Neuroscience of sex differences

Neuroscience of sex differences is the study of the characteristics of the brain that separate the male brain and the female brain. Unlike sexual characteristics, which are the physical qualities that separate the two sexes of an organism, the neurological differences are not visually apparent and therefore hard to study. Psychological sex differences are thought by some to reflect the interaction of genes, hormones and social learning on brain development throughout the lifespan. Some evidence from brain morphology and function studies indicates that male and female brains cannot always be assumed to be identical from either a structural or functional perspective, and some brain structures are sexually dimorphic.^[1]^[2]

History

Ideas of differences in the male and female brain circulated during the time of ancient Greek philosophers around 850 B.C. Aristotle claimed that males did not "receive their soul" until 40 days post-gestation and females did not until 80 days. In 1854, Emil Huschke discovered that "the frontal lobe in the male is all of 1% larger than that of the female."^[3] As the 19th century progressed, scientists began researching sexual dimorphisms in the brain significantly more.^[4] Until around 21 years ago, scientists knew of several structural sexual dimorphisms of the brain, but they did not think that sex had any impact on how the human brain performs daily tasks. Through fMRI and PET scan studies a great deal of information regarding the differences between male and female brains and how much they differ in regards to both structure and function has been uncovered.^{[citation needed]}

Evolutionary explanations

Sexual selection

It is thought that male and female differences in learning ability have contributed to sexual selection and mate preference throughout evolution. Females prefer males that exhibit "enhanced learning ability" because that shows that they can adapt to the changing environment well and increase their chances of survival. Brain structures associated with learning ability, such as the hippocampus, are resultantly prone to sexual selection over time. The hippocampus has even been found to exhibit seasonal activity in some mammals where it is active during breeding periods but inactive during hibernation; this is because spatial learning is more present during the breeding season.^[5]

Females show enhanced information recall compared to males. This may be due to the fact that females' approach to mate competition is a lot less physical and more focused on mental and cognitive based reasoning. For example, the ability to recall information better than males most likely originated from sexual selective pressures on females during competition with other females in mate selection. Recognition of social cues was an advantageous characteristic because it ultimately maximized offspring and was therefore selected for during evolution.^[1]

Oxytocin is a hormone that induces contraction of the uterus and lactation in mammals. It is also a characteristic hormone of nursing mothers. Studies have found that oxytocin improves spatial memory. Through activation of the MAP kinase pathway, oxytocin plays a role in the enhancement of long-term synaptic plasticity, which is a change in strength between two neurons over a synapse that lasts for minutes or longer, and long-term memory. This hormone may have helped mothers remember the location of distant food sources so they could better nurture their offspring ^[1]

Male vs. female brain anatomy

Hemisphere differences

A popular theory regarding language functions is that women use both hemispheres more equally, whereas men are more strongly lateralized to the left hemisphere.^[6] This theory found initial support in a high-profile study of 19 men and 19 women, which found stronger lateralization in men during one of the three language tasks assessed.^[7] In 2008, some researchers concluded that further studies have failed to replicate this finding, and a meta-analysis of 29 studies comparing language lateralization in males and females found no overall difference.^[8] However, in 2013, researchers at the Perelman School of Medicine at the University of Pennsylvania mapped notable differences in male and female neural wiring. The study used diffusion tensor imaging of 949 individuals aged 8–22 years, and concluded that in all supratentorial regions of the brain inter-hemispheric connectivity was greater in women's and girls' brains, whereas intra-hemispheric connectivity was greater in the brains of men and boys. The effect was reversed in cerebellar connections.^[9] The detected differences in neural connectivity were negligible up to the age of 13, but became much more prominent in the 14 to 17-year-olds.^[9] In terms of the potential effect on behaviour, the authors concluded, "Overall, the results suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes".^[9]

