The brain differences

The Differences

Structural Differences

The size of the brain is established at an early age, with the whole brain volume at 95% of its adult size by the age of 4. However, the brain continues to develop through the teen age, with many of these changes being sex specific. In the adult brain, the overall cerebral size is larger in men than women, but there are specific parts that are larger in women. These include the caudate nucleus, hippocampus, some prefrontal cortical regions, superior temporal gyrus, and some white matter structures such as the anterior commisure . In the male, the hypothalamus, stria terminalis, cerebral ventricles, and the splenium and genu of the corpus callosum are proportionally larger. In regions where the volume of the structure may not be different, there may be a difference in neuron density. For example, a region of the suprachiasmatic nucleus contains twice as many neurons in men until middle age, when the sex difference reverses and then ultimately disappears.

Frederikse et.al. found sex differences in the inferior parietal lobule (IPL) of the brain (the IPL is shown in yellow in the above diagram). The IPL, a neocortical region, is part of the heteromodal association complex (HASC), which includes the Broca's area among other parts. The IPL is believed to have a role in processing information from the visual, auditory and somatosensory association cortices as well as having connections with other HASC regions, the limbic system and the hypothalamus. In their study of 15 pairs of normal male and female subjects, Frederikse et.al. concluded that men have a larger total IPL volumes than women, with this difference primarily as a result of a larger left male IPL volume. This study supports previous evidence that men tend to outperform women on tasks of visuospatial processing, a function primarily of the left side of the IPL.

Use difference
Research found that men tend to use one side of their brain (particularly the left side for verbal reasoning) while women tend to use both cerebral areas for visual, verbal and emotional responses. These differences in brain use cause a difference in behavior between men and women. Women tend to be better at sensing emotional messages in conversations, gestures, and facial expressions, and are thus more sensitive. Women start to speak and read at an earlier age than men and are generally better in verbal skills, such as learning a different language. They tend to have a better grasp on grammar and spelling, and girls have better handwriting than boys do. Women have better sight at night and have a more acute sense of smell, taste and hearing.

Men are better in spatial coordination and have a better sense of direction (usually!). They excel in math and are great at interpreting three-dimensional objects. They have a better hand-eye coordination and more precise control of large muscle movement. They have poor peripheral vision but better sight in bright light and a better sense of perspective. Since they use one side of their brain more than the other, they tend to use the left side for verbal reasoning and the right for visual and emotional activities (if they are right handed).

These differences are not rules. It is easy to find women who excel in math and men who have excellent language skills (and it is even easier to find men with no sense of direction). Chances are the above statements are not going to work for your everyday situation, but these have been shown to be true in scientific studies, based on large, diverse populations. When looking at large populations, these differences between men and women become evident, and proper statistical analysis takes care of the exceptions.

Differences in brain structure cause very interesting difference in behavior and are thus important to the paleoanthropological study of humans. It is often these variations in behavior that aid researchers in determining the functions of brain areas. Whether these could be correlated to behavior will depend on the way the study is performed, but anthropologists should take the variations between men and women into consideration as they study human societies.

His Brain, Her Brain

May 2005 Scientific American

It turns out that male and female brains differ quite a bit in architecture and activity. Research into these variations could lead to sex-specific treatments for disorders such as depression and schizophrenia

