Beyond the binary: Characterizing the relationships between sex and neuropeptide receptor binding density measures in the rat brain.

Sex differences exist in numerous parameters of the brain. Yet, sex-related factors are part of a large set of variables that interact to affect many aspects of brain structure and function. This raises questions regarding how to interpret findings of sex differences at the level of single brain measures and the brain as a whole. In the present study, we reanalyzed two datasets consisting of measures of oxytocin, vasopressin V1a, and mu opioid receptor binding densities in multiple brain regions in rats. At the level of single brain measures, we found that sex differences were rarely dimorphic and were largely persistent across estrous stage and parental status but not across age or context. At the level of aggregates of brain measures showing sex differences, we tested whether individual brains are 'mosaics' of female-typical and male-typical measures or are internally consistent, having either only female-typical or only male-typical measures. We found mosaicism for measures showing overlap between females and males. Mosaicism was higher a) with a larger number of measures, b) with smaller effect sizes of the sex difference in these measures, and c) in rats with more diverse life experiences. Together, these results highlight the limitations of the binary framework for interpreting sex effects on the brain and suggest two complementary pathways to studying the contribution of sex to brain function: (1) focusing on measures showing dimorphic and persistent sex differences and (2) exploring the relations between specific brain mosaics and specific endpoints.

How hype and hyperbole distort the neuroscience of sex differences.

Sex/gender differences in the human brain attract attention far beyond the neuroscience community. Given the interest of nonspecialists, it is important that researchers studying human female-male brain difference assume greater responsibility for the accurate communication of their findings.

The gender-binary cycle: the perpetual relations between a biological-essentialist view of gender, gender ideology, and gender-labelling and sorting.

Gender inequality is one of the most pressing issues of our time. A core factor that feeds gender inequality is people's gender ideology-a set of beliefs about the proper order of society in terms of the roles women and men should fill. We argue that gender ideology is shaped, in large parts, by the way people make sense of gender differences. Specifically, people often think of gender differences as expressions of a predetermined biology, and of men and women as different 'kinds'. We describe work suggesting that thinking of gender differences in this biological-essentialist way perpetuates a non-egalitarian gender ideology. We then review research that refutes the hypothesis that men and women are different 'kinds' in terms of brain function, hormone levels and personality characteristics. Next, we describe how the organization of the environment in a gender-binary manner, together with cognitive processes of categorization drive a biological-essentialist view of gender differences. We then describe the self-perpetuating relations, which we term the gender-binary cycle, between a biological-essentialist view of gender differences, a non-egalitarian gender ideology and a binary organization of the environment along gender lines. Finally, we consider means of intervention at different points in this cycle. This article is part of the theme issue 'The political brain: neurocognitive and computational mechanisms'.

Beyond the binary: Rethinking sex and the brain.

The paper reviews the relations between sex and brain in light of the binary conceptualization of these relations and the challenges posed to it by the 'mosaic' hypothesis. Recent formulations of the binary framework range from arguing that the typical male brain is different from the typical female brain to claiming that brains are typically male or female because brain structure can be used to predict the sex category (female/male) of the brain's owner. These formulations are challenged by evidence that sex effects on the brain may be opposite under different conditions, that human brains are comprised of mosaics of female-typical and male-typical features, and that sex category explains only a small part of the variability in human brain structure. These findings led to a new, non-binary, framework, according to which mosaic brains reside in a multi-dimensional space that cannot meaningfully be reduced to a male-female continuum or to a binary variable. This framework may also apply to sex-related variables and has implications for research.

Beyond sex differences and a male-female continuum: Mosaic brains in a multidimensional space.

In the last two decades, the 60 years old view that in utero exposure to testosterone irreversibly masculinizes the brain of males away from a default female form has been replaced by a complex scenario according to which sex affects the brains of both females and males via multiple mechanisms, which are susceptible to internal and external factors. These observations led to the "mosaic" hypothesis-the expectation that the degree of "maleness"/"femaleness" of different features within a single brain would not be internally consistent. Following a short review of the animal studies providing the basis of the mosaic hypothesis, I describe three studies conducted in humans that assessed internal consistency in regional volume, cortical thickness, and connectivity as revealed by magnetic resonance imaging (MRI); in neuronal numbers in the postmortem hypothalamus; and in changes in regional volume and cortical thickness (assessed with MRI) following exposure to extreme real-life stress. The conclusion from these studies, that human brains are largely composed of unique mosaics of female-typical and male-typical features, was supported by recent findings that the brain "types" typical of women are also typical of men, and vice versa. Lastly, I discuss criticism of the mosaic hypothesis and suggest replacing the framework of a male-female continuum with thinking about mosaic brains residing in a multidimensional space.