Past literature demonstrates emotions are strongly lateralized in the right hemisphere in males and also have have higher activation level in males as compared to females.^[10]It also found an asymmetrical activation of the visual cortex in men (with right-hemisphere predominance), and bilateral activity in women.^[10] Gasbarri et al. (2007) observed a sex related hemispheric lateralization of electrical potentials evoked by arousing negative pictures. Negative pictures elicited more robust effects in the left hemisphere in women and in the right hemisphere in men.^[10]

Amygdala

The amygdala plays a large role in emotional memory formation and storage. It has been found that it exhibits structural differences in male versus female brains. Some of these differences include size (men have a larger amygdala than women), rate of development, number of sex hormone receptors, medial amygdala (male rats have "around 80% more excitatory synapses/neuron than do females").^[11]

Several functional differences have been observed in the male and female amygdala as well. One functional difference is emotional memory retention. On average, women retain emotional memories more vividly than do men. Sometimes, however, this can have a negative effect on women and they may have impaired memory at times due to strong emotional overlap. Another negative outcome of women forming strong emotional memories is an increased 'vulnerability to depression". Females tend to dwell on negative feelings or "memories of negative life experiences" which can lead to depression^{[citation needed]}. Post-traumatic stress disorder (PTSD), an anxiety disorder, is also more prevalent in women (2 times more common in women than in men) for similar reasons. Emotional memory encoding also differs between the male and female amygdala; males encode emotional memories using the right side of their amygdala while women use the left. A behavioral difference that has been linked to the amygdala's size is sexual drive. Men have a greater sex drive than women;^{[citation needed]} this may be due to the fact that males have a larger amygdala.^[12]

Large sex differences in emotional responses and experience have been reported in previous neuropsychological studies. For example, women have greater response to negative emotional stimuli while men have greater response to positive emotional stimuli.^[13] In a meta-analysis of neuroimaging studies, women for negative emotion exhibited greater activation than men in the left amygdala, regions in the left thalamus, hypothalamus, mammillary bodies, left caudate, and medial prefrontal cortex. For positive emotion, men exhibited greater activation than women in the left amygdala, regions in the bilateral inferior frontal gyrus and right fusiform gyrus.^[14]

Hippocampus

Several studies have shown the hippocampi of men and women to differ anatomically, neurochemically, and also in degree of long-term potentiation. Such evidence indicates that sex should influence the role of the hippocampus in learning. One experiment examined the effects of stress on Pavlovian conditioning performance in both sexes and found that males’ performance under stress was enhanced while female performance was impaired. Activation of the hippocampus is more dominant on the left side of hippocampus in females, while it is more dominant on the right side in males. This in turn influences cognitive reasoning; women use more verbal strategies than men when performing a task that requires cognitive thinking.^[15] The hippocampus’s relationship with other structures in the brain influences learning and has been found to be sexually dimorphic as well.^[1]

Oestradiol has been found to influence hippocampal development. Studies have shown neurogenesis, or the formation of new neurons, to be higher in the male hippocampus than in that of the female. This may be due to the lower levels of estradiol in the male brain compared to the female brain. providing a more optimal environment for neurogenesis.^[16]

Limbic System

The limbic brain displays sexual asymmetries. A brain region closely associated with the limbic system known as the ventromedial prefrontal cortex (VMPC), plays a key role in social emotional processing. In accordance with the sexual dimorphism of the amygdala, the right VPMC is more dominant in an active limbic system for males while the left is more dominant in females. These differences carry out to a behavioral level. For example, Koscik et al. wrote:

"A man with a unilateral right VMPC lesion, who was well educated and had worked successfully as a minister, was entirely unable to return to any form of gainful employment after his brain damage. He requires supervision for daily tasks and demonstrates severe disturbances in behavior and emotional regulation, including impulsivity and poor judgment. By contrast, a man with a unilateral left VMPC lesion was able to return to his job at a grain elevator and remains successfully employed there. He is remarkably free of disturbances to his social life and emotional functioning"

In addition, a study where a group of individuals were asked to engage in a Trust Game, "a neuroeconomics task game" found that men and women who exhibited lesions in their right and left VPMC's had less trust in others.^[17]

