Introduction

The brain is a complex neural structure that plays a vital role in maintaining our survival. It is constantly receiving complex information from our environment through our senses (sight, smell, hearing, touch, taste), interpreting this to achieve optimal functioning and health.¹ With the advances in neuroscience and psychology, this has provided new insights into our understanding of brain functioning, particularly in the study of sex differences. These highlight various sex differences in biological, psychological, and social aspects of brain functioning. Understanding these differences can help lead to informed decisions in more effective and targeted treatment pathways for neurological and psychiatric disorders for men and women.² 

Biological foundations of brain differences

Brain structure variations

Research has suggested that several brain structure variations exist between males and females. On average, males tend to have 9-12% larger overall brain volumes with higher levels of white matter. White matter facilitates communication networks between different regions of the brain. Further regions identified, including the amygdala, which is responsible for emotional regulation and reactivity, have been shown to be larger in men.³

In comparison, women have higher cortical density in some brain regions and their grey matter. Grey matter is responsible for processing and interpreting information, aiding cognitive memory and learning. Literature highlights, alongside this, that the prefrontal cortex and hippocampus, important in executive functions, decision-making, and working memory, appear larger and have early maturation in women.⁴ Similarly, the corpus callosum that facilitates communication and coordination between the two brain hemispheres shows a greater density and thickness in women, while having a greater surface area in men.⁵

Hormonal influences

Hormones are naturally occurring chemical messengers that coordinate bodily functions. Sex differences in brain functioning have been tied to the production of particular sex hormones in males and females. For example, the way testosterone and estrogen are distributed can shape the brain in utero in the prenatal period and during puberty. This impacts the secretion of hormones during different life periods.⁶

In males, testosterone is a predominant sex hormone that can impact brain structures such as the amygdala and hypothalamus, influencing recognition of threatening cues and spatial cognition tasks. Various studies have found a correlation between elevated testosterone and higher spatial navigation in males compared to their counterparts.⁷

In females, estrogen is the predominant sex hormone, implicated in the maturation of the prefrontal cortex and hippocampus; influencing memory retention and verbal fluency. This can further be affected according to the phases of a woman's menstrual cycle. The changes that occur during these phases can influence brain activation in neurotransmitters such as serotonin, impacting mood regulation.⁸

Other hormones such as oxytocin and cortisol, have shown sex differences in brain functioning. Oxytocin has been linked to our ability to bond and build empathy for others, enhancing positive social interaction. Studies have found sex differences in the way oxytocin influences the processing of social stimuli, particularly in the amygdala. In men, oxytocin can reduce amygdala activity in response to negative stimuli, such as threatening faces or emotional scenes. In comparison, in women, oxytocin may increase amygdala activity in response to threatening stimuli. This demonstrates that oxytocin may influence threat-based systems differently in each sex, whereby it may serve to promote detection of threatening stimuli in females, while reducing threat sensitivity in males.⁹

Cortisol is the body's primary stress hormone, helping to prepare our ‘fight or flight’ response. Research reveals that cortisol impacts the amygdala, responding differently to stress in males and females. In women, higher levels of cortisol can negatively impact connectivity to the amygdala and impact emotional processing. Whereas in men, this appears to have the opposite effect, with higher levels of cortisol being positively associated with the functional connectivity of the amygdala. Therefore appears cortisol enhances the communication of regions involved in emotion and action processing in men. When accounting for other sex hormone differences such as testosterone, it appeared that when cortisol was heightened, high testosterone was associated with larger hippocampal volume and better memory performance, potentially mediating the neurotoxic effects cortisol can have on the brain.^10,11

Genetic contributions

Sex differences in gene expression have been highlighted as another contributing factor in brain functioning, particularly in the development of the X and Y chromosomes. Women have XX chromosomes, while men have XY chromosomes. The Y chromosome provides the foundation for the male developing brain and the formation of testosterone. It has been found that the X and Y chromosomes can affect overall brain size and impact neural connectivity in regions such as the cerebral cortex, where social perception and decision-making occur.¹²

Most recently, literature has investigated changes in epigenetics in sex-specific genes. Key findings demonstrate that environmental factors in lifestyle choices such as diet and stress have the ability to increase or decrease sex differences in genes, and therefore impact the brain.¹³