By Larry Cahill

Scientists sizing up the brains of both sexes began using their main finding--that female brains tend to be smaller--to bolster the view that women are intellectually inferior to men.   To date, no one has uncovered any evidence that anatomical disparities might render women incapable of achieving academic distinction in math, physics or engineering. And the brains of men and women have been shown to be quite clearly similar in many ways. Nevertheless, over the past decade investigators have documented an astonishing array of structural, chemical and functional variations in the brains of males and females.   These inequities are not just interesting idiosyncrasies that might explain why more men than women enjoy the Three Stooges. They raise the possibility that we might need to develop sex-specific treatments for a host of conditions, including depression, addiction, schizophrenia and post-traumatic stress disorder (PTSD). Furthermore, the differences imply that researchers exploring the structure and function of the brain must take into account the sex of their subjects when analyzing their data--and include both women and men in future studies or risk obtaining misleading results. Sculpting the Brain Not so long ago neuroscientists believed that sex differences in the brain were limited mainly to those regions responsible for mating behavior. In a 1966 Scientific American article entitled "Sex Differences in the Brain," Seymour Levine of Stanford University described how sex hormones help to direct divergent reproductive behaviors in rats--with males engaging in mounting and females arching their backs and raising their rumps to attract suitors. Levine mentioned only one brain region in his review: the hypothalamus, a small structure at the base of the brain that is involved in regulating hormone production and controlling basic behaviors such as eating, drinking and sex. A generation of neuroscientists came to maturity believing that "sex differences in the brain" referred primarily to mating behaviors, sex hormones and the hypothalamus. Differences in the size of brain structures are generally thought to reflect their relative importance to the animal. For example, primates rely more on vision than olfaction; for rats, the opposite is true. As a result, primate brains maintain proportionately larger regions devoted to vision, and rats devote more space to olfaction. So the existence of widespread anatomical disparities between men and women suggests that sex does influence the way the brain works. Other investigations are finding anatomical sex differences at the cellular level. For example, Sandra Witelson and her colleagues at McMaster University discovered that women possess a greater density of neurons in parts of the temporal lobe cortex associated with language processing and comprehension. On counting the neurons in postmortem samples, the researchers found that of the six layers present in the cortex, two show more neurons per unit volume in females than in males. Similar findings were subsequently reported for the frontal lobe. With such information in hand, neuroscientists can now explore whether sex differences in neuron number correlate with differences in cognitive abilities--examining, for example, whether the boost in density in the female auditory cortex relates to women's enhanced performance on tests of verbal fluency. Differences in the size of brain structures are generally thought to reflect their relative importance to the animal. For example, primates rely more on vision than olfaction; for rats, the opposite is true. As a result, primate brains maintain proportionately larger regions devoted to vision, and rats devote more space to olfaction. So the existence of widespread anatomical disparities between men and women suggests that sex does influence the way the brain works. Other investigations are finding anatomical sex differences at the cellular level. For example, Sandra Witelson and her colleagues at McMaster University discovered that women possess a greater density of neurons in parts of the temporal lobe cortex associated with language processing and comprehension. On counting the neurons in postmortem samples, the researchers found that of the six layers present in the cortex, two show more neurons per unit volume in females than in males. Similar findings were subsequently reported for the frontal lobe. With such information in hand, neuroscientists can now explore whether sex differences in neuron number correlate with differences in cognitive abilities--examining, for example, whether the boost in density in the female auditory cortex relates to women's enhanced performance on tests of verbal fluency. Such anatomical diversity may be caused in large part by the activity of the sex hormones that bathe the fetal brain. These steroids help to direct the organization and wiring of the brain during development and influence the structure and neuronal density of various regions. Interestingly, the brain areas that Goldstein found to differ between men and women are ones that in animals contain the highest number of sex hormone receptors during development. This correlation between brain region size in adults and sex steroid action in utero suggests that at least some sex differences in cognitive function do not result from cultural influences or the hormonal changes associated with puberty--they are there from birth. Inborn Inclinations Several intriguing behavioral studies add to the evidence that some sex differences in the brain arise before a baby draws its first breath. Through the years, many researchers have demonstrated that when selecting toys, young boys and girls part ways. Boys tend to gravitate toward balls or toy cars, whereas girls more typically reach for a doll. But no one could really say whether those preferences are dictated by culture or by innate brain biology. #1 To address this question, Melissa Hines of City University London and Gerianne M. Alexander of Texas A&M University turned to monkeys, one of our closest animal cousins. The researchers presented a group of vervet monkeys with a selection of toys, including rag dolls, trucks and some gender-neutral items such as picture books. They found that male monkeys spent more time playing with the "masculine" toys than their female counterparts did, and female monkeys spent more time interacting with the playthings typically preferred by girls. Both sexes spent equal time monkeying with the picture books and other gender-neutral toys. Because vervet monkeys are unlikely to be swayed by the social pressures of human culture, the results imply that toy preferences in children result at least in part from innate biological differences. This divergence, and indeed all the anatomical sex differences in the brain, presumably arose as a result of selective pressures during evolution. In the case of the toy study, males--both human and primate--prefer toys that can be propelled through space and that promote rough-and-tumble play. These qualities, it seems reasonable to speculate, might relate to the behaviors useful for hunting and for securing a mate. Similarly, one might also hypothesize that females, on the other hand, select toys that allow them to hone the skills they will one day need to nurture their young. Simon Baron-Cohen and his associates at the University of Cambridge took a different but equally creative approach to addressing the influence of nature versus nurture regarding sex differences. Many researchers have described disparities in how "people-centered" male and female infants are. For example, Baron-Cohen and his student Svetlana Lutchmaya found that one-year-old girls spend more time looking at their mothers than boys of the same age do. And when these babies are presented with a choice of films to watch, the girls look longer at a film of a face, whereas boys lean toward a film featuring cars. Of course, these preferences might be attributable to differences in the way adults handle or play with boys and girls. To eliminate this possibility, Baron-Cohen and his students went a step further. They took their video camera to a maternity ward to examine the preferences of babies that were only one day old. The infants saw either the friendly face of a live female student or a mobile that matched the color, size and shape of the student's face and included a scrambled mix of her facial features. To avoid any bias, the experimenters were unaware of each baby's sex during testing. When they watched the tapes, they found that the girls spent more time looking at the student, whereas the boys spent more time looking at the mechanical object. This difference in social interest was evident on day one of life--implying again that we come out of the womb with some cognitive sex differences built in. Under Stress In many cases, sex differences in the brain's chemistry and construction influence how males and females respond to the environment or react to, and remember, stressful events. Take, for example, the amygdala. Goldstein and others have reported that the amygdala is larger in men than in women. And in rats, the neurons in this region make more numerous interconnections in males than in females. These anatomical variations would be expected to produce differences in the way that males and females react to stress. To assess whether male and female amygdalae in fact respond differently to stress, Katharina Braun and her co-workers at Otto von Guericke University in Magdeburg, Germany, briefly removed a litter of Degu pups from their mother. For these social South American rodents, which live in large colonies like prairie dogs do, even temporary separation can be quite upsetting. The researchers then measured the concentration of serotonin receptors in various brain regions. Serotonin is a neurotransmitter, or signal-carrying molecule, that is key for mediating emotional behavior. (Prozac, for example, acts by increasing serotonin function.) The workers allowed the pups to hear their mother's call during the period of separation and found that this auditory input increased the serotonin receptor concentration in the males' amygdala, yet decreased the concentration of these same receptors in females. Although it is difficult to extrapolate from this study to human behavior, the results hint that if something similar occurs in children, separation anxiety might differentially affect the emotional well-being of male and female infants. Experiments such as these are necessary if we are to understand why, for instance, anxiety disorders are far more prevalent in girls than in boys. Another brain region now known to diverge in the sexes anatomically and in its response to stress is the hippocampus, a structure crucial for memory storage and for spatial mapping of the physical environment. Imaging consistently demonstrates that the hippocampus is larger in women than in men. These anatomical differences might well relate somehow to differences in the way males and females navigate. Many studies suggest that men are more likely to navigate by estimating distance in space and orientation ("dead reckoning"), whereas women are more likely to navigate by monitoring landmarks. Interestingly, a similar sex difference exists in rats. Male rats are more likely to navigate mazes using directional and positional information, whereas female rats are more likely to navigate the same mazes using available landmarks. (Investigators have yet to demonstrate, however, that male rats are less likely to ask for directions.) Even the neurons in the hippocampus behave differently in males and females, at least in how they react to learning experiences. For example, Janice M. Juraska and her associates at the University of Illinois have shown that placing rats in an "enriched environment"--cages filled with toys and with fellow rodents to promote social interactions--produced dissimilar effects on the structure of hippocampal neurons in male and female rats. In females, the experience enhanced the "bushiness" of the branches in the cells' dendritic trees--the many-armed structures that receive signals from other nerve cells. This change presumably reflects an increase in neuronal connections, which in turn is thought to be involved with the laying down of memories. In males, however, the complex environment either had no effect on the dendritic trees or pruned them slightly. But male rats sometimes learn better in the face of stress. Tracey J. Shors of Rutgers University and her collaborators have found that a brief exposure to a series of one-second tail shocks enhanced performance of a learned task and increased the density of dendritic connections to other neurons in male rats yet impaired performance and decreased connection density in female rats. Findings such as these have interesting social implications. The more we discover about how brain mechanisms of learning differ between the sexes, the more we may need to consider how optimal learning environments potentially differ for boys and girls.

