1Policy Research Team, Korea Center for Gendered Innovations for Science and Technology Research (GISTeR), Seoul, Korea
2Korea Center for Gendered Innovations for Science and Technology Research (GISTeR), Seoul, Korea
3Ewha Womans University, Seoul, Korea
*Corresponding author: Hack-Lyoung Kim,
Policy Research Team, Korea Center for Gendered Innovations for Science and
Technology Research (GISTeR), 22 Teheran-ro 7-gil, Gangnam-gu, Seoul 06130,
Korea, E-mail: khj826@gister.re.kr
• Received: February 29, 2024 • Revised: April 22, 2024 • Accepted: April 24, 2024
This is an Open-Access article distributed under the terms of the
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This review aims to highlight the importance of research on structural,
functional, molecular-biological, and disease-specific sex differences in the
brain, and to examine current bibliometric indicators related to research on sex
differences. The Web of Science Core Collection was searched for related
articles from 2010 to 2023. Structural and functional brain differences
according to sex, including variations in communication patterns between
hemispheres, may play a role in mental disorders. Sex differences in
neurotransmitters such as serotonin, dopamine, and γ-aminobutyric acid
contribute to disparities in mental health, addiction, and neurodevelopmental
conditions. Neurodevelopmental disorders such as autism spectrum disorder and
schizophrenia exhibit sex-based differences in prevalence, symptoms, brain
changes, and neurotransmitter disruptions under hormonal influence. There is a
growing body of research on depression, adolescence, the hippocampus, the
amygdala, and cognition, highlighting the importance of considering sex/gender
factors. Recent studies on sex differences in brain diseases have identified
variations in brain structure, function, and neurophysiological substances, as
well as in hormones and genes between the sexes. The incidence of psychiatric
disorders such as autism spectrum disorder, depression, anxiety, and
Alzheimer’s disease is increasingly being linked to sex differences, and
the need for research into the mechanisms underlying these differences is
gaining recognition. However, there remains a significant gap in sex-specific
neuroscience research related to the diagnosis, treatment, prevention, and
management of these conditions. Advancing inclusive research will require
comprehensive training, a consensus on methodology, diverse perspectives through
collaborative frameworks, governmental/institutional support, and dedicated
funding to create suitable research environments and implementation
strategies.
The latest Global Burden of Disease (GBD) report [1] indicates that the worldwide need for diagnosing and treating
mental disorders has surged significantly in recent years. This category
includes depressive disorders, anxiety disorders, bipolar disorder,
schizophrenia, autism spectrum disorder (ASD), attention-deficit/hyperactivity
disorder (ADHD), and neurodegenerative brain disorders. Notably, substantial sex
differences have been observed in the prevalence of depression, anxiety
disorders, ASD, and neurodegenerative brain disorders (Fig. 1) [2–6].
Fig. 1.
Several neurological disorders that exhibit sex differences. Male
bias (grey), female bias (yellow). ADHD, attention-deficit/hyperactivity
disorder.
Depressive disorders, characterized by changes in mood, interest, energy, sleep,
and appetite, occur more than twice as often in women as in men. ASD, a
significant brain development disorder marked by difficulties in social
communication and interaction, along with repetitive behavior patterns or
interests, is approximately four times more prevalent in men than in women
[5,7,8]. Alzheimer's
disease (AD), a common condition of aging where the brain gradually loses
function and disrupts daily living, occurs twice as frequently in women as in
men [9–11]. Parkinson's disease (PD), a movement disorder
that impairs the ability to control movement, has been reported to be more than
twice as common in men as in women [12–14]. Sex
differences have been observed in several psychiatric disorders, but the causes
of these differences remain largely unknown [4,15,16]. Several factors are thought to be involved, including
genetic, biological, and environmental factors, but more research is needed to
elucidate these influences.
