Table 6.
Significant findings of investigations of sex/gender-by-diagnosis interactions and sex/gender-stratified analysis of autism-control differences in brain morphometry (structural MRI).
| 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) |
|---|---|---|---|---|---|---|---|
|
Schumann et al., 2010 (longitudinal study) |
United States |
sMRI (ROIs: frontal gray, temporal gray, parietal gray, occipital gray, cingulate gray, total gray, total white, total cerebral volume) gender stratified |
cerebral GM and WM volume |
41 autism (32:9) 44 TD (32:12) |
all participants 1–2 yr at start of study final visit: autism 1.8–5.6 yr (M) 2.2–4.8 yr (F) TD 1.0–5.3 yr (M) 1.0–5.1 yr (F) |
age at scan |
autistic females showed more pronounced abnormal growth profile in more brain regions than autistic males males – frontal and temporal GM volumes (ASD > TD); females – total cerebrum, WM, GM, frontal and temporal volumes (ASD > TD) |
|
Lai et al., 2013b (MRC- AIMS) |
United Kingdom |
sMRI (whole-brain) sex*dx |
brain GM and WM volume |
60 autism (30:30) 60 TD (30:30) |
all participants 18–49 yr |
age |
significant sex*dx interaction in two clusters in bilateral temporo-parieto-occipital regions, involving posterior portion of bilateral cingulum, ILF, CC (splenium), right AF with the females show ASD > TD and males show ASD = TD significant sex*dx interaction in two clusters involving internal capsule bilaterally at the level around the basal ganglia and thalamus where the females show ASD < TD and males show ASD > TD |
|
Schaer et al., 2015 (ABIDE) |
Inter-national |
sMRI (whole-brain) sex*dx |
local cortical morphometry (volume, thickness, gyrification) |
106 autism (53:53) 104 TD (53:51) |
all participants 6–56 yr |
site, age, cortical volume |
local cortical volume: no sex*dx interaction local cortical thickness: no sex*dx interaction local cortical gyrification: significant sex*dx interaction in VMPFC/OFC cluster |
|
Sussman et al., 2015 (POND) |
Canada |
sMRI (ROIs: cortical segmentation into 78 brain regions; volumes for cerebellum, hippocampus, striatum, pallidum, thalamus and associated sub-regions (MAGeT Brain algorithm) sex*dx |
total brain volume, total surface area, mean cortical thickness |
72 autism (61:11) 138 TD (116:22) |
all participants 4–18 yr |
age |
no sex*dx interaction effect was found for total surface area or mean cortical thickness significant sex*dx interaction was found in total brain volume, relative volume of cerebellar lobules 8b and 10, total hippocampus, left hippocampus and hippocampal subiculum |
|
Retico et al., 2016 |
Italy |
sMRI (whole-brain) gender stratified |
GM and WM volume, CSF volume, TIV (sum of GM, WM, CSF volumes) |
76 autism (38:38) 76 TD (38:38) |
autism 2.1–7.3 yr TD 1.8–7.4 yr |
none reported |
autistic males showed increased GM volume in left middle occipital gyrus and right superior temporal gyrus compared to TD males autistic females showed increased GM volume in bilateral frontal regions, right anterior cingulate cortex, right cerebellum compared to TD females |
|
Irimia et al., 2018 (GENDAAR) |
United States |
sMRI (ROIs: 165 brain regions identified using a probabilistic atlas to parcel a total of 74 cortical structures [gyri and sulci] in each hemisphere and the brain stem) sex*dx |
GM thickness, volume, cortical area, mean curvature, CD |
110 autism (55:55) 83 TD (43:40) |
no range; autism 12.7 ± 2.8 yr TD 13.0 ± 3.0 yr |
age, site |
significant sex*dx interaction in temporal pole, parahippocampal gyrus, superior temporal gyrus, occipital poles, cuneus |
|
Zhang et al., 2018 (ABIDE) |
Inter-national |
sMRI (whole-brain) sex*dx age*sex*dx |
GM and WM volume and subcortical structure volumes |
401 autism (351:50) 458 TD (378:80) |
all participants 6.5–64.0 yr |
FSIQ, total brain volume |
no significant sex*dx interaction; age*sex*dx interaction in total GM, total WM, hippocampal volumes, caudate volumes and putamen volumes |
|
Ecker, 2019 (MRC-AIMS) |
United Kingdom |
sMRI (whole-brain) sex*dx |
cortical thickness |
98 autism (49:49) 98 TD (51:47) |
autism 18–41 yr TD 18–42 yr |
total GM volume |
significant interaction in bilateral parahippocampal and entorhinal cortex, fusiform and lingual gyrus, inferior or middle temporal lobe |
|
Bosco et al., 2019 |
Italy |
sMRI (ROIs: brainstem) gender stratified |
volume and shape of brainstem |
76 autism (38:38) 76 TD (38:38) |
autism 2.1–7.3 yr TD 1.8–7.4 yr |
age, total intracranial volume |
brainstem volume in males (ASD > TD); no significant autism-control difference in female groups |