Although the hippocampus of the female rat can show a decrement in response to acute stress, it appears to be more resilient than its male counterpart in the face of chronic stress. Cheryl D. Conrad and her co-workers at Arizona State University restrained rats in a mesh cage for six hours--a situation that the rodents find disturbing. The researchers then assessed how vulnerable their hippocampal neurons were to killing by a neurotoxin--a standard measure of the effect of stress on these cells. They noted that chronic restraint rendered the males' hippocampal cells more susceptible to the toxin but had no effect on the females' vulnerability. These findings, and others like them, suggest that in terms of brain damage, females may be better equipped to tolerate chronic stress than males are. Still unclear is what protects female hippocampal cells from the damaging effects of chronic stress, but sex hormones very likely play a role. The Big Picture Extending the work on how the brain handles and remembers stressful events, my colleagues and I have found contrasts in the way men and women lay down memories of emotionally arousing incidents--a process known from animal research to involve activation of the amygdala. In one of our first experiments with human subjects, we showed volunteers a series of graphically violent films while we measured their brain activity using PET. A few weeks later we gave them a quiz to see what they remembered. We discovered that the number of disturbing films they could recall correlated with how active their amygdala had been during the viewing. Subsequent work from our laboratory and others confirmed this general finding. But then I noticed something strange. The amygdala activation in some studies involved only the right hemisphere, and in others it involved only the left hemisphere. It was then I realized that the experiments in which the right amygdala lit up involved only men; those in which the left amygdala was fired up involved women. Since then, three subsequent studies--two from our group and one from John Gabrieli and Turhan Canli and their collaborators at Stanford--have confirmed this difference in how the brains of men and women handle emotional memories. The realization that male and female brains were processing the same emotionally arousing material into memory differently led us to wonder what this disparity might mean. To address this question, we turned to a century-old theory stating that the right hemisphere is biased toward processing the central aspects of a situation, whereas the left hemisphere tends to process the finer details. If that conception is true, we reasoned, a drug that dampens the activity of the amygdala should impair a man's ability to recall the gist of an emotional story (by hampering the right amygdala) but should hinder a woman's ability to come up with the precise details (by hampering the left amygdala). Propranolol is such a drug. This so-called beta blocker quiets the activity of adrenaline and its cousin noradrenaline and, in so doing, dampens the activation of the amygdala and weakens recall of emotionally arousing memories. We gave this drug to men and women before they viewed a short slide show about a young boy caught in a terrible accident while walking with his mother. One week later we tested their memory. The results showed that propranolol made it harder for men to remember the more holistic aspects, or gist, of the story--that the boy had been run over by a car, for example. In women, propranolol did the converse, impairing their memory for peripheral details--that the boy had been carrying a soccer ball. In more recent investigations, we found that we can detect a hemispheric difference between the sexes in response to emotional material almost immediately. Volunteers shown emotionally unpleasant photographs react within 300 milliseconds--a response that shows up as a spike on a recording of the brain's electrical activity. With Antonella Gasbarri and others at the University of L'Aquila in Italy, we have found that in men, this quick spike, termed a P300 response, is more exaggerated when recorded over the right hemisphere; in women, it is larger when recorded over the left. Hence, sex-related hemispheric disparities in how the brain processes emotional images begin within 300 milliseconds--long before people have had much, if any, chance to consciously interpret what they have seen. These discoveries might have ramifications for the treatment of PTSD. Previous research by Gustav Schelling and his associates at Ludwig Maximilian University in Germany had established that drugs such as propranolol diminish memory for traumatic situations when administered as part of the usual therapies in an intensive care unit. Prompted by our findings, they found that, at least in such units, beta blockers reduce memory for traumatic events in women but not in men. Even in intensive care, then, physicians may need to consider the sex of their patients when meting out their medications. Sex and Mental Disorders ptsd is not the only psychological disturbance that appears to play out differently in women and men. A PET study by Mirko Diksic and his colleagues at McGill University showed that serotonin production was a remarkable 52 percent higher on average in men than in women, which might help clarify why women are more prone to depression--a disorder commonly treated with drugs that boost the concentration of serotonin. A similar situation might prevail in addiction. In this case, the neurotransmitter in question is dopamine--a chemical involved in the feelings of pleasure associated with drugs of abuse. Studying rats, Jill B. Becker and her fellow investigators at the University of Michigan at Ann Arbor discovered that in females, estrogen boosted the release of dopamine in brain regions important for regulating drug-seeking behavior. Furthermore, the hormone had long-lasting effects, making the female rats more likely to pursue cocaine weeks after last receiving the drug. Such differences in susceptibility--particularly to stimulants such as cocaine and amphetamine--could explain why women might be more vulnerable to the effects of these drugs and why they tend to progress more rapidly from initial use to dependence than men do.   Certain brain abnormalities underlying schizophrenia appear to differ in men and women as well. Ruben Gur, Raquel Gur and their colleagues at the University of Pennsylvania have spent years investigating sex-related differences in brain anatomy and function. In one project, they measured the size of the orbitofrontal cortex, a region involved in regulating emotions, and compared it with the size of the amygdala, implicated more in producing emotional reactions. The investigators found that women possess a significantly larger orbitofrontal-to-amygdala ratio (OAR) than men do. One can speculate from these findings that women might on average prove more capable of controlling their emotional reactions. In additional experiments, the researchers discovered that this balance appears to be altered in schizophrenia, though not identically for men and women. Women with schizophrenia have a decreased OAR relative to their healthy peers, as might be expected. But men, oddly, have an increased OAR relative to healthy men. These findings remain puzzling, but, at the least, they imply that schizophrenia is a somewhat different disease in men and women and that treatment of the disorder might need to be tailored to the sex of the patient. Sex Matters in a comprehensive 2001 report on sex differences in human health, the prestigious National Academy of Sciences asserted that "sex matters. Sex, that is, being male or female, is an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of biomedical and health-related research." Neuroscientists are still far from putting all the pieces together--identifying all the sex-related variations in the brain and pinpointing their influences on cognition and propensity for brain-related disorders. Nevertheless, the research conducted to date certainly demonstrates that differences extend far beyond the hypothalamus and mating behavior. Researchers and clinicians are not always clear on the best way to go forward in deciphering the full influences of sex on the brain, behavior and responses to medications. But growing numbers now agree that going back to assuming we can evaluate one sex and learn equally about both is no longer an option. LARRY CAHILL received his Ph.D. in neuroscience in 1990 from the University of California, Irvine. After spending two years in Germany using imaging techniques to explore learning and memory in gerbils, he returned to U.C. Irvine, where he is now an associate professor in the department of neurobiology and behavior and a Fellow of the Center for the Neurobiology of Learning and Memory.