Sex differences in the incidence of mental disorders serve as both direct and
indirect indicators that biological or social factors may predispose different
sexes to various brain diseases. This recognition has spurred a growing interest
in researching the causes behind these sex differences in mental disorders
[1,4,17,18]. For mental disorders with evident sex differences, it
is advisable to design and conduct studies specifically aimed at identifying the
underlying causes of these disparities. By analyzing the sex/gender-specific
characteristics of brain diseases and uncovering the mechanisms behind sex
differences, researchers can develop more effective and safer diagnostic and
treatment strategies, as well as preventive and rehabilitative measures to
enhance mental health.
To date, several biological factors—including variations in brain
structure and function, influences of neurotransmitters and hormones, and
genetics—as well as sociocultural factors, such as individual experiences
and learning, have been suggested as potential explanations for sex differences
in mental disorders [19,20]. In light of these factors, research
into sex differences in the brain seeks to uncover the physiological and
structural distinctions between male and female brains [21]. The field of research on sex differences in the brain
is growing, driven by advances in various technologies such as brain imaging,
genetic analysis, neural network studies, big data, and artificial
intelligence.
Objectives
This review highlights the importance of research into sex differences in
neuroscience. It specifically updates the following areas: structural and
functional sex differences in the brain, sex differences in neurotransmitters,
sex differences in mental disorders, and bibliometric findings related to sex
differences in neuroscience research.
Methods
Ethics statement
This study does not involve human subjects; therefore, neither institutional
review board approval nor informed consent was required.
Study design
This study was a narrative review and bibliometric study based on a literature
database search.
Literature search/information source and search strategy
The Web of Science Core Collection (Clarivate) was searched for the bibliometric
analysis. The authors reviewed the presence of sex/gender-specific keywords in
the titles and abstracts of articles and reviews within the field of biological
sciences, published from 2010 to 2023. The search utilized the keywords
["sex factor*" OR "sex characteristic*" OR
"sex difference*" OR "gender factor*" OR
"gender characteristic*" OR "gender difference*"]
NOT ["sex* partner*" OR "sex* selection*" OR
"sex* behavior*" OR "sex* behavior*"]. More specific
search terms are included in Supplement 1. Additionally, to identify the main
keywords and major research areas related to sex differences in neuroscience and
psychiatry, we analyzed the keyword network using Vos Viewer (https://www.vosviewer.com/).
The associations between article titles and keywords, identified using
sex/gender-specific search terms through Vos Viewer, revealed that research
primarily focused on three main topics: brain structure and function (fMRI,
amygdala, hippocampus, etc.), mental disorders (depression, anxiety,
schizophrenia, etc.), and neurotransmitters (dopamine, etc.). The existing
literature on these topics, with an emphasis on sex/gender differences, was
thoroughly identified and reviewed.
Results
A total of 5,491 articles were identified that discussed structural and functional
sex differences in the brain; 4,227 articles addressed sex differences in
neurotransmitters, and 14,401 articles explored sex differences in mental
disorders.
Structural and functional sex differences in the brain
Recent meta-analyses [18,22] have demonstrated structural sex
differences in various brain regions. These differences include the amygdala,
hippocampus, temporal lobe, and insular regions, with men generally having a
larger overall brain volume than women. Specific areas such as the left frontal
gyrus, left occipital gyrus, left insula, right frontal orbital gyrus, and left
occipital sulcus also showed differences. Additionally, variations in white
matter regions were observed in the following sequence: midbrain, corpus
callosum, right anterior cingulate gyrus, right superior colliculus, and left
medial anterior cingulate gyrus [22].
Furthermore, a study on the diffusion-based structural connectome of the brain
[23] confirmed that men's
brains exhibit more intra-hemispheric communication, whereas women's
brains show more inter-hemispheric communication. This study also indicated that
brain development in men and women diverges from an early age, leading to
structural and functional brain differences in adolescence and adulthood. These
structural and functional changes may influence the development of
neuropsychiatric disorders, particularly during adolescence—a period when
physiological and behavioral differences between the sexes become more
pronounced, and the risk of developing neuropsychiatric disorders increases
[24]. Notably, activity in the left
amygdala significantly increases in women during adolescence, which is partly
associated with heightened anxiety.