The Complex Relationships between Sex and the Brain.

In the past decennia, our understanding of the sexual differentiation of the mammalian brain has dramatically changed. The simple model according to which testosterone masculinizes the brain of males away from a default female form, was replaced with a complex scenario, according to which sex effects on the brain of both females and males are exerted by genetic, hormonal, and environmental factors. These factors act via multiple partly independent mechanisms that may vary according to internal and external factors. These observations led to the "mosaic" hypothesis-the expectation of high variability in the degree of "maleness"/"femaleness" of different features within a single brain. Here, we briefly review animal data that form the basis of current understanding of sexual differentiation; present, in this context, the results of co-analyses of human brain measures obtained by magnetic resonance imaging or postmortem; discuss criticisms and controversies of the mosaic hypothesis and implications for research; and conclude that co-analysis of several (preferably, many) features and going back from the group level to that of the individual would advance our understanding of the relations between sex and the brain in health and disease.

A mosaic of sex-related structural changes in the human brain following exposure to real-life stress.

Whereas sex differences in the brain's response to stress have been reported in both humans and animals, it is unknown whether they 'add up' consistently within individual brains. Here, we studied this question in a unique data set of magnetic resonance imaging (MRI) scans obtained before and after exposure to extreme real-life stress in the form of combative military service in 34 (15 women) young (18-19 years old) healthy soldiers. Across two data sets, one of regional volume and one of cortical thickness, only a few regions (seven and three, respectively) showed sex/gender-specific changes (i.e., the most common structural change in women and men was different). The number of internally consistent brains (a male-typical or a female-typical response in all regions) was not different from the number expected by chance nor from that observed in regions showing a sex-similar response, and was lower than the number of mosaic brains (at least one region with a male-typical response and one with a female-typical response). 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.

Macro- and microstructural gray matter alterations in sexually assaulted women.

BACKGROUND: Studies with trauma survivors documented structural alterations in brain regions involved in posttraumatic stress disorder (PTSD) neurocircuitry. Nonetheless, whether such alterations exist in women who were sexually assaulted in adulthood is not clear. We investigated the macro- and microstructure of key regions implicated in PTSD pathophysiology, namely the amygdala, hippocampus, anterior cingulate cortex (ACC), and insula, in this population. METHODS: Thirty-eight sexually assaulted women (PTSD, n = 25; non-PTSD, n = 13) and 24 non-exposed controls (NEC) were studied with T1- and diffusion-weighted MRI. Gray matter volume, mean diffusivity (MD), and fractional anisotropy (FA) were calculated for each region. Between-group comparisons and correlations with PTSD symptom severity were performed. RESULTS: Volumetric analyses revealed lower amygdala and insula volumes in the PTSD compared with the non-PTSD group. In contrast, altered microstructure was observed in both traumatized groups compared with NEC, including higher MD and lower FA in the right amygdala, and higher FA in the ACC bilaterally. Finally, the non-PTSD group had higher FA in the right insula compared with the PTSD group. PTSD symptom severity was correlated with amygdala and insula volumes, as well as with hippocampal FA and MD. LIMITATIONS: Sample size may have led to reduced statistical power. CONCLUSIONS: Sexual assault and the development of PTSD in women are linked with structural alterations in key regions implicated in PTSD following other trauma types (e.g., combat), though hippocampal and ACC volumes were preserved. Further studies are needed to disentangle the unique contribution of trauma type and of sex/gender to these observations.

Self-Reported Gender Identity and Sexuality in an Online Sample of Cisgender, Transgender, and Gender-Diverse Individuals: An Exploratory Study.