Sex Differences in the Brain

How male and female brains diverge is a hotly debated topic, but the study of model organisms points to differences that cannot be ignored.

By Margaret M. McCarthy | October 1, 2015

© ISTOCK.COM/SERGIYN

"We have raised our children in a gender-neutral household since the day they were born, and we never allowed any sort of weapons, not even a water pistol," a young mother told me emphatically from the microphone in the lecture hall where I'd just given a talk on the differences between male and female brains. "But the other day my seven-year-old son bit his peanut butter and jelly sandwich into the shape of a gun and started shooting his little sister with it!" The audience laughed appreciatively; everyone had a similar story. "What did we do wrong?" she pleaded.

This story is a common refrain I hear when discussing my research on sex differences in the brain. There is no single correct answer when it comes to human behavior. Some researchers would insist that there is nothing parents can do to suppress the innate tendencies of boys to gravitate to guns and trucks while girls prefer dolls and tea sets. Others would disagree, arguing that there is no inherent biological difference between the brains of boys and girls. Rather, it is the parents' own implicit biases and those of society at large that influence their children to behave in gender-typical ways. In the end, my response is that sex differences in the brain are more than some would like and less than others believe.

Just how large those differences are, however, is the crux of an ongoing debate in science. And how much a brain's function can be attributed to biology versus cultural expectations is a challenging question to answer. Confounding the issue is the concept of gender, a purely human construct that can itself influence brain development. Gender refers to both personal and societal perceptions of one's sex, and embodies all the complexities of cultural expectations, inherent biases, and predetermined norms of behavior, each of which differs for boys and girls and can affect the young brain. Debates are most heated on questions of sex differences in cognitive abilities and emotionality, and for good reason: biological evidence of superior cognitive ability in one sex could have devastating consequences for equality.

To justify this male bias in laboratory experiments, most research­ers maintain that there are no sex differ­ences in brain function outside of the con­text of reproduction.

Studies of laboratory animal models—for which social biases and constructs such as gender are absent—have revealed significant anatomical differences between the brains of males and females that arise in fetal and early postnatal development, as well as a role for hormones, which differ greatly between the sexes, in the functioning of the adult brain. For these reasons, researchers assiduously avoid experimenting with female animals. A recent comparison of the representation of male and female animals in preclinical research found the discipline of neuroscience to be one of the most strongly skewed toward the exclusive study of males, with five times more studies conducted solely with male animals than with females or a mixture of the sexes.¹ To justify this male bias in laboratory experiments, most researchers maintain that there are no sex differences in brain function outside of the context of reproduction, and that the so-called masculinization of the male brain occurs only in those areas that govern reproductive behaviors.