Although numerous studies have analyzed the structure and function of the brain,
significant gaps remain in our understanding of the behavioral and physiological
differences between men and women, as well as the specific variations in brain
structure and function related to mental disorders. Further research into brain
structure, function, and sex-specific symptoms is essential to enhance the
diagnosis and treatment of the growing prevalence of mental disorders
worldwide.
Sex differences in neurotransmitters
Sex differences have also been reported in neurotransmitters that play a crucial
role in regulating brain function, such as serotonin, dopamine, and
γ-aminobutyric acid (GABA). Serotonin, a neurotransmitter involved in
mood regulation, including depression and anxiety disorders [3,25–28], exhibits sex
differences in its expression, role, and receptor [25]. Women have higher levels of serotonin in their blood
compared to men [18], and these elevated
serotonin levels have been linked to higher levels of estrogen, a sex hormone
associated with female reproductive organs [27]. Additionally, women show significantly higher expression of
5-HT1A receptors in various cortical and subcortical brain regions than men
[25]. However, the rate of serotonin
synthesis is 52% faster in men than in women [26]. This sex difference in serotonin has been proposed as a
potential cause for the varying incidence of depression, anxiety disorders, and
bipolar disorder between sexes, suggesting that sex-specific treatments and
prevention methods warrant further investigation [28].
Sex differences also exist in dopamine, which plays a crucial role in regulating
the motor and reward systems [29,30]. Notably, female hormones such as
β-estradiol have been shown to enhance the activity of dopamine cells,
resulting in increased dopamine release [15]. Additionally, several physiological sex differences have been
identified, including variations in the neuroanatomical distribution of dopamine
neurons, basal dopamine levels, and the influence of ovarian hormones [30]. Sex differences in dopamine have been
suggested to contribute to sex differences in addiction [29,31] and PD [12,18,29], but more detailed
research on disease-, brain region-, and behavior-specific mechanisms is
needed.
GABA, an inhibitory neurotransmitter that acts as an excitatory neurotransmitter
in the developing brain, is regulated by sex hormones, particularly estrogen,
during the perinatal period of sensitivity. Researchers have observed sex
differences in the volume of certain nuclei and in the frequency and type of
synapses in areas such as the hypothalamus, hippocampus, and preoptic area
[32]. Additionally, estrogen has been
shown to modulate GABA receptors, controlling their synaptic inhibitory efficacy
and leading to differences in signal transduction between the sexes [33]. These findings have led to the
hypothesis that sex differences may contribute to conditions such as ASD, ADHD,
and epilepsy that develop during this critical period [32,34,35]. However, further research is necessary
to fully understand the underlying mechanisms and potential treatments.
Sex differences in mental disorders
Brain developmental disorders
ASD, the most common brain developmental disorder, affects approximately 1 in
36 children; boys are four times more likely to be affected than girls, and
their symptoms tend to differ [7]. In
a study involving over 2,400 individuals with ASD aged 4–18 years
[5], it was found that females
with ASD generally exhibited greater impairments in social communication
skills, overall IQ, and adaptive functioning. In contrast, males with ASD
displayed more prevalent restricted and repetitive behaviors (RRBs).
Additionally, males with ASD had larger than normal volumes of grey matter,
white matter, and the hippocampus, whereas females with ASD showed smaller
volumes in the right hippocampus compared to typical levels [8]. Sex hormones, particularly estrogen,
have been demonstrated to influence brain development by affecting the
synthesis and receptor expression of GABA, an inhibitory neurotransmitter
[7]. Estrogen has also been shown
to increase levels of glutamate, a brain-active neurotransmitter, which
affects receptor signaling and enhances NMDA receptor expression [34]. Moreover, progesterone can inhibit
glutamatergic responses and exhibits sexual dimorphism in certain brain
regions. Lower plasma glutamate levels have been observed in individuals
with ASD [36].
