Exploring the Impact of Sex and Gender in Brain Function: Implications and Considerations

Abstract

Introduction

Sex and gender are crucial variables in understanding brain development and disease. Biological sex is determined by genetic and hormonal factors, whereas gender is a multidimensional construct shaped by social and cultural influences. The interplay of these factors contributes to sex-specific susceptibilities and disease progression in psychiatric and neurological disorders. However, sex and gender are often considered as a single variable, which can lead to biased data analysis and interpretation.

This commentary aims to analyze how sex and gender influence brain structure and function, with implications for personalized medicine, research, and the development of gender-sensitive clinical guidelines.

Methods

Findings from various studies employing neuroimaging techniques and animal models are discussed, as well as the impact of biological sex, gender, environmental, cultural, and social factors on brain development, organization, and behavior.

Results

Evidence suggests that sex differences in brain structure and function are not only genetically determined but are also influenced by gender-related experiences and societal contexts. Importantly, discrepancies between male and female brains are reduced in gender-equal societies. Preclinical studies play a pivotal role in determining the influence of biological sex, independent of gender, in different disease models.

Conclusion

The findings underscore the need to consider both sex and gender in research and clinical practice to avoid biases and promote equitable health outcomes. Moving forward, we advocate for gender-sensitive approaches to be integrated into brain research and in clinical guidelines to achieve personalized and precision medicine.

Key Summary Points

Both biological sex and gender-related factors (e.g., social roles, cultural context) significantly influence brain development and function, shaping susceptibility to psychiatric and neurological disorders.

Many studies on sex differences in brain function have not fully considered the impact of gender, which can vary depending on environmental and societal contexts, leading to biases and limiting personalized approaches in research and treatment.

Integrating sex and gender in research design and clinical practice is crucial to gain comprehensive insights into neurological and psychiatric disorders and to improve clinical outcomes.

Considering sex and gender as distinct but interacting variables is essential to advance precision medicine, reduce biases, and develop effective, gender-sensitive clinical guidelines.

Commentary

The brain, like many organs, shows differences attributable to sex and gender, both during health and during disease [1]. For example, women are more likely to suffer from depression, anxiety, and eating disorders, while conditions such as autism, attention deficit hyperactivity disorder, and schizophrenia are more common in men, often with sex-specific symptoms and outcomes [2]. Two-thirds of patients with Alzheimer’s disease are women, while Parkinson’s disease affects twice as many men as women. Multiple sclerosis, on the other hand, is three times more common in women, though men with the condition tend to develop neurological disabilities at a faster rate [3, 4].

As outlined by the Institute of Medicine Committee on Understanding the Biology of Sex and Gender Differences in 2001, sex pertains to the classification of living beings as male or female based on reproductive organs and functions, while gender encompasses self-representation and societal responses to gender presentation, shaped by environmental and experiential factors [5]. It is well known that biological sex and sex genes are the basis for brain development in its early biological life [6], whereas gender influences brain development mainly in the second part of its neuro- and psycho-development [7]. Sexual hormones can induce significant shifts in trajectory during brain development [8–10], also playing a key role in aging, and the onset and progression of psychiatric and neurological disorders.

Recently, an article entitled “Deep learning models reveal replicable, generalizable, and behaviorally relevant sex differences in human functional brain organization” was published in Proceedings of the National Academy of Sciences (PNAS) [11]. The authors employed deep learning, an artificial intelligence model based on algorithm training, to distinguish between male and female brains using functional magnetic resonance imaging (fMRI) data. This technique allows for the examination of differences in blood flow between brain regions. The results were consistent across different sessions demonstrating an accuracy of over 90%, indicating the model was reliable in detecting sex differences in brain function without the need for further model training [11].