But there is now increasing evidence that differences in brain function are prevalent across the sex divide, and that these differences manifest in surprising ways in animal models of both health and disease. (See "Gender bias in neuropsychiatric disorders.") Many sex differences in adult brain structure and behaviors are the result of in utero organizational effects of gonadal steroid hormones, in particular androgens and their aromatized derivatives, estrogens, both of which are present in substantially higher concentrations in male fetuses due to testicular steroidogenesis. Brain differences between the sexes can also arise from diverse factors, including the expression of genes carried on the sex chromosomes and discrepancies in maternal treatment of male and female progeny. Together, these factors mediate differences in neurogenesis, myelination, synaptic pruning, dendritic branching, axonal growth, apoptosis, and other neuronal parameters.

This is not to say that everything is different. Indeed, much of the brain and its functions are indistinguishable between the two sexes. But when it is different, the question is, how did the differences come about? By what cellular mechanisms did the course of development change in a particular region that differs between males and females?

Early studies have focused on the usual suspects: neurotransmitters, neurotrophins, and transcription factors, for example. But we are now in the midst of a major rethinking of the origins of sex differences in the mammalian brain with a shift in emphasis away from traditional agents and a new understanding of steroid hormone action.

Female by default

SEX ON THE BRAIN: A mammalian embryo is female by default. Males develop when the Sry gene of the Y chromosome is expressed, spurring the development of testes. During fetal development, the testes produce large amounts of testosterone, much of which is converted to estrogen. Both hormones then act on the brain, inducing the cellular process of masculinization.
See full infographic: WEB | PDF© EVAN OTO/SCIENCE SOURCEThe gonads of the developing fetus are the epicenters of sex determination. All other primary and secondary sex characteristics depend on hormones emanating from the testes or ovaries at specific points later in development. By default, the gonadal precursor will differentiate into an ovary; formation of a testis requires a transcription factor coded for by the Sry gene on the Y chromosome. Likewise, the brain will develop as a female brain by default and be directed towards masculinization only if exposed to the steroids produced by the testis.

Developmental masculinization of the brain leads to significant structural differences in the brains of the two sexes. (See illustration.) Some brain regions are larger in males; others are smaller. Collections of cells that constitute nuclei or subnuclei of the brain differ in overall size due to differences in cell number and/or density, as well as in the number of neurons expressing a particular neurotransmitter. The length and branching patterns of dendrites and the frequency of synapses also vary between males and females—in specific ways in specific regions—as does the number of axons that form projections between nuclei and across the cerebral hemispheres. Even nonneuronal cells are masculinized. Astrocytes in parts of the male brain are more "bushy," with longer and more frequent processes than those in the same regions of the female brain. And microglia, modified macrophages that serve as the brain's innate immune system, are more activated in parts of the male brain and contribute to the changes seen in the neurons.

Steroid hormones induce such changes by binding to transcription factors that then translocate to the cell nucleus to initiate gene transcription. For example, estradiol binds to its receptor to induce expression of the gene for cyclooxygenase, which mediates the rate-limiting step in the production of a short-lived signaling molecule called prostaglandin E2 (PGE2). A little more than 10 years ago, my colleagues and I made the surprising discovery that PGE2 is both necessary and sufficient for the fetal masculinization of the preoptic area, a brain region that is essential for sexual behavior in male mice.² In males, levels of PGE2 are upregulated selectively in this brain region by estradiol-induced synthesis of the cyclooxygenase enzyme. PGE2 then initiates a signal transduction cascade that leads to activation of AMPA glutamate receptors and the formation and stabilization of synapses on the dendrites of neurons in this brain region. As a result, male mice have twice the density of excitatory synapses in the preoptic area as females, and this positively correlates with expression of male copulatory behavior in adulthood.³

We subsequently discovered that microglia, which have recently begun to be appreciated for their role in sculpting neuronal circuits,6 are the predominant source of PGE2.⁴ Not only are there more of these innate immune cells in young male brains, their morphology reflects a more activated state, and they produce more PGE2 than do the microglia in female brains. Pharmacological treatments given early in development to shift microglia away from an activated state resulted in lower PGE2 production and prevented masculinization induced by estradiol.⁵ Thus, a nonneuronal cell, microglia, and an inflammatory mediator, PGE2, are essential for the normal masculinization of the preoptic area in mice.

Another region of the brain that is masculinized during development is the amygdala, which in addition to its roles in the processing of emotions is a key region regulating social play behavior by juveniles, sometimes called rough-and-tumble play, which differs markedly in males and females across a wide range of species. The dimorphism in the frequency and intensity of play is particularly interesting in that it is expressed during a time of life when there are minimal to no circulating steroids, and thus any differences in males and females are either genetic or the result of earlier organizational effects of steroids on the brain.⁷ Sex differences in the synaptic patterning of the amygdala are not as readily apparent as in the preoptic area, but there is a notable difference in cell genesis during the neonatal sensitive period—at least the first four days of life in mice and up to a week in rats—with the amygdala of females making more new neurons and astrocytes than the same region in males.⁸

This particular sex difference appears to be mediated by endocannabinoids, natural ligands for the receptors that are activated by the psychoactive components of marijuana. Specifically, higher endocannabinoid levels in the male amygdala act to suppress cell genesis. Increasing endocannabinoid levels or administering endocannabinoid mimetics to females during the first week of life reduces the level of cell genesis in their amygdalas to that of males. And, quite interestingly, this correlates with an increase in rough-and-tumble play by these females as juveniles.

Although it is unknown how endocannabinoids reduce cell genesis in the amygdala, emerging evidence suggests the resident microglia of this brain region may be critical mediators of cell number, just as they are elsewhere in the brain. Microglia can regulate cell number in two ways: by phagocytosing dead or dying cells, or by engulfing and actually killing live cells, a process recently termed phagoptosis.⁹ Appropriate control of cell number is critical to a healthy brain. If dying cells are not efficiently removed, toxic cell contents are spilled into the extracellular space, leading to additional cell death. Conversely, if cells proliferate excessively, the ability to form and maintain organized connections is lost. Microglia are essential guardians of both these processes, and ongoing work suggests that this is likely also true in the control of sex differences in cell number in specific subnuclei.