The relations between self-reported aspects of gender identity and sexuality were studied in an online sample of cisgender (n = 4,954), transgender (n = 406), and gender-diverse (n = 744) groups. Aspects of gender identity and sexual fantasies, attraction, behavior, and romantic relations were assessed using the Multi-gender Identity Questionnaire (Multi-GIQ) and a sexuality questionnaire. Results show a wide spectrum of gender experiences and sexual attractions within each group, an overlap among the groups, and very weak relations between atypical gender identity and atypical sexuality. At the group level, aspects of gender identity and sexuality were mainly predicted by gender and sex-gender configuration, with little contribution of sex assigned at birth. A principal component analysis (PCA) revealed that measures of gender identity and of sexuality were independent, the structure of sexuality was mostly related to gender, whereas the structure of gender identity was mostly related to sex-gender configuration. The results of both approaches suggest that measures of gender identity could roughly be divided into three classes: one including feeling as a man and feeling as a woman; a second including measures of nonbinary and "trans" feelings; and a third including feeling as a "real" woman and feeling as a "real" man. Our study adds to current scientific data that challenge dichotomous conventions within gender identity and sexuality research. Possible social and clinical implications are discussed.

The future of sex and gender in psychology: Five challenges to the gender binary.

The view that humans comprise only two types of beings, women and men, a framework that is sometimes referred to as the "gender binary," played a profound role in shaping the history of psychological science. In recent years, serious challenges to the gender binary have arisen from both academic research and social activism. This review describes 5 sets of empirical findings, spanning multiple disciplines, that fundamentally undermine the gender binary. These sources of evidence include neuroscience findings that refute sexual dimorphism of the human brain; behavioral neuroendocrinology findings that challenge the notion of genetically fixed, nonoverlapping, sexually dimorphic hormonal systems; psychological findings that highlight the similarities between men and women; psychological research on transgender and nonbinary individuals' identities and experiences; and developmental research suggesting that the tendency to view gender/sex as a meaningful, binary category is culturally determined and malleable. Costs associated with reliance on the gender binary and recommendations for future research, as well as clinical practice, are outlined. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Analysis of Human Brain Structure Reveals that the Brain "Types" Typical of Males Are Also Typical of Females, and Vice Versa.

Findings of average differences between females and males in the structure of specific brain regions are often interpreted as indicating that the typical male brain is different from the typical female brain. An alternative interpretation is that the brain types typical of females are also typical of males, and sex differences exist only in the frequency of rare brain types. Here we contrasted the two hypotheses by analyzing the structure of 2176 human brains using three analytical approaches. An anomaly detection analysis showed that brains from females are almost as likely to be classified as "normal male brains," as brains from males are, and vice versa. Unsupervised clustering algorithms revealed that common brain "types" are similarly common in females and in males and that a male and a female are almost as likely to have the same brain "type" as two females or two males are. Large sex differences were found only in the frequency of some rare brain "types." Last, supervised clustering algorithms revealed that the brain "type(s)" typical of one sex category in one sample could be typical of the other sex category in another sample. The present findings demonstrate that even when similarity and difference are defined mathematically, ignoring biological or functional relevance, sex category (i.e., whether one is female or male), is not a major predictor of the variability of human brain structure. Rather, the brain types typical of females are also typical of males, and vice versa, and large sex differences are found only in the prevalence of some rare brain types. We discuss the implications of these findings to studies of the structure and function of the human brain.

An Exploration of the Relations Between Self-Reported Gender Identity and Sexual Orientation in an Online Sample of Cisgender Individuals.