The study revealed that specific brain regions and networks contribute to the observed sex differences in functional brain organization. Among these are areas associated with the default mode network (DMN), a large-scale brain network of highly correlated regions that is active during passive rest and involved in processing self-referential information, introspection, and retrieving autobiographical memory [12, 13]. Notably, the areas showing the greatest differences between the sexes were the posterior cingulate cortex, precuneus, and ventromedial prefrontal cortex. The authors suggest that these areas, differently activated in female and male individuals, could influence self-regulation, expectations, social interactions, and the ways individuals remember past experiences, form self-concepts, or think prospectively [11]. The analysis also highlighted sex-specific differences in the striatum and limbic networks. The striatum, an area important for learning signal associations, reinforcement learning, and reward sensitivity, had not previously been a focus of investigations into sex-specific differences in human functional brain organization, although evident sexual dimorphism in its anatomy was already known [14]. The limbic network also demonstrated sex-specific differences, particularly in the orbitofrontal cortex, which engages in stimulus-reinforcement learning and reversal, as well as representing reward value and subjective pleasure of reinforcements. This could explain sex-specific differences in hedonic experiences [11].

Interestingly, the DMN, striatum, and limbic network are also areas of dysfunction in psychiatric and neurodegenerative disorders and neurodiversity, including depression, schizophrenia, autism, attention deficit disorders, addiction, and Parkinson’s disease, all of which have different prevalences in the two sexes and sex-specific manifestations and outcomes [8, 15–19].

The fact that men’s and women’s brains are different is not novel, but identifying the areas activated during cognitive and affective processes in both sexes is an important result. Notably, Ryali et al. state that their findings highlight the crucial role of biological sex in human brain organization, with significant implications for the development of personalized, sex-specific biomarkers in psychiatric and neurological disorders [11]. However, it is necessary to make a clear distinction between factors attributable to biological sex and those derived from gender, especially when investigating brain function. In their study, Ryali et al. utilized spatiotemporal deep neural networks (stDNN) analyzing fMRI images of young adults (20–35 years) collected during previous studies [20–22] under the Human Connectome Project (HCP—http://www.humanconnectomeproject.org), a project supported by the National Institutes of Health, which aims to gather and provide neural data from large populations to researchers. Therefore, it is difficult to state that a study conducted on adult brains would only involve the biological sex component. More likely, the study examined brains were already shaped by education and experience, which in turn cannot be separated from gender.

Researchers have raised controversial discussions regarding sex dimorphism in the brain, beyond the apparent differences in brain areas linked to reproductive functions [23].

Indeed, sex is a modifier of disease risk and progression; and when properly documented and studied, sex and gender differences are key to pursuing precision medicine, leading to new treatments that target sex hormone and sex-chromosome effects [3].

A widely discussed MRI study captured the public’s imagination by presenting contrasting “subway map” images of men’s and women’s brains [24]. The study reported diametrically opposed subway maps of men’s and women’s brains, with connections in women mostly between hemispheres, and those in men within them, concluding that this explained why women’s brains are said to be wired for empathy and intuition, whereas male brains are supposed to be optimized for reason and action. However, meta-analyses highlight variations in gender differences across ages and contexts [25]. Even Ryali et al. hypothesize that inconsistency in findings from previous fMRI studies could be due to wide age ranges and the inclusion of individuals with psychopathology [11].

Other studies suggest that sex/gender differences in abilities and qualities are mostly nonexistent or minimal, with significant overlap between male and female individuals even in areas where larger differences are observed, such as behaviors, interests, occupational preferences, and attitudes [25, 26]. Moreover, there are no or only weak correlations between gender characteristics [27, 28]. The effects of sex can also vary or even be opposite under different environmental conditions, and these interactions may differ across various brain features. In fact, animal models have shown a lack of internal consistency within a single brain [29, 30]. Data show that brains with consistent features at one end of the “maleness–femaleness” continuum are rare. Instead, most brains comprised unique “mosaics” of features—some more common in females, some more common in males, and some shared by both [1, 27, 28, 31]. Finally, the existence of individuals identifying beyond the traditional male–female binary model further challenges simplistic notions of brain classification. Overall, the data support a model of the human brain that encompasses both masculine and feminine traits, challenging the traditional binary model of masculinity and femininity [1]. Despite the numerous intellectual contributions made by women, unfounded bias against their intellectual abilities still exists and is often internalized from childhood, thus discouraging women and girls from pursuing fields traditionally male-dominated studies, such as science, technology, engineering, and mathematics (STEM), despite no evidence supporting such exclusion [32]. While differences between female and male brains exist, the challenge moving forward is to prevent these differences from being used to justify societal inequalities.

