Beyond sex differences: new approaches for thinking about variation in brain structure and function

Abstract

In the study of variation in brain structure and function that might relate to sex and gender, language matters because it frames our research questions and methods. In this article, we offer an approach to thinking about variation in brain structure and function that pulls us outside the sex differences formulation. We argue that the existence of differences between the brains of males and females does not unravel the relations between sex and the brain nor is it sufficient to characterize a population of brains. Such characterization is necessary for studying sex effects on the brain as well as for studying brain structure and function in general. Animal studies show that sex interacts with environmental, developmental and genetic factors to affect the brain. Studies of humans further suggest that human brains are better described as belonging to a single heterogeneous population rather than two distinct populations. We discuss the implications of these observations for studies of brain and behaviour in humans and in laboratory animals. We believe that studying sex effects in context and developing or adopting analytical methods that take into account the heterogeneity of the brain are crucial for the advancement of human health and well-being.

Reply to Del Giudice et al., Chekroud et al., and Rosenblatt: Do brains of females and males belong to two distinct populations?

“…Current data are not sufficient, however, to fully characterize the relations between sex and the brain (4). Such characterization is necessary for studying sex effects on the brain as well as for studying brain structure, function, and dysfunction in general (4). We hope future studies will soon fill in this gap.…”

“…Clearly, sex affects the brain, as evidenced in differences between brains from females and brains from males in both macroscopic and microscopic features. However, the fact that sex affects the brain does not necessarily entail that there are two distinct types of brains, "male brains" and "female brains," as there are two distinct types of genitalia (2)(3)(4). Answering this question was the aim of our study.…”

“…Although the different supervised learning methods achieve better accuracy in predicting sex category than the simple method described above, they have the same conceptual problem, namely, it is unclear what the biological meaning of the new space is and in what sense brains that seem close in this space are more similar than brains that seem distant. Moreover, it is unclear whether the brain variability that is represented in the new space is related to sex or rather to physiological, psychological, or social variables that correlate with sex (e.g., weight, socioeconomic status, or type of education) or to a chance difference between the males and females in the sample (2,4). One way to answer this question is by checking whether a model created to predict sex category in one dataset can accurately predict sex category in another dataset.…”

Incorporating Sex As a Biological Variable in Neuropsychiatric Research: Where Are We Now and Where Should We Be?

“…As has been noted by several authors, it is impossible to disentangle sex and gender in humans (eg, Rippon et al (2014)). However, as both scientifically and clinically it is important to understand the origins of observed sex differences in brain and behavior, it is important that studies of such differences measure or manipulate relevant internal and external variables and not assume that a sex difference necessarily reflects a direct sex effect (Rippon et al, 2014;Joel and Fausto-Sterling, 2016). In summary, although to date the kingsroad to study sex effects on the brain is to compare males and females on specific end points, the above discussion highlights that the existence of a sex difference in an end point does not necessarily entail that sex directly affects this end point or that this effect is permanent and will be seen under all conditions.…”

Multifaceted origins of sex differences in the brain

“…Because the majority of sex differences in the brain are established early by gonadal steroids that differ in males and females, and because the brain resides in a body that is either male or female, there is an implicit, even inherent bias, that brains are male versus female. In this issue, Joel and Fausto-Sterling [8] challenge this view and cite empirical evidence based on MRI that humans are a single heterogeneous population when considering the brain [9]. Multifaceted origins of sex differences in the brain.…”