The present study explored the relations between self-reported aspects of gender identity and sexual orientation in an online sample of 4756 cisgender English-speaking participants (1129 men) using the Multi-Gender Identity Questionnaire and a sexual orientation questionnaire. Participants also labeled their sexual orientation. We found a wide range of gender experiences in the sample, with 38% of the participants feeling also as the "other" gender, 39% wishing they were the "other" gender, and 35% wishing they had the body of the "other" sex. Variability in these measures was very weakly related to sexual orientation, and these relations were gender-specific, being mostly U shaped (or inverted-U shaped) in men and mostly linear asymptotic in women. Thus, in women, feeling-as-a-woman was highest in the exclusively heterosexual group, somewhat lower in the mostly heterosexual group, and lowest in the bisexual, mostly homosexual, and exclusively homosexual groups, which did not differ, and the reverse was true for feeling-as-a-man (i.e., lowest in the exclusively heterosexual group and highest in the bisexual, mostly homosexual, and exclusively homosexual groups). In men, feeling-as-a-man was highest at both ends of the sexual orientation continuum and lowest at its center, and the reverse was true for feeling-as-a-woman. Similar relations were evident also for the other aspects of gender identity. This study adds to a growing body of literature that questions dichotomous conventions within the science of gender and sexuality. Moreover, our results undermine the tight link assumed to exist between sexual and gender identities, and instead posit them as weakly correlated constructs.

Assault-related self-blame and its association with PTSD in sexually assaulted women: an MRI inquiry.

Sexual assault is a frequent interpersonal trauma, which often leads to post-traumatic stress disorder (PTSD). Among other postassault characteristics, self-blame attributions were suggested to play an important role in sexually assaulted individuals' coping and were consistently associated with PTSD in this population. The present study aimed to elucidate the neural underpinnings that may associate self-blame and PTSD in women who experienced sexual assault at adulthood, using structural and resting-state functional MRI. Thirty-eight sexually assaulted women and 24 non-exposed matched controls were studied (mean age: 25 years). Among the sexually assaulted participants, assault-related self-blame was negatively correlated with gray matter volume (GMV) bilaterally in the lingual gyrus and adjacent intracalcarine cortex. GMV in this cluster was also predicted by intrusion symptoms and negative social reactions. Resting-state functional connectivity (rs-FC) of this cluster with the left anterior temporal fusiform cortex significantly differed between PTSD and non-PTSD sexually assaulted participants, and was inversely correlated with intrusion symptoms and with peritraumatic dissociation. Finally, lingual cluster's GMV and rs-FC with the anterior fusiform mediated the association between self-blame and intrusion symptoms across sexually assaulted participants. These findings link assault-related self-blame, disrupted postassault recovery and the neural circuitry involved in the processing of traumatic memories.

Sex-Linked Behavior: Evolution, Stability, and Variability.

Common understanding of human sex-linked behaviors is that proximal mechanisms of genetic and hormonal sex, ultimately shaped by the differential reproductive challenges of ancestral males and females, act on the brain to transfer sex-linked predispositions across generations. Here, we extend the debate on the role of nature and nurture in the development of traits in the lifetime of an individual, to their role in the cross-generation transfer of traits. Advances in evolutionary theory that posit the environment as a source of trans-generational stability, and new understanding of sex effects on the brain, suggest that the cross-generation stability of sex-linked patterns of behavior are sometimes better explained in terms of inherited socioenvironmental conditions, with biological sex fostering intrageneration variability.

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

Understanding the multiplicity of ways in which sex can alter the brain is essential to crafting policies and treatments that are beneficial for all human beings. This is particularly true for the field of neuropsychopharmacology, as many neuropsychiatric disorders exhibit gender bias in the frequency, severity, or response to treatment. The goal of this circumspective is to provide two views on the current state of the art of the relations between sex and the brain, relations that are studied almost exclusively by comparing females and males on specific end points, from gene expression to behavior. We start by suggesting a framework for defining what is being measured and what it means. We suggest that 'sex differences' can be classified on four dimensions: (1) persistent vs transient across the lifespan; (2) context independent vs dependent; (3) dimorphic vs continuous; and (4) a direct vs an indirect consequence of sex. To accurately classify a sex difference along these dimensions, one may need to compare females and males under varied conditions. We next discuss current data on the mechanisms of sexual differentiation of the brain and on sex differences in the brain to conclude that the brain of each male and female is a mosaic of relative masculinization, feminization, and sameness, which theoretically could produce an infinite variety of individuals. We also raise the possibility that sex differences in the brain are canalized, which may act to both enhance and restrain variation between males and females. We end by discussing ways to consider sex when studying neuropsychiatric disorders.

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

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.

Sex beyond the genitalia: The human brain mosaic.

Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only "male" or only "female" features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the "maleness-femaleness" continuum are rare. 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. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain.