The prevailing view of sex and gender differences in the mammalian brain has shifted in recent years from one centered on testosterone as the key differentiating factor to a recognition that a combination of genetic, hormonal, and environmental factors influence the brain in both males and females.1 Despite the acknowledgment of the complex contributions of these various factors, debates remain regarding the significance of the resulting sex differences and the extent to which the human brain may be categorized as either male or female.

“I think it’s fair to say that there’s a degree of consensus that both sex-linked biology (that is, sex-differentiated genetic and hormonal effects) and gender (that is, the socially expected behavior, norms, and hierarchy associated with being female and male) influence brain development and functioning,” explained Cordelia Fine, PhD, professor of history and philosophy of science at the University of Melbourne, Australia, and the author of several books including Delusions of Gender: How Our Minds, Society, and Neurosexism Create Difference and Testosterone Rex: Myths of Sex, Science, and Society. “The debate is more around how to interpret reported findings of difference,” she told Psychiatry Advisor.

According to Dr Fine, “gender stereotypes can be projected onto findings of sex differences in the brain and can be powerful enough to make completely contradictory interpretations seem plausible.” For example, in a 2018 article published in the Lancet, she points to a “feminist analysis by philosopher Robyn Bluhm [which] shows how the conflicting findings of various functional neuroimaging studies of emotion are nonetheless all interpreted to be consistent with the stereotype that women are the emotional ones.”6,7

Together with Gina Rippon, PhD, honorary professor of cognitive neuroimaging at Aston Brain Centre at Aston University in Birmingham, England, and author of The Gendered Brain: The New Neuroscience That Shatters the Myth of the Female Brain, as well as Daphna Joel, PhD, professor of psychology and neuroscience at Tel Aviv University, Israel, and author of the book Gender Mosaic: Beyond the Myth of the Male and Female Brain, Dr Fine coauthored an article highlighting points to consider when sorting through the range of literature on sex and gender.2 Noting the independent and combined effects of both sex and gender on the brain and behavior, they use the term “sex/gender” to “avoid prejudging causes of differences between the sexes.”

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Mosaic vs dichotomy

Findings that demonstrate sex/gender differences in the human brain are often perceived as evidence of sexual dimorphism. “However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (ie, little overlap between the forms of these features in males and females) and internally consistent (ie, a brain has only “male” or only “female” features),” wrote Dr Joel and colleagues in a 2015 paper.3

To the contrary, in an analysis of magnetic resonance imaging scans from more than 1400 people, they observed “extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed.” Moreover, internal consistency was rare, as very few individuals were found to be consistently at the “female end” or the “male end” of the continuum. Rather, “most brains are comprised of unique ‘mosaics’ of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males.” These results align with those of another analysis of more than 5500 participants, according to the study by Joel et al, which showed that most humans possess a mosaic of feminine and masculine characteristics in terms of sex or gender differences in personality traits, attitudes, interests, and behaviors.3

Subsequent analyses by Joel et al demonstrated that “a male and a female are almost as likely to have the same brain ‘type’ as two females or two males are,” with large sex differences “found only in the frequency of some rare brain ‘types.’ “4

In a study published in Brain Structure & Function in December 2019, Dr Joel and colleagues analyzed magnetic resonance imaging scans of 34 healthy soldiers (15 women) aged 18 to 19 years to explore sex differences in the brain’s response to extreme real-life stress; in this case, combative military service.5 They noted sex/gender-specific changes in a few regions, and the number of brains showing only male-typical or only female-typical responses was lower than the number of “mosaic brains” characterized by “at least one region with a male-typical response and one with a female-typical response,” they reported. “Although these findings do not reveal the source of sex/gender differences in response to stress and of within-brain variability in this response, they demonstrate that these differences do not consistently add up to create a female-typical and a male-typical neural response to stress.”

Implications for nonbinary gender

Mosaic brains were also observed for a few measures of the human hypothalamus, which show the largest sex/gender differences known to date, according to Dr Joel. Researchers have found that these measures were of a similar size in cisgender (those who self-identify in a binary way) women and transgender women, suggesting that they may be related to gender identity.8

Although this hypothesis requires further investigation, the “finding that these measures do not add up consistently in all cisgender men, cisgender women, and transgender women runs against the hypothesis that there are male and female brains, and that transgender individuals have the brain of the other sex,” she stated. “Although we haven’t tested the entire brain of nonbinary people, as we’ve done with cisgender people, I believe that like most other humans, nonbinary individuals possess unique mosaics of brain characteristics.”