|
Peterson et al., 2019 |
United States |
sMRI and Arterial Spin Labeling (ASL) (whole-brain) sex*dx |
regional cerebral blood flow (rCBF) |
44 autism (32:12) 66 TD (50:16) |
autism 5.9–60.7 yr TD 6.9–59.0 yr |
age, FSIQ, psychotropic medication use |
significant sex*dx effect on rCBF in limbic regions (subgenual ACC, ventral striatum, amygdala, parietal WM) |
|
Postema et al., 2019 (ENIGMA) |
Inter-national |
sMRI (whole-brain) sex*dx + sex stratified |
structural brain asymmetry for multiple brain regional and global hemispheric measures (i.e., cortical thickness, cortical surface area, subcortical volume) |
1778 autism (1504:274) 1829 TD (1400:429) |
all participants 2–64 yr |
corrected for ‘data set’ as a random effect in analysis (to account for heterogeneity of imaging protocols) |
significant sex*dx interaction in the rostral anterior cingulate thickness asymmetry index (AI); this AI had shown a significant effect of diagnosis in the primary analysis. In analysis within the sexes separately, this AI was associated with diagnosis in males but not females |
|
Bedford et al., 2020 (MRC-AIMS, CFSA, ABIDE, Hospital for Sick Children, NIMH) |
Inter-national |
sMRI (whole-brain) sex*dx + sex stratified |
cortical morphometry (cortical thickness, surface area, cortical volume, total GM, total WM, total brain volume) |
491 autism (362:129) 836 TD (481:355) |
all participants 2–65 yr |
age (and using a prospective meta-analytic technique to account for inter-site differences) |
no significant sex*dx interactions found autistic males had significantly greater cortical volume, mean cortical thickness in the bilateral superior temporal, inferior frontal, and right precentral gyri compared to TD males; WM volume was also greater in autistic males compared to TD males; no differences in total surface area or GM volume autistic females had greater mean cortical thickness in the bilateral prefrontal and occipital cortices, and left posterior parietal cortex and pre- and postcentral gyri compared to TD females; no differences observed for total brain volume, total surface area, cortical volume, GM or WM |
|
Williams et al., 2020 (ABIDE) |
Inter-national |
sMRI (whole-brain) sex*dx*linear age (replication of Zhang et al., 2018) |
subcortical allometric and volumetric group differences |
302 autism (265:37) 352 TD (283:69) |
autism 7.0–26.9 yr TD 6.5–26.9 yr |
FSIQ, total brain volume |
replicated significant sex*dx*linear age interaction in hippocampal volumes found by Zhang et al. (2018) |
|
Olafson et al., 2021 (MRC-AIMS, CFSA, ABIDE, Hospital for Sick Children, etc.) |
Inter-national |
sMRI (whole-brain) sex stratified |
Boundary sharpness coefficient (BSC) – proxy for alterations in micro-structure at cortical GWM boundary |
415 autism (303:112) 721 TD (438:283) |
all participants 2–65 yr |
age, FIQ (and using a prospective meta-analytic technique to account for inter-site differences) |
females with ASD showed significantly greater BSC in bilateral superior parietal gyrus and superior temporal gyrus males with ASD showed significantly greater BSC in bilateral inferior temporal gyrus and left inferior frontal lobe |
|
Hammill et al., 2021 (POND, Hospital for Sick Children) |
Canada |
sMRI (whole-brain) overall sex modulation pattern (local magnitude model – quantitative sex modulation; spatial dissimilarity model – qualitative sex modulation) |
cortical thickness, surface area, volume, mean absolute curvature, and subcortical volume |
373 autism (299:74) 466 TD (240:226) |
all participants 2.8–50 yr |
total brain volume (and its exponential transform), age (linear or quadratic), their interactions with sex, and scanner version – determined via model selection |
no evidence supporting quantitative sex modulation; some evidence supporting qualitative sex modulation in terms of cortical mean absolute curvature and subcortical volume |
Abbreviations: ABIDE, Autism Brain Imaging Data Exchange; ACC, anterior cingulate cortex; CC, corpus callosum; CD, connectivity density; CFSA, Cambridge Family Study of Autism; CR, corona radiata; CSF, cerebrospinal fluid; ENIGMA, Enhancing Neuro Imaging Genetics through Meta-Analysis; FSIQ, full scale intelligence quotient; GM, gray matter; GWM, gray-white matter; MRC-AIMS, Medical Research Council Autism Imaging Multicentre Study; NIMH, National Institute of Mental Health; OFC, orbitofrontal cortex; PFC, prefrontal cortex; POND, Province of Ontario Neurodevelopmental Disorders Network; ROI, region-of-interest; TIV, total intracranial volume; WM, white matter