Functional brain differences

Neural connectivity 

Neural Connectivity refers to the way brain regions communicate with each other. Several studies have observed connectivity differences with the use of functional imaging techniques (FMRI), showing sex differences in brain activation patterns. In men, it has been recognised that there being stronger intra-hemispheric connections, linking different brain structures within the same hemisphere. Such higher connectivity has been linked to activation of motor sensory regions and visual and parietal regions, assisting with spatial awareness and sensorimotor integration.¹⁴ 

In women, it has been observed that there are stronger inter-hemispheric connections facilitating the communication between the left and right hemispheres. In particular, higher connections between the frontal lobes aid empathy and greater cognitive flexibility. In addition, women have a stronger Default Mode Network (DMN); a network in charge of monitoring one's internal reflective thoughts, feelings and experiences.¹⁵

Psychological and behavioural implications

Mental health differences

Observing the prevalence rates of mental health disorders, it is well-established that there are sex differences among various conditions. For example, women have higher rates of diagnosed depression and anxiety, compared to men having higher rates of diagnosed autism spectrum disorder and schizophrenia.¹⁶ 

In women, this can be attributed to the differences in hyperconnectivity being greater in limbic and default mode networks, identified as key factors in depression.¹⁷ In men, this has been potentially connected to the disrupted attention and executive control network activity within autism spectrum disorder and schizophrenia.¹⁸

Other individual sex differences have been considered the difference in women's cycles, where longitudinal studies note women who experience premature hormonal menopause and estrogen deficiency are at heightened risk for first-onset depression.¹⁹ This, therefore, implicates hormonal differences between men and women as another potential factor contributing to various conditions. 

Environmental influences on brain functioning 

While the biological foundations of sex differences have been explored, evidence has suggested that the environment plays a fundamental role in brain development. The brain is constantly learning through our experiences, allowing neural networks to adapt and change, known as neuroplasticity. In this process, the brain can reorganise new adaptive connections (synapses) through experiences across our lifespan. 

This can be mapped onto the variations in early socialisation with cultural expectations and gender roles, influencing brain development. For example, different cultural norms and socioeconomic status have differential emphasis for young men and women to engage in activities and develop distinct traits that can be reinforced in the environment through parenting styles, in turn leading to sex differences in brain activity and structure.²⁰

Similarly, in an MRI study across countries, greater gender inequality and adverse social environments were associated with sex differences in brain structures involved in emotional control, particularly impacting women.²¹ Therefore, in certain social contexts, reinforcement in experiences has the power to either enhance positive or negative brain functioning. 

Criticisms and future directions in research 

While there is considerable research investigating sex differences in brain functioning, conclusions should be treated with caution. With today’s changing society, there is a need for studies to consider intersectionality and inclusivity. Many studies observing these differences, particularly older research, fail to account for beyond binary models, by observing ‘gender identity’ and ‘biological sex’ as separate factors. It would be useful for future studies to consider diversity in the social constructs by defining gender differences and how this interlinks with gender-related experiences shaping brain functioning. 

In addition, the way gender and sex interact with other factors of the environment, such as race, socioeconomic status, culture, etc, needs to be explored, which may vary findings. Without acknowledging this limitation, risks of overgeneralisation and misinterpreting brain research to reinforce sex biases.²²

There are methodological challenges to be mindful of in studies where many have small sample sizes, a lack of longitudinal data and the use of animal studies.²³ This may limit the reliability in translating findings of sex differences to the wider population.

Summary

The development in imaging methods has afforded the opportunity to grow research into understanding sex differences in brain regions, functioning and connectivity between men and women. These observed differences can have implications for future directions in diagnostic clinical guidance and tailoring therapeutic interventions according to individualised needs. In doing so, it may allow early diagnosis and implement a preventative approach for accurate treatment, and better disease management in disorders common in each sex. It should be noted that while some brain differences are observed between males and females, these are based on averages where significant individual variation exists with great complexity between sexes and the brain. With this in mind, the complexity of the brain should not be reduced in explaining such differences by biology alone, but should strive to create a framework acknowledging brain diversity amongst the population.