction clusters (left amygdala, left DMPFC, left ventral PFC, left lingual gyrus, between right amygdala and right poster cingulate cortex) |
|
Hernandez et al., 2020 (GENDAAR) |
United States |
rs-fMRI (ROIs: bilateral NAcc – correlated with every other voxel in the brain to generate functional connectivity maps) genetic risk*sex*dx |
reward network resting-state functional connectivity (with additive impact of genetic risk – ASD-associated OXTR variants) |
87 autism (37:50) 86 TD (34: 52) |
all participants 8–17 yr |
MRI data collection site, IQ, number of functional volumes remaining after motion scrubbing |
sex significantly modulated the relationship between OXTR genetic risk and NAcc connectivity in the ASD group only. Relative to their male counterparts, as genetic risk for ASD increased, females with ASD showed significantly greater connectivity between the NAcc and regions of the mesolimbic reward system, including the caudate, pallidum, and putamen, as well as bilateral thalamus, right prefrontal cortex, and left medial prefrontal cortex |
|
Lawrence et al., 2020a (GENDAAR) |
United States |
rs-fMRI (whole-brain and ROIs: SN, DMN, CEN) sex*dx + sex stratified |
within- and between-network functional connectivity of SN, DMN, and CEN |
80 autism (34:46) 89 TD (41:48) |
no range; autism (M) 13.32 ± 3.04 yr autism (F) 13.50 ± 2.52 yr TD (M) 13.71 ± 2.64 yr TD (F) 13.15 ± 3.04 yr |
general cognitive ability, pubertal development, site/scanner |
whole-brain functional connectivity (sex stratified): female ASD group displayed no significantly atypical patterns of connectivity; male ASD group exhibited atypical SN connectivity whole-brain functional connectivity (sex*dx): significant sex*dx interaction observed in SN connectivity with left posterior parietal cortex and precuneus ROI-based network functional connectivity (sex stratified): female ASD group exhibited increased positive connectivity between the DMN (PCC) and CEN (L PPC); male ASD group displayed less positive connectivity with the CEN (R DLPRC with R PPC) ROI-based network functional connectivity (sex*dx): sex*dx interaction between the DMN and the CEN, in the within- and between-network connectivity of the SN (did not attain statistical significance after correction for multiple comparisons) |
|
Kozhemiako et al., 2020 (ABIDE) |
International |
rs-fMRI (ROIs: seven network mask of cerebellum – visual, somatomotor, dorsal attention, ventral attention, limbic, fronto-parietal control, DMN) sex stratified |
local connectivity quantified as regional homogeneity (ReHo) – concordance of time-series of neighbouring voxels |
194 autism (102:92) 196 TD (104:92) |
all participants 6–26 yr |
none reported |
increases in local connectivity in participants with ASD in the somatomotor and limbic networks and decreased local connectivity within the default mode network – alterations were more pronounced in females with ASD ASD(M): decreased local connectivity in ventral attention and DMN compared to TD males ASD(F): decreased local connectivity in ventral attention, frontoparietal control, DMN; increased local connectivity in limbic network compared to TD females |
|
Trakoshis et al., 2020 (MRC-AIMS) |
United Kingdom |
rs-fMRI (whole brain) sex*dx |
Hurst exponent (H) in BOLD time-series as an index for synaptic excitation: inhibition (E:I) ratio |
68 autism (34:34) 67 TD (33:34) |
all participants 18–49 yr |
mean frame-wise displacement, FSIQ |
significant sex*dx interaction in VMPFC where interaction effect is driven by large TD > ASD effect in males and a small ASD > TD effect in females |
|
Olson et al., 2020 (ABIDE) |
International |
rs-fMRI (whole brain) sex*dx |
sex-related patterns of whole brain functional connectivity patterns and relation to ASD symptoms |
69 autism (34:35) 72 TD (36:36) |
all participants 7–17 yr |
root mean squared displacement |
sex*dx effects were identified between sensorimotor and higher-order supramodal networks, default mode network |
|
Floris et al., 2021 (ABIDE - discovery) (EU-AIMS LEAP, GENDAAR - replication) |
International, United States |
rs-fMRI (whole brain) sex*dx |
PCC-iFC, VMHC, ReHo, network degree centrality, fALFF |
ABIDE 444 autism (362:82) 575 TD (409:166) EU-AIMS LEAP 176 autism (133:43) 133 TD (85:48) GENDAAR 87 autism (43:44) 109 TD (56:53) |
all participants 7–18 yr |
mean frame-wise displacement |
sex*dx interaction identified in the dorsolateral occipital cortex, with reduced VMHC in autistic females compared to autistic males and TD controls, whereas TD females had higher VMHC than the other three groups; sex‐by‐diagnosis interaction was replicated in the larger of the two replication samples—EU‐AIMS LEAP |
Abbreviations: AAL, automated anatomical labelling; ABIDE, Autism Brain Imaging Data Exchange; ALFF, amplitude of low-frequency fluctuations; BOLD, blood oxygen level dependent; CEN, central executive network; CFSA, Cambridge Family Study of Autism; DLPFC, dorsolateral prefrontal cortex; DMN, default mode network; DMPFC, dorsomedial prefrontal cortex; EU-AIMS, European Autism Interventions - A Multicentre Study for Developing New Medications; fALFF, fractional amplitude of low frequency fluctuations; FSIQ, full scale intelligence quotient; GENDAAR, Gender Exploration of Neurogenetics and Development to Advance Autism Research; iFC, intrinsic functional connectivity; LEAP, Longitudinal European Autism Project; lFCD, local functional connection density; LI, laterality index; MRC-AIMS, Medical Research Council Autism Imaging Multicentre Study; MTG, middle temporal gyrus; NAcc, nucleus accumbens; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PPC, posterior parietal cortex; ReHo, regional homogeneity; ROI, region-of-interest; SFG, superior frontal gyrus; SN, salience network; STS, superior temporal sulcus; TPJ, temporo-parietal junction; TR, repetition time; VMHC, voxel-mirrored homotopic connectivity; VMPFC, ventromedial prefrontal cortex.