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Cited by 149Sex and Gender in HealthcareSexual Differentiation and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Sex differences in the human brain: a roadmap for more careful analysis and interpretation of a biological reality

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DeCasien, Alex R., Guma, Elisa, Liu, Siyuan, Raznahan, Armin·2022·Biology of Sex Differences
DOI 10.1186/s13293-022-00448-wPMC PMC9327177
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Abstract

The presence, magnitude, and significance of sex differences in the human brain are hotly debated topics in the scientific community and popular media. This debate is largely fueled by studies containing strong, opposing conclusions: either little to no evidence exists for sex differences in human neuroanatomy, or there are small-to-moderate differences in the size of certain brain regions that are highly reproducible across cohorts (even after controlling for sex differences in average brain size). Our Commentary uses the specific comparison between two recent large-scale studies that adopt these opposing views—namely the review by Eliot and colleagues (2021) and the direct analysis of ~ 40k brains by Williams and colleagues (2021)—in an effort to clarify this controversy and provide a framework for conducting this research. First, we review observations that motivate research on sex differences in human neuroanatomy, including potential causes (evolutionary, genetic, and environmental) and effects (epidemiological and clinical evidence for sex-biased brain disorders). We also summarize methodological and empirical support for using structural MRI to investigate such patterns. Next, we outline how researchers focused on sex differences can better specify their study design (e.g., how sex was defined, if and how brain size was adjusted for) and results (by e.g., distinguishing sexual dimorphisms from sex differences). We then compare the different approaches available for studying sex differences across a large number of individuals: direct analysis, meta-analysis, and review. We stress that reviews do not account for methodological differences across studies, and that this variation explains many of the apparent inconsistencies reported throughout recent reviews (including the work by Eliot and colleagues). For instance, we show that amygdala volume is consistently reported as male-biased in studies with sufficient sample sizes and appropriate methods for brain size correction. In fact, comparing the results from multiple large direct analyses highlights small, highly reproducible sex differences in the volume of many brain regions (controlling for brain size). Finally, we describe best practices for the presentation and interpretation of these findings. Care in interpretation is important for all domains of science, but especially so for research on sex differences in the human brain, given the existence of broad societal gender-biases and a history of biological data being used justify sexist ideas. As such, we urge researchers to discuss their results from simultaneously scientific and anti-sexist viewpoints.

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  • The brain exhibits clear structural and functional differences based on sex.

    “The brain exhibits clear structural and functional differences based on sex [1–3].”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [1]

    The Conclusions report reproducible sex differences in regional brain anatomy, but qualify them as small-to-moderate differences in the means of largely overlapping distributions. Part 4, “Framing and interpreting the results,” says that describing anatomical differences is distinct from establishing their functional implications, which remain uncertain. The source therefore supports the structural part of the claim, but not an unqualified assertion of clear functional differences. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
DeCasien, A. R., Guma, E., Liu, S., & Raznahan, A.
Affiliations
National Institutes of Health (US)
Corresponding author
DeCasien, Alex R.
ORCID
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2022-07-26
Volume
13
Issue
1
Pages
43-43
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/s13293-022-00448-w
PMC
PMC9327177
OpenAlex
W4288054125
Cited by
149
References
14
Citations by year
2026: 27 · 2025: 45 · 2024: 52 · 2023: 24 · 2022: 1
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Mental Health (1ZIAMH002949)
  • National Institute of Child Health and Disease (R01HD100298)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
sexual dimorphism, amygdala volume, neuroanatomy, structural MRI, meta-analysis, sex as a variable, brain disorders, gender bias in science, research design
MeSH terms
Brain, Female, Humans, Magnetic Resonance Imaging, Male, Research Design, Sex Characteristics

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