There are also sex differences in locus coeruleus dendritic structure that allow for an increased reception and processing of limbic information in females compared to males.^[10]Amygdala volume on the other hand correlates positively with fearfulness in girls but not in boys.^[10]Aggressive and defiant behavior is also associated with decreased right anterior cingulate cortex (ACC) volume in boys.^[10]

White/grey matter

Global and regional grey matter (GM) differs in men and women. Women have larger left orbitofrontal GM volumes and overall cortical thickness than men.^[18] Behavioral implications of the greater volume have not yet been discovered. Women have a higher percentage of GM, whereas men have a higher percentage of white matter (WM) and of CSF (cerebrospinal fluid). In men the percentage of GM was higher in the left hemisphere, the percentage of WM was symmetric, and the percentage of CSF was higher in the right. Women showed no asymmetries. Both GM and WM volumes correlated moderately with global, verbal, and spatial performance across groups. However, the regression of cognitive performance and WM volume was significantly steeper in women.^[19]

In a 2013 meta-analysis, researchers found on average males had larger grey matter volume in bilateral amygdalae, hippocampi, anterior parahippocampal gyri, posterior cingulate gyri, precuneus, putamen and temporal poles, areas in the left posterior and anterior cingulate gyri, and areas in the cerebellum bilateral VIIb, VIIIa and Crus I lobes, left VI and right Crus II lobes.^[20] On the other hand, females on average had larger grey matter volume at the right frontal pole, inferior and middle frontal gyri, pars triangularis, planum temporale/parietal operculum, anterior cingulate gyrus, insular cortex, and Heschl's gyrus; bilateral thalami and precuneus; the left parahippocampal gyrus and lateral occipital cortex (superior division).^[20]The meta-analysis found larger volumes in females were most pronounced in areas in the right hemisphere related to language in addition to several limbic structures such as the right insular cortex and anterior cingulate gyrus.^[20]

Amber Ruigrok's 2013 meta-analysis also found greater grey matter density in the average male left amygdala, hippocampus, insula, pallidum, putamen ,claustrum and right cerebellum.^[20]The meta-analysis also found greater grey matter density in the average female left frontal pole^[20]

Orbital prefrontal cortex

Positron emission tomography studies have shown that men and women ranging from the ages of 19 to 32 years old metabolize glucose at significantly different rates in the orbital prefrontal cortex. Furthermore, MRI images display reduced hemispheric brain volumes, specifically in the frontal and temporal regions, in men more so than women. Infant males who exhibited lesions on their orbital prefrontal cortex struggled with object reversal experiments, but females exhibiting such lesions did not have impaired performance in object reversal.^[21]

Brain differences between homo- and heterosexuals

Brain wiring comparisons of homosexuals and that of the opposite sex shows that homosexuals may be born with a predisposition to be gay. Research at the Stockholm Brain Institute in Sweden found that gay men and straight women have similar brain characteristics. Specifically, these similarities are in the overall size of the brain and the activity of the amygdala. The same is for heterosexual men and lesbian women. Molecular biologist at the National Institutes of Health, Dean Hamer, says, “this is from a series of observations showing there’s a biological reason for sexual orientation”.^[22] Ivanka Savic – Berglund conducted a study in which MRIs were used to measure the volume and shapes of the brain. She also used PET scans to view blood flow to the amygdala. Savic – Berglund found that in gay men and women, the blood flowed to areas involved in fear and anxiety, whereas in straight men and lesbians it tended to flow to pockets linked to aggression. When looking at hemisphere differences, the right hemisphere was found to be slightly larger than the left in heterosexual males and lesbians, whereas those of gay men and straight women were more symmetrical.^[23] Research has indicated that the corpus callosum is larger in gay men than in heterosexual men. This is significant because the corpus callusum is a structure that is developed early. In the Journal Science Simon LeVay showed that the third interstitial nucleus of the hypothalamus has neurons that are packed more together in homosexual men than in heterosexual men.^[24] Connections from the amygdala to other parts of the brain are similar between homosexuals and their opposite genders as shown through PET and MRI scans. For example, in homosexual men (HoM) and heterosexual women (HeW), there were more connections from the left amygdala. In homosexual women (HoW) and heterosexual men (HeM), there were more connections from the right amygdala. LeVay's results were not replicated in other studies. A 2001 study that attempted to replicate the findings concluded that "Although there was a trend for INAH3 to occupy a smaller volume in homosexual men than in heterosexual men, there was no difference in the number of neurons within the nucleus based on sexual orientation." ^[25]