Schizophrenia is classified as a brain developmental disorder. Research has
shown that men are more likely to exhibit positive symptoms such as
delusions, hallucinations, and aggression, whereas women tend to develop
negative symptoms like depression, anxiety, and social isolation [37]. The typical age of onset varies by
sex, occurring between 15 to 25 years in men and 25 to 35 years in women,
with another peak occurring after menopause. Changes in brain structure and
function are also evident; in men, the prefrontal lobe decreases in size and
becomes more asymmetrical than normal, whereas in women, the prefrontal lobe
increases in size and shows enhanced white matter connectivity. Furthermore,
neurotransmitter activity differs between the sexes, with an overactivity of
dopamine in males and glutamate in females [29,37].
Mood disorders
Depressive disorders, including post-traumatic stress disorder, generalized
anxiety disorder, and major depressive disorder, are more common in women
than in men [1,3,28,38]. Brain imaging analyses of male and
female patients with depressive disorders [38] have revealed changes in the size of the hippocampus,
amygdala, habenula, anterior cingulate cortex, and corpus callosum. These
analyses also showed altered function in the frontal and temporal gyri,
caudate nucleus, and prefrontal cortex, as well as microstructural changes
in the corpus callosum and its prefrontal projections. Additionally, sex
differences in brain circuitry and related systems have been identified
[3]. When examining the circuits
activated by a stimulus that leads to a behavioral or physiological
response, comparisons between the sexes may reveal that the same circuits
are involved, but the response may be more intense or prolonged in one sex
compared to the other. For instance, corticotropin-releasing factor
activates the arousal system more significantly in women than in men.
Alternatively, it may be activated only in one sex; for example, flight
stress activates anterior limbic projections to the dorsal thalamus,
mediating stress in men but not in women, and sometimes results in
completely different behaviors in men and women. For instance, oxytocin
activation of oxytocin receptor-containing interneurons in the medial
prefrontal cortex induces anxiety in men and altruistic behavior in women.
In some cases, the physiological and/or behavioral effects may be the same
in both sexes, but there are sex differences in the circuits and mechanisms
that produce these effects. For example, when recalling emotional content,
the right amygdala is activated in men, whereas the left amygdala is
activated in women. While sex differences have been observed in various
brain regions and systems associated with depressive disorders, we have yet
to identify sex-specific etiologies and mechanisms for treatment,
management, and prevention. More focused research on sex differences is
essential to unravel the complexities of brain circuitry, hormonal
influences, and physiological and behavioral differences.
Neurodegenerative disorders
Neurodegenerative disorders are characterized by the loss of neurons,
typically associated with aging. AD, a major neurodegenerative disorder,
disproportionately affects women, with incidence rates more than twice those
in men. Conversely, PD predominantly affects men, with rates more than twice
as high as those in women.
AD, one of the most common neurodegenerative disorders, is a progressive
condition that begins with mild memory loss and can progress to a complete
inability to interact with others or respond to the environment. This
progression occurs as the brain regions responsible for thinking, memory,
and language become impaired. Women with AD experience a faster cognitive
decline than men, and studies have shown that brain atrophy also occurs more
rapidly in women [9,39]. Furthermore, depression, sleep
disorders, and stress are risk factors for developing AD. Notably,
depression, which is more commonly diagnosed in women, increases the risk of
AD. Sleep disorders, which tend to worsen during menopause, contribute to
the accumulation of amyloid beta, a protein implicated in AD. Estrogen also
plays a significant role in AD. It regulates synaptic plasticity and
enhances neural survival. However, the rapid fluctuations in estrogen levels
after menopause are linked to an increased risk of brain damage [11].