Gender is a multidimensional construct affected by cultural norms, social contexts, and individual perceptions, varying across demographics and locations [33]. Factors such as ethnicity, socioeconomic status, and structural dynamics all interact with gender and sex; therefore, considering intersectionality is essential in health research design and analysis [34].

Indeed, there is evidence that in gender-equal countries, sex differences in brain anatomy such as thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, are less evident than in countries with greater gender inequality, thus highlighting the key role of the environment on brain development and sex-based differences, supporting the importance of gender equality in education and suggesting the need to provide neuroscience-informed gender equality policies [35].

In addition, environmental, cultural, experiential and social factors, including gender roles and gender role expectations, may influence the higher prevalence in female individuals of conditions characterized by chronic pain, such as fibromyalgia and chronic fatigue syndrome [36]. Sex bias may stem from factors that predispose individuals to chronic pain, such as abuse, anxiety, and coping mechanisms, which are more common in female subjects. Additionally, gender stereotypes may discourage men from seeking healthcare for chronic pain, while women are expected and therefore more easily facilitated to access care. This dynamic often leads to the underestimation of chronic pain in men [36]. Finally, the minority stress theory highlights how ongoing stressors related to discrimination, stigma, and social disadvantage have significant implications for minority groups, such as the lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) community, leading to adverse mental and physical health outcomes [37, 38]. Future research should explore diverse demographic groups to elucidate stable features and differences across populations and genders, correlating brain function with reported gender identity and biological sex characteristics, including sexual hormone levels [5].

To further advance equitable, personalized and precision medicine and abandon gender stereotypes, it is important that researchers are aware of the interplay between biological factors such as sex and environmental and social structures such as gender. To do so, it is crucial that both sex and gender differences are considered at different levels of medicine from basic to clinical science [8]. Animal models are crucial in biomedical research as they are not influenced by the social and cultural factors, such as gender, that affect human subjects [8]. These models are pivotal for investigating whether sex differences impact disease manifestations or biological mechanisms. For example, the study of sex differences in pain by means of animal models has led to the knowledge that microglia are responsible for mechanical allodynia after nerve injury in male but not in female mice [39]; that activating microglia via Toll-like receptor 4 (TLR4) signaling induces a higher production of cytokines and chemokines that promote pain when cells derive from males than female mice [40], and that female mice require a higher dose of opioids to achieve analgesia than males [41]. Despite the importance of studying both sexes, an ongoing male bias in animal studies has been evident over the past 50 years, particularly in neuroscience, where studies involving only male animals outnumber those involving females by around sixfold [42]. This is due to the presumed stability of male animals. Indeed, a group of researchers has shown that female mice, even with ongoing hormonal fluctuations under the influence of the menstrual cycle, exhibit more consistent exploratory behavior than their male counterparts [43].

The future of research must focus on bringing clarity through gender medicine at all levels, from preclinical studies to clinical research and guideline development, to avoid biases stemming from confusion between biological sex and gender-based differences. Prospective studies examining how brain function varies in animal models with different hormonal and environmental factors and within the same subject in clinical studies, considering factors such as age, or in different subjects with different development and education, would contribute to clarify the mechanisms underlying these differences [10].

In the era of personalized medicine, regarding the central nervous system solely as a binary model influenced by sex disregards the multifaceted and complex impact of gender-related factors, which collectively shape the brain and, ultimately, the mind.

We anticipate that future investigations on brain function will incorporate not only sex-specific differences but also education, habits, behaviors, and gender.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Author Contribution

Roberta Gualtierotti, Cinzia Bressi, Barbara Garavaglia and Paolo Brambilla have all reviewed the literature conceived and drafted the first version of the manuscript and have read and approved the final version of the manuscript.

Funding

Authors (Roberta Gualtierotti, Cinzia Bressi, Barbara Garavaglia and Paolo Brambilla) were partially supported by the Italian Ministry of Health, Bando Ricerca Corrente - Ministero della Salute, Ricerca Corrente.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Roberta Gualtierotti is on the advisory boards of Bayer, Roche, Sanofi, SOBI, and Novo Nordisk, and has participated in speaker bureau/educational meetings for Pfizer, SOBI, Takeda, and Novo Nordisk. Cinzia Bressi, Barbara Garavaglia and Paolo Brambilla have nothing to disclose.

Ethics Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.