Recent studies of both adults and children have shown that many cisgender individuals actually experience their gender in a nonbinary way. In a research study published in 2013 in Psychology & Sexuality, Dr Joel and colleagues used the Multi-Gender Identity Questionnaire to assess measures of gender identity in 570 cisgender men and 1585 cisgender women.9 More than 35% of participants indicated that they felt like the “other” gender, both genders, or neither gender to some extent. Similar results have been found in more recent work, as well as in research involving children.10,11

Key takeaways

“I believe these findings should be used to widen societal norms regarding what is an acceptable gender experience and performance,” said Dr Joel, “In particular, we should oppose the common belief that the possession of female or male genitals should be accompanied by a specific experience of the self and a specific set of psychological characteristics, preferences, and behaviors, and advocate, instead, a culture that celebrates the enormous human variability.”

Taken together, such observations reiterate the critical need to tailor mental health care to each patient, and to remain mindful about assumptions regarding sex and gender and their role in a given patient’s specific challenges. Dr Joel emphasized the importance of resisting the binary framework in the diagnostic process in particular. She explained that although sex/gender differences in the prevalence of several psychiatric disorders have been observed, such as higher rates of Alzheimer disease and major depressive disorder in women vs men, and higher rates of schizophrenia and attention deficit hyperactivity disorder in men vs women,12 there is no condition that could be considered uniquely “male” or “female.”

For example, findings by Cheng et al showed that postpartum depression is only slightly less common among fathers compared with mothers (4.4% vs 5.0%).13 “Avoiding fitting humans into the female/woman or male/man boxes may prevent over- and underdiagnosis, both of which may be harmful,” said Dr Joel.

As a more general concern, psychiatrists may overlook more important variables if they are focused on sex category, which is “rarely the cause of sex/gender differences in brain structure, function or dysfunction, presenting symptoms, or response to treatment,” Dr Joel noted. Rather, such differences tend to reflect the action of variables that correlate with sex category, such as sex-related genes and hormones, societal factors, and physical, psychological, and behavioral characteristics. “Detecting the relevant variables would not only advance our mechanistic understanding of psychiatric conditions but may also advance treatment, because while sex category cannot be changed, many of the variables listed here can.”

References

1. Joel D, Garcia-Falgueras A, Swaab D. The complex relationships between sex and the brain. [published online September 11, 2019.] Neuroscientist. doi:10.1177/1073858419867298

2. Fine C, Joel D, Rippon G. Eight things you need to know about sex, gender, brains, and behavior: a guide for academics, journalists, parents, gender diversity advocates, social justice warriors, Tweeters, Facebookers, and everyone else. S&F Online. 2019;15(2).

3. Joel D, Berman Z, Tavor I, et al. Sex beyond the genitalia: The human brain mosaic. Proc Natl Acad Sci U S A. 2015;112(50):15468-15473.

4. Joel D, Persico A, Salhov M, et al. Analysis of human  brain structure reveals that the brain “types” typical of males are also typical of females, and vice versa. Front Hum Neurosci. 2018;12:399.

5. Shalev G, Admon R, Berman Z, Joel D. A mosaic of sex-related structural changes in the human brain following exposure to real-life stress. Brain Struct Funct.  2020;225(1):461-466

6. Fine C. Feminist science: who needs it? Lancet. 2018;392(10155):1302-1303.

7. Bluhm R. Self-fulfilling prophecies: the influence of gender stereotypes on functional neuroimaging research on emotion. Hypatia. 2013;28(4):870-886.

8. Garcia-Falgueras A, Swaab DF. A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity. Brain. 2008;131(Pt 12):3132-3146.

9. Joel D, Tarrasch R, Berman Z, Mukamel M, Ziv E. Queering gender: studying gender identity in ‘normative’ individuals. Psychology Sexuality. 2014;5(4):291-321.

10. Jacobson R, Joel D. Self-reported gender identity and sexuality in an online sample of cisgender, transgender, and gender-diverse individuals: an exploratory study. J Sex Res. 2019;56(2):249-263.

11. Martin CL, Andrews NC, England DE, Zosuls K, Ruble DN. A dual identity approach for conceptualizing and measuring children’s gender identity. Child Dev. 2017;88(1):167-182.

12. Wickens MM, Bangasser DA, Briand LA. Sex differences in psychiatric disease: a focus on the glutamate system. Front Mol Neurosci. 2018;11:197.

13. Cheng ER, Downs SM, Carroll AE. Prevalence of depression among fathers at the pediatric well-child care visit. JAMA Pediatr. 2018;172(9):882-883.