PD is the second most common neurodegenerative disease after AD and is
characterized by severe movement disorders such as bradykinesia, rigidity,
tremor, and gait disturbances, which are caused by the loss of midbrain
dopaminergic neurons [40]. The
incidence of PD is higher in men than in women; however, women experience
higher mortality rates and faster disease progression. Additionally, motor
and rapid eye movement sleep behavior disorder symptoms are more prevalent
in men, and studies have shown that the cortex is thinner in men than in
women in the central and pre-central regions. Moreover, men exhibit greater
total cortical and subcortical atrophy, and the volumes of the thalamus,
caudate, insula, globular bodies, hippocampus, and brainstem are smaller in
men [14]. A recent study revealed
that cortical thickness varies between male and female patients with PD,
influenced by age and disease duration [13]. Specifically, in men with PD, cortical thinning in six
frontal lobes (bilateral caudal middle frontal gyrus, bilateral superior
frontal gyrus, left frontal gyrus, and right orbitofrontal gyrus), three
parietal lobes (bilateral inferior parietal gyrus and left superior parietal
gyrus), and one limbic system region (right posterior cingulate gyrus) was
associated with longer disease duration and older age. In contrast, in women
with PD, only limbic regions showed an association with disease
duration.
Bibliometric analysis of sex differences in neuroscience research papers and
related keywords
A total of 57,628 articles are included in this bibliometric analysis. As
research continues to uncover sex differences in brain structure, function, and
neurotransmitters in various brain disorders, the importance of
sex/gender-specific research is becoming increasingly recognized. Specifically,
understanding the sex-specific mechanisms involved in anxiety, depression, ASD,
AD, and PD is crucial for the prevention and treatment of mental disorders and
for protecting sex/gender-specific mental health.
Major scientific journals such as Nature [41,42], The
Lancet [43,44] and Cell [45] have recognized the importance of
integrating sex and gender considerations into research and are actively
promoting and disseminating this approach. Concurrently, there has been an
increase in the publication of sex/gender-specific research articles. Our search
indicated a general rise in these publications (Fig. 2), with neuroscience and psychiatry experiencing a significant
uptick since 2018. In contrast, cell biology and biology have shown minimal
changes. This trend underscores the widespread sex differences observed in
research findings within neuroscience and psychiatry, highlighting the critical
need for sex/gender-specific research in these disciplines.
Fig. 2.
Trends in sex/gender-specific papers (number of publications) in
neuroscience (red), psychiatry (pink), behavioral sciences (green), cell
biology (blue), and biology (purple).
It was found that the keywords related to sex differences were most commonly
associated with depression, anxiety, adolescence, and stress, and are connected
through brain diseases, functions, and research methods (Fig. 3). Specifically, the brain regions of the hippocampus
and amygdala were identified as having strong associations with
sex/gender-related keywords. Additionally, topics such as age, stress, estrogen,
and cognition were found to be closely linked with studies on sex/gender
differences.
Fig. 3.
Keyword co-occurrence networks in brain research. The colors of
circles are used to identify the clusters resulting from analyses of the
relationships provided by the VOS Viewer software (red: disorders, blue:
complex, green: method, purple: addiction, cluster size:
frequency).
Discussion
Interpretation and suggestion
In this comprehensive review, we have substantiated the existence of both
structural and functional disparities between sexes in the brain, while also
elucidating the underlying mechanisms that contribute to sex/gender-specific
differences in various disease states. The complex orchestration of perceptual,
learning, emotional, cognitive, and behavioral functions across all brain
regions highlights the complexity of brain function. Consequently, the
identification of sex differences in individual brain regions, along with
multifaceted influencing factors, emphasizes the presence of sex/gender-specific
differentials in overall brain function.
However, most existing brain research, particularly in animals, has focused on
males. This has resulted in a body of knowledge that is biased and lacks
consideration of sex-specific differences. A deficiency in sex/gender-specific
research can lead to drug side effects and inefficiencies that vary between
sexes/genders. Moreover, generalizing findings can result in the absence of
tailored treatments and discrimination, as well as broader health issues due to
insufficient knowledge.
Recent research into the fundamental causes of sex differences in brain disorders
highlights a growing consensus that sex/gender-specific vulnerabilities and
resilience to diseases might originate from the brain's sexual
dimorphism. This view is supported by evidence indicating that biological
differences, such as hormonal and genetic variations, affect brain structure,
function, and neurotransmitter systems during development.