Epigenetics and the brain

The hormonally mediated masculinization of the brain is referred to as an "organizational" event in recognition of its relative permanency, but how this state endures has been unknown. In the preoptic area, an area closely associated with the hypothalamus and which controls male sexual behavior, we find consistent sex differences in synaptic density across rodent life stages. Males have about twice as many synapses for a given length of a neuronal dendrite as females have, and this is true in newborn rats, adolescents, and adults.³ Something is maintaining the spacing of the synapses.

One likely suspect is epigenetic modifications to the genome, which we now know can store such cellular memory. By interfering with DNA methyltransferases (DNMTs) to cause widespread demethylation of the genome, my group found evidence of greater DNMT activity in female rats that correlated perfectly with an increase in DNA methylation for the brain region controlling masculinization of sexual behavior.¹⁰ Inhibiting DNMTs in females during the first week of life resulted in rats that were more male-like in both brain structure and behavior, presumably as a consequence of reduced DNA methylation and increased expression of a suite of genes critical for masculinization. Surprisingly, if we treated females with a DNMT inhibitor outside of the sensitive period, they were still masculinized, suggesting that DNA methylation is critical to the maintenance of feminization by actively repressing masculinization genes. The same was found to be true for mice in which the enzyme DNMT3a was genetically deleted in the preoptic area. Identification of what genes are emancipated by the loss of methylation is ongoing, but early analysis implicates genes associated with microglia and with mast cells, another component of the innate immune system of the brain.

Changes in the epigenome are a component of sexual differentiation of the brain, but we are only beginning
to crack this complex code.

The role of DNA methylation in brain sex differences is not cut-and-dried, however. The canonical view is that epigenetic marks are established early and then endure. But studies have found there can also be a delayed epigenetic response to early hormonal treatment, a sort of epigenetic echo. For example, geneticist Eric Vilain of the University of California, Los Angeles, and colleagues observed many more sex differences in DNA methylation in adult mice than in newborns, both in the striatum and the preoptic area, and that treatment of newborn female mice with testosterone shifted their DNA methylation profile to that of males, but not until they were adults.¹¹ In a similar study, researchers at the University of Maryland in Baltimore found sex differences in methylation of the promoter regions of the estrogen and progesterone receptors in the hippocampus, preoptic area, and hypothalamus, but the pattern of methylation changed over the course of the animals' lives, from neonate to adolescent to adult.¹² There is clearly an organizational effect of hormones in the brain, but the appearance of those effects in the epigenome is not tied closely to the time of exposure. How this is occurring at the cellular level is currently a mystery.

Histone modifications also appear to be important in the differentiation of male and female brains. One particular histone modification, called H3K4me3, clusters at transcription start sites and is generally, but not exclusively, associated with increased gene expression. A genome-wide analysis in the murine preoptic area found some 250 genes with a sex difference in the amount of associated H3K4me3, more than 70 percent of which were higher in females. Many of these genes were involved in synaptic transmission, neuronal growth, and differentiation.¹⁴

Not surprisingly, there are also sex differences in the levels of histone deacetylases (HDACs), which mediate such epigenetic marks. There are higher levels of HDACs in the preoptic area of neonatal male mice, and these enzymes tend to be associated with the promoter regions of the estrogen receptor and the aromatase enzyme, which makes estradiol. Deacetylation is associated with decreased gene expression, and both the estrogen receptor and aromatase are more highly expressed in males prenatally, but decline after birth when testosterone levels drop and masculinization is finalized. Blocking HDAC activity during the first week of life impairs male sexual performance in adulthood, confirming the importance of deacetylation for normal masculinization.¹³

Thus, just as with DNA methylation, changes in the epigenome of the histones are a component of sexual differentiation of the brain, but we are only beginning to crack this complex code.

The mosaic brain

© ISTOCK.COM/RUDALL30/MARINAZAKHAROVASo to what extent do these brain sex differences identified in rodents also exist in humans? While we can't experiment on humans for obvious reasons, we can rely on "natural experiments" in which a hormonal profile or sensitivity has been altered due to genetic anomalies. Two well-studied examples are congenital adrenal hyperplasia (CAH), in which the adrenal glands produce excessive androgens during fetal development, and complete androgen insensitivity syndrome (CAIS), in which a mutation in the androgen receptor makes it incapable of binding testosterone and other androgens. In both cases, gonadal development occurs according to the chromosomally dictated sex—i.e., XX embryos will develop ovaries and XY embryos, testes—but the secondary sex characteristics often align with the opposite sex. CAH girls are born with masculinized genitalia, for example, due to their in utero androgen exposure, while CAIS boys appear as normal girls when born due to the lack of differentiation of the external male sex organs.

These conditions provide the opportunity to ask whether brain sex matches gonadal sex. In the case of CAIS, the answer is emphatically no, as these XY individuals consistently identify as females. This finding is in line with the notion that early life exposure to androgens is necessary for development of a male identity. For the CAH girls, the shift in hormonal profile is not as dramatic as that for CAIS individuals, and thus the changes in brain and behavior are also less dramatic. Still, there is typically evidence for a degree of "masculinization" of their brains when assessed for behavioral traits such as toy choice. Thus, despite some differences between humans and animal models, the preponderance of evidence supports the notion that humans undergo a hormonally mediated process of sexual differentiation of the brain just like animals.

The brain is a mix of relative degrees of masculinization in some areas and feminization in others.