Neurochemical differences

Hormones

Steroid hormones have several effects on brain development as well as maintenance of homeostasis throughout adulthood. One effect they exhibit is on the hypothalamus, where they increase synapse formation.^[26] Estrogen receptors have been found in the hypothalamus, pituitary gland, hippocampus, and frontal cortex, indicating the estrogen plays a role in brain development. Gonadal hormone receptors have also been found in the basal forebrain nuclei.^[27]

Estrogen and the female brain

Estradiol influences cognitive function, specifically by enhancing learning and memory in a dose-sensitive manner. Too much estrogen can have negative effects by weakening performance of learned tasks as well as hindering performance of memory tasks; this can result in females exhibiting poorer performance of such tasks when compared to males.^[28]

It has been suggested that during development, estrogen can exhibit both feminizing and defeminizing effects on the human brain; high levels of estrogen induce male neural traits to develop while moderate levels induce female traits. In females, defeminizing effects are resisted due to the presence of α-fetoprotein (AFP), a carrier protein proposed to transport estrogen into brain cells, allowing the female brain to properly develop. The role of AFP is significant at crucial stages of development, however. Prenatally, AFP blocks estrogen. Postnatally, AFP decreases to ineffective levels; therefore, it is probable that estrogen exhibits its effects on female brain development postnatally.^[29]

Ovariectomies, surgeries inducing menopause, or natural menopause cause fluctuating and decreased estrogen levels in women. This in turn can “ attenuate the effects” of endogenous opioid peptides. Opioid peptides are known to play a role in emotion and motivation. β-endorphin (β-EP), an endogenous opioid peptide, content has been found to decrease (in varying amounts/brain region),post ovariectomy, in female rats within the hypothalamus, hippocampus, and pituitary gland. Such a change in β-EP levels could be the cause of mood swings, behavioral disturbances, and hot flashes in post menopausal women.^[27]

Testosterone and the male brain

Testosterone has been found to play a big role during development but may have independent effects on sexually dimorphic brain regions in adulthood. Studies have shown that the medial amygdala of male hamsters exhibits lateralization and sexual dimorphism prior to puberty. Furthermore, organization of this structure during development is influenced by the presence of androgens and testosterone. This is evident when comparing medial amygdala volume of male and female rats, adult male brains have a medial amygdala of greater volume than do adult female brains which is partially due to androgen circulation.^[11] It also heavily influences male development; a study found that perinatal females introduced to elevated testosterone levels exhibited male behavior patterns. In the absence of testosterone, female behavior is retained.^[26] Testosterone's influence on the brain is caused by organizational developmental effects. It has been shown to influence proaptotic proteins so that they increase neuronal cell death in certain brain regions. Another way testosterone affects brain development is by aiding in the construction of the "limbic hypothalamic neural networks".^[26]

Similar to how estrogen enhances memory and learning in women, testosterone has been found to enhance memory recall in men. In a study testing a correlation between memory a recall and testosterone levels in men, "fMRI analysis revealed that higher testosterone levels were related to increased brain activation in the amygdala during encoding of neutral pictures".^[30]

Oxytocin and Vasopressin

Oxytocin is positively correlated with maternal behaviours, social recognition ,social contact, sexual behaviour and pair bonding. Oxytocin appears higher in females than it does for males.^[31] Vasopressin on the other hand is enhanced in males and mediates sexual behavior and other social functions.^[31]

