Testing the extreme male brain hypothesis: Is autism spectrum disorder associated with a more male‐typical brain?

Summary & key facts

The authors made a score that measures how male-typical a person’s subcortical brain shape is. They trained this score on 2,153 people and then measured it in 1,060 people with autism and 1,166 neurotypical controls. People with autism had a small, higher average “brain maleness” score (d = 0.20), and brain maleness related to autistic traits. However, people with autism also had slightly larger brains, and when the researchers adjusted for brain size the maleness difference and the link with symptoms disappeared. The authors conclude that the small shift toward a more male-typical brain in autism is explained by brain size differences, not by a distinct extra-male brain pattern.

Key facts:

• The brain-malness score was trained on two population samples: Queensland Twin Imaging (N = 1,040) and the Human Connectome Project (N = 1,113), for a combined training N = 2,153.
• The clinical test sample combined Autism Brain Imaging Data Exchange I and II with 1,060 individuals with ASD and 1,166 neurotypical controls (total N = 2,226).
• Mean brain maleness was higher in the ASD group than in controls with effect size d = 0.20 (95% CI 0.12–0.29).
• For comparison, control males scored higher than control females on brain maleness with effect size d = 1.17 (95% CI 1.05–1.29).
• Individuals with ASD had slightly larger overall brains than controls (d = 0.17, 95% CI 0.08–0.25). Males had larger brains than females (d = 0.96, 95% CI 0.84–1.07).
• When the authors adjusted for overall brain size, the difference in brain maleness between ASD and controls disappeared, and the association between brain maleness and autistic symptoms no longer remained significant after correcting for mu
• The brain-maleness measure was based on subcortical brain shape because cortical measures showed too much measurement error in the data used.
• The authors state that greater maleness of the autistic brain appears to be driven by brain size, and they note that brain maleness may be influenced by the same factors that influence brain size.

Abstract

Autism spectrum disorder (ASD) is more common in males than females and has been linked to male-typical behavior. Accordingly, the "Extreme Male Brain" hypothesis suggests that ASD is associated with an exaggeratedly male-typical brain. To test this hypothesis, we derived a data-driven measure of individual differences along a male-female dimension based on sex differences in subcortical brain shape (i.e., brain maleness) by training our algorithm on two population samples (Queensland Twin IMaging study and Human Connectome Project; combined N = 2153). We then applied this algorithm to two clinical datasets (Autism Brain Imaging Data Exchange I and II; ASD N = 1060; neurotypical controls N = 1166) to obtain a brain maleness score for each individual, representing maleness of their brain on a male-female continuum. Consistent with the Extreme Male Brain hypothesis, we found a higher mean brain maleness score in the ASD group than in controls (d = 0.20 [0.12-0.29]), parallel to higher scores for control males than control females (d = 1.17 [1.05-1.29]). Further, brain maleness was positively associated with autistic symptoms. We tested the possibility this finding was driven by the ASD group's larger brains than controls (d = 0.17 [0.08-0.25]), given that males had larger brains than females (d = 0.96 [0.84-1.07]). Indeed, after adjusting for differences in brain size, the brain maleness difference between the ASD group and controls disappeared, and no association with autistic symptoms remained (after controlling for multiple comparisons), suggesting greater maleness of the autistic brain is driven by brain size. Brain maleness may be influenced by the same factors that influence brain size. LAY SUMMARY: A popular theory proposes that individuals with autistic spectrum disorder (ASD) have an "extreme male brain", but this has not been subject to rigorous, direct tests. We developed a measure of individual differences along a male-female dimension and then derived this measure for 1060 individuals with ASD and 1166 neurotypical controls. Individuals with ASD had slightly more male-type brains. However, this difference is accounted for by males and individuals with ASD having relatively larger brains than females and controls, respectively.

Topics

Autism Spectrum Disorder Research Functional Brain Connectivity Studies Genetics and Neurodevelopmental Disorders

Categories

Cognitive Neuroscience Life Sciences Neuroscience

Tags

Audiology Autism Autism spectrum disorder Brain activity and meditation Brain development Brain size Developmental psychology Electroencephalography Environmental health Magnetic resonance imaging Medicine Neuroscience Neurotypical Population Psychology Radiology