However, while both the popular and scientific presses make reference to "male" and "female" brains, the brain is in reality not a unitary organ like the liver or the kidney. It is a compilation of multiple independent yet interacting groups of cells that are subject to both external and internal factors. This is abundantly true for hormonal modulation, with many and varied signal transduction pathways invoked. As a result, it is quite literally impossible for the brain to take on a uniform "maleness" or "femaleness." Instead, the brain is a mix of relative degrees of masculinization in some areas and feminization in others. On average, there are likely to be some areas that are more strongly feminized in a female and others that are more strongly masculinized in a male, but averages are never predictive of an individual's profile. Moreover, a mosaic is not a blend—there is not a continuum of maleness to femaleness—and there are many parameters that are neutral in regard to sex, with no consistent differences between males and females.

Evolutionarily, the creation of a maleness-femaleness mosaic within one brain makes sense, providing organisms with greater variability and therefore adaptability to changing environments. But another striking aspect of brain sexual differentiation that my colleagues and I have noted is that for each endpoint we examine, we find the magnitude of the sex difference to be constrained within the relatively low range of just one- to twofold. While this is still significantly greater than the extremely small variance within each sex, it is by no means colossal, as one might describe the difference between a male peacock's tail and that of a peahen. It is as if something is both pushing the brains of the sexes apart and keeping them together at the same time.

This interpretation is consistent with the concept of canalization, originally proposed by British biologist Conrad Waddington in the late 1940s and now embraced by evolutionary biologists as a means by which species maintain robustness in the face of ever-present internal and external challenges. Chaperone proteins and other agents act to buffer an organism against changes in pH or salinity and other environmental threats by assisting in proper protein folding or maintaining order in intracellular traffic, for example. We propose that, during embryonic development or during the first week of life, many sexually differentiated endpoints are subject to canalization, assuring that males will stay in one canal and females in another, and that the two canals will never merge or grow too far apart.

In humans, an additional canalization factor could be parental, societal, and cultural influences early in life. Gender-specific behaviors may be rewarded, for example, or punished if considered not in line with a child's sex. While these factors remain difficult to tease apart, it is clear that the brains of males and females diverge as they develop, and it should be self-evident that using only male animals to probe mammalian brain function does not reveal the whole picture. 

© ISTOCK.COM/FRIKOTA GENDER BIAS IN NEUROPSYCHIATRIC DISORDERS Some neuropsychiatric disorders are thought to originate during fetal development, even if patients are not typically diagnosed until adolescence or young adulthood. Of these, most are much more common in males. Other disorders begin to manifest at puberty or later in life, and these occur more frequently in females. The biological reasons for these sex biases in disease prevalence are currently under investigation. Major depressive disorder: One of the most common neuropsychiatric disorders, MDD is considered strongly gender biased, with women twice as likely as men to be diagnosed. This bias is seen worldwide, suggesting a biological as opposed to cultural origin. Dysregulation of the stress axis and its convergence with the dynamic nature of reproductive hormones in women are implicated as root causes of greater risk in women, although more recent evidence suggests this dysregulation may have its origins in very early childhood. However, the importance of other variables contributing to the gender bias, such as the willingness of women to seek help while men tend to self-medicate with drugs and alcohol, cannot be discounted. Anorexia nervosa: Strictly postpubertal in onset, anorexia nervosa is predominantly a young woman's disease, with a gender bias greater than 10:1 that is almost assuredly driven by perceived societal pressures. Interestingly, bulimia nervosa, a disorder of binge eating but in which normal body weight is maintained, is much less gender biased, with women only three times as likely as men to suffer the disorder. Autism spectrum disorder: While ASD was originally considered only twice as prevalent in boys, recent estimates put the ratio closer to 5:1. A currently popular but unproven theory postulates that elevated testosterone in utero leads to ASD-like behaviors by placing boys on the extreme end of the male spectrum. A counter-theory is that girls are underdiagnosed for ASD due to physician bias and a different presentation, with fewer social and cognitive defects. Others argue that girls are more resilient and require a greater load of genetic insult before the disorder manifests, and empirical evidence supports this view for those limited instances in which a genetic origin of ASD is clear. Attention deficit hyperactivity disorder: Reports of the degree to which ADHD occurs more frequently in boys than girls vary widely and are likely influenced as much by cultural factors as biological ones. Additionally, males tend to show greater impairments, making them at least four times more likely to be diagnosed. Schizophrenia: When considered for the population overall, there is no clear gender bias in the frequency of schizophrenia. However, diagnosis is much more common in boys and young men than in girls, whereas diagnosis in middle age or older is substantially more frequent in women. Differential responses to stress, with distinct brain regions being over- or underactivated in men versus women, further contribute to divergence in the disease. Biplolar disorder: Rates of bipolar disorder do not vary between men and women, yet a genetic polymorphism strongly associated with the disorder is relevant to risk in women but not men. This highlights how much we have to learn about the nature of sex differences in neuropsychiatric disorders and the multiple ways in which some differences can manifest.

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Margaret M. McCarthy is chair of the Department of Pharmacology and a member of the Program in Neuroscience at the University of Maryland School of Medicine in Baltimore.