The findings from non-clinical studies on microglia published in 2018 were
particularly revealing, as they highlighted sex-dependent disparities in gene
transcription, protein synthesis, and cellular function and activity [46,47]. Microglia, small cells in the central nervous system, play a
crucial role in managing immune and inflammatory responses and are essential for
neuron survival and the formation of neural circuits [48]. Initially observed in the early 2000s in response to
estrogen, the detailed differences in microglial function between sexes were
only thoroughly described in 2018. For example, it was discovered that female
brains typically exhibit weaker inflammatory responses, which may provide
increased resistance to certain diseases, while male brains may suffer
exacerbated brain damage due to stronger inflammatory reactions [47]. Additionally, male microglia appear to
be more reactive and mobile and exhibit a heightened expression of certain
proteins compared to their female counterparts, which demonstrate a higher
capacity for phagocytosis and gene expression related to cell repair and
inflammation management [49]. These
functional disparities could potentially explain the varied susceptibility to
diseases between sexes, underscoring the need for further research to fully
understand how microglial sexual dimorphism contributes to these differences
[50].
The importance of understanding biological sex differences in the brain is
paramount. These differences are essential for enhancing the effectiveness and
personalization of prevention, management, and treatment strategies for
sex-specific conditions. Additionally, they provide insights into the intricate
interplay of biological, environmental, and developmental factors that influence
human behavior and identity. This knowledge also supports ethical and social
debates, fostering inclusion and understanding across various sectors of
society. Consequently, global neuroscience research initiatives are increasingly
concentrating on exploring these mechanisms through the lens of sex differences.
Notably, the Women's Brain Project [39,51] serves as a key
platform for advocating and disseminating research focused on understanding the
numerous factors that affect women's brain health and the
pathophysiological mechanisms of mental disorders that are commonly observed in
women. This initiative is crucial in addressing the male bias in brain health
research and aims to advance precision medicine by establishing a solid
foundation of knowledge on sex/gender-specific brain functions.
The author suggests that research on neuroscience and psychiatric disorders
should incorporate sex-specific considerations, particularly when studying
conditions such as depression, anxiety, stress, adolescence, schizophrenia, and
the hippocampus.
Conclusion
The predominance of single-sex studies in research has introduced biases, and a
general lack of sex/gender-aware studies has hindered the expansion of informed
clinical trials. These trials, which are essential for verifying the safety and
efficacy of treatments, must incorporate sex/gender considerations in their
designs and outcomes. The advancement of sex/gender-inclusive research relies on
comprehensive training in these concepts, agreement on methodologies, and the
integration of diverse perspectives through collaborative frameworks.
Additionally, governmental and institutional support, coupled with appropriate
funding, is crucial for enhancing research environments and ensuring the
thorough implementation of inclusive research strategies.
Authors' contributions
Project administration: Kim H, Lee H
Conceptualization: Kim H
Methodology & data curation: Kim H, Lee H
Funding acquisition: Lee H
Writing – original draft: Kim H
Writing – review & editing: Kim H, Lee H
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
Korea Center for Gendered Innovations for Science and Technology research
(GISTeR), through the Center for Women in Science, Engineering and Technology
(WISET) funded by the Ministry of Science and ICT (WISET202403GI01).
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Current status and significance of research on sex differences in
neuroscience: a narrative review and bibliometric analysis
Fig. 1.
Several neurological disorders that exhibit sex differences. Male
bias (grey), female bias (yellow). ADHD, attention-deficit/hyperactivity
disorder.
Fig. 2.
Trends in sex/gender-specific papers (number of publications) in
neuroscience (red), psychiatry (pink), behavioral sciences (green), cell
biology (blue), and biology (purple).
Fig. 3.
Keyword co-occurrence networks in brain research. The colors of
circles are used to identify the clusters resulting from analyses of the
relationships provided by the VOS Viewer software (red: disorders, blue:
complex, green: method, purple: addiction, cluster size:
frequency).
Fig. 1.
Fig. 2.
Fig. 3.
Current status and significance of research on sex differences in
neuroscience: a narrative review and bibliometric analysis
