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

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.

Mode-based morphometry: A multiscale approach to mapping human neuroanatomy

“…When interpreted with respect to our simulations, this result suggests that while there may be some consistent sex differences in CT that can be observed under resampling, they are likely subtle relative to the effects of individual variability. This interpretation aligns with ongoing debates over the consistency of sex differences in neuroanatomy [3, 18, 19].…”

“…Voxel-based morphometry (VBM) [1] and surface-based morphometry (SBM) [2] are the most commonly used techniques for studying neuroanatomical variations with magnetic resonance imaging (MRI). They are used to find associations between morphometric quantities (e.g., cortical thickness, surface area, grey matter volume) and diverse sociodemographic [3, 4, 5], behavioral [6, 7, 8], and clinical [9] variables. Throughout this article, we will focus principally on applications that examine neuroanatomical differences between two experimental groups (e.g., males and females, patients and controls), but our arguments and techniques easily generalize to cross-sectional analyses of inter-individual variability (e.g., brain-wide association analyses [10]).…”

Fundamental neurochemistry review: Old brain stories ‐ Influence of age and sex on the neurodegeneration‐associated lipid changes

“…These are few of the examples of the extensive influence of sex steroids in the brain which have been extensively described and reviewed in the literature by others (for details, see Chowen et al, 2000; DeCasien et al, 2022; Hansberg‐Pastor et al, 2015; Kight et al, 2020; Panzica & Melcangi, 2016; Uhl et al, 2022).…”

Brain structural correlates of psychopathic traits in elite female combat-sports athletes

“…Moreover, the vast majority of these previous studies tested only men, and most of those that did include women did not consider sex as a factor of interest, thus limiting the generalizability of the findings. This is particularly relevant given the sex differences reported, on the one hand, in terms the emotional and cognitive correlates of psychopathic traits (Efferson & Glenn, 2018), on the other, in brain morphology of several regions putatively affected in psychopathy, particularly the amygdala (for a review and discussion of this topic, see (DeCasien et al, 2022).…”