Neurotransmitters

Whole level 5-HT serotonin levels are higher in women versus men while men synthesize serotonin significantly faster than women. Healthy women also have higher 5-HT transport availability in the diencephalon and brainstem areas of the brain.^[32] Dopamine function is also increased in women especially dopamine transporter which regulates the availability of receptors. Women before the onset of menopause synthesize higher levels of striatal presynaptic dopamine than age-matched men.^[33]Other neurotransmitters like μ-opioids show significantly higher binding potential in the cerebellum, amygdala and the thalamus for women than it does so for men.^[34] Women are also more dependent on norepinephrine in the formation of long term emotional memories than men are.^[35]

Male vs. female brain functionality

Neural masculinization is a developmental process where different sex hormones assist in the expression of male behavior.^[36]

Stress

Stress has been found to induce an increase in serotonin, norepinephrine, and dopamine levels within the basolateral amygdala of male rats, but not within that of female rats. Furthermore, object recognition is impaired in males as a result of short term stress exposure. Neurochemical levels in the brain can change under the influence of stress exposure, particularly in regions associated with spatial and non-spatial memory, such as the prefrontal cortex and the hippocampus. Dopamine metabolite levels decrease post stress in male rats’ brains, specifically within the CA1 region of the hippocampus.^[37]

In female rats, both short term (1 hour) and long term (21 days) stress has been found to actually enhance spatial memory. Under stress, male rats exhibit deleterious effects on spatial memory, however female rats show a degree of resistance to this phenomenon. Stressed female rats’ norepinephrine (NE) levels go up by about 50% in their prefrontal cortex while that of male rats goes down 50%.^[37]

Cognitive tasks

It was once thought that sex differences in cognitive task and problem solving did not occur until puberty. However, new evidence now suggests that cognitive and skill differences are present earlier in development. For example, researchers have found that three- and four-year-old boys were better at targeting and at mentally rotating figures within a clock face than girls of the same age were. Prepubescent girls, however, excelled at recalling lists of words. These sex differences in cognition correspond to patterns of ability rather than overall intelligence (although some researchers, such as Richard Lynn of the University of Ulster in Northern Ireland, have argued that there exists a small IQ difference favoring human males). Laboratory settings are used to systematically study the sexual dimorphism in problem solving task performed by adults.^[38]

On average, males excel relative to females at certain spatial tasks. Specifically, males have an advantage in tests that require the mental rotation or manipulation of an object.^[39] They tend to outperform females in mathematical reasoning and navigation. In a computer simulation of a maze task, males completed the task faster and with fewer errors than their female counterparts. Additionally, males have displayed higher accuracy in tests of targeted motor skills, such as guiding projectiles.^[38]Males are also faster on reaction time and finger tapping tests.^[40]

On average, females excel relative to males on tests that measure recollection. They have an advantage on processing speed involving letters,digits and rapid naming tasks.^[40] Females tend to have better object location memory and verbal memory.^[41]They also perform better at verbal learning.^[42] Females have better performance at matching items and precision tasks, such as placing pegs into designated holes. In maze and path completion tasks, males learn the goal route in fewer trials than females, but females remember more of the landmarks presented. This shows that females use landmarks in everyday situations to orient themselves more than males. Females are better at remembering whether objects had switched places or not.^[38]

Studies using the Iowa gambling task, or Iowa Card Task, have examined cognitive reasoning and decision-making in males and females. A study in which participants of various age groups who were asked to perform the Iowa Card Task produced data showing that males and females differ in their decision making processes on the neurological level. The study suggests that decision-making in females may be guided by avoidance of negativity while decision making in males is mainly guided by assessing the long term outcome of a situation. They also found that males outperformed females in the Iowa Card Task, but there was a negative correlation between elevated testosterone levels and performance in the card task which indicates gonadal hormones influence decision-making.^[21]

There are minimal differences in fluency tasks.^{[clarification needed]}^{[citation needed]}

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