References

1. A.K. Beery, I. Zucker, "Sex bias in neuroscience and biomedical research," Neurosci Biobehav Rev, 35:565-72, 2011.
2. S.K. Amateau, M.M. McCarthy, "Induction of PGE(2) by estradiol mediates developmental masculinization of sex behavior," Nat Neurosci, 7:643-50, 2004.
3. C.L. Wright et al., "Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates," Dev Neurobiol, 68:1406-19, 2008.
4. K.M. Lenz et al., "Microglia are essential to masculinization of brain and behavior," J Neurosci, 33:2761-72, 2013.
5. K.M. Lenz, M.M. McCarthy, "A starring role for microglia in brain sex differences," Neuroscientist, 21:306-21, 2015.
6. D.P. Schafer et al., "Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner," Neuron, 74:691-705, 2012.
7. M.J. Meaney et al., "Sexual differentiation of social play in rat pups is mediated by the neonatal androgen-receptor system," Neuroendocrinology, 37:85-90, 1983.
8. D.L. Krebs-Kraft et al., "Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior," PNAS, 107:20535-40, 2010.
9. G.C. Brown, J.J. Neher, "Microglial phagocytosis of live neurons," Nat Rev Neurosci, 15:209-16, 2014.
10. B.M. Nugent et al., "Brain feminization requires active repression of masculinization via DNA methylation," Nat Neurosci, 18:690-97, 2015.
11. N.M. Ghahramani et al., "The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging," Biol Sex Differ, 5:8, 2014.
12. J.M. Schwarz et al., "Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span," Endocrinology, 151:4871-81, 2010.
13. K.I. Matsuda et al., "Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior," Endocrinology, 152:2760-67, 2011.
14. E.K. Murray et al., "Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis," Endocrinology, 150:4241-47, 2009.

Correction (October 7): This story has been updated to correctly reflect that deacetylation is associated with decreased, not increased, gene expression. The Scientist regrets the error.

Sex Differences in the Brain

Men and women display patterns of behavioral and cognitive differences that reflect varying hormonal influences on brain development By Doreen Kimura (May 13, 2002)
Men and women differ not only in their physical attributes and reproductive function but also in many other characteristics, including the way they solve intellectual problems. For the past few decades, it has been ideologically fashionable to insist that these behavioral differences are minimal and are the consequence of variations in experience during development before and after adolescence. Evidence accumulated more recently, however, suggests that the effects of sex hormones on brain organization occur so early in life that from the start the environment is acting on differently wired brains in boys and girls. Such effects make evaluating the role of experience, independent of physiological predisposition, a difficult if not dubious task. The biological bases of sex differences in brain and behavior have become much better known through increasing numbers of behavioral, neurological and endocrinological studies. We know, for instance, from observations of both humans and nonhumans that males are more aggressive than females, that young males engage in more rough-and-tumble play than females and that females are more nurturing. We also know that in general males are better at a variety of spatial or navigational tasks. How do these and other sex differences come about? Much of our information and many of our ideas about how sexual differentiation takes place derive from research on animals. From such investigations, it appears that perhaps the most important factor in the differentiation of males and females and indeed in differentiating individuals within a sex is the level of exposure to various sex hormones early in life.		Image: DOREEN KIMURA AND JOHN MENGEL
In most mammals, including humans, the developing organism has the potential to be male or female. Producing a male, however, is a complex process. When a Y chromosome is present, testes, or male gonads, form. This development is the critical first step toward becoming a male. When no Y chromosome is present, ovaries form. Testes produce male hormones, or androgens (testosterone chief among them), which are responsible not only for transformation of the genitals into male organs but also for organization of corresponding male behaviors early in life. As with genital formation, the intrinsic tendency that occurs in the absence of masculinizing hormonal influence, according to seminal studies by Robert W. Goy of the University of Wisconsin, is to develop female genital structures and behavior. Female anatomy and probably most behavior associated with females are thus the default modes in the absence of androgens. If a rodent with functional male genitals is deprived of androgens immediately after birth (either by castration or by the administration of a compound that blocks androgens), male sexual behavior, such as mounting, will be reduced, and more female sexual behavior, such as lordosis (arching of the back when receptive to coitus), will be expressed. Likewise, if androgens are administered to a female directly after birth, she will display more male sexual behavior and less female behavior in adulthood. These lifelong effects of early exposure to sex hormones are characterized as 'organizational' because they appear to alter brain function permanently during a critical period in prenatal or early postnatal development. Administering the same sex hormones at later stages or in the adult has no similar effect. Not all the behaviors that distinguish males are categorized at the same time, however. Organization by androgens of the male-typical behaviors of mounting and of rough-and-tumble play, for example, occur at different times prenatally in rhesus monkeys. The area in the brain that regulates female and male reproductive behavior is the hypothalamus. This tiny structure at the base of the brain connects to the pituitary, the master endocrine gland. It has been shown that a region of the hypothalamus is visibly larger in male rats than in females and that this size difference is under hormonal control. Scientists have also found parallel sex differences in a clump of nerve cells in the human brain--parts of the interstitial nucleus of the anterior hypothalamus--that is larger in men than in women. Even sexual orientation and gender identity have been related to anatomical variation in the hypothalamus. Other researchers, Jiang-Ning Zhou of the Netherlands Institute of Brain Research and his colleagues there and at Free University in Amsterdam, observed another part of the hypothalamus to be smaller in male-to-female transsexuals than in a male control group. These findings are consistent with suggestions that sexual orientation and gender identity have a significant biological component.
Hormones and Intellect What of differences in intellectual function between men and women? Major sex differences in function seem to lie in patterns of ability rather than in overall level of intelligence (measured as IQ), 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. Differences in intellectual pattern refer to the fact that people have different intellectual strengths. For example, some people are especially good at using words, whereas others are better at dealing with external stimuli, such as identifying an object in a different orientation. Two individuals may have differing cognitive abilities within the same level of general intelligence.		Image: DOREEN KIMURA TESTOSTERONE LEVELS can affect performance on some tests. Women with high levels of testosterone perform better on spatial tasks (top) than women with low levels do, but men with low levels outperform men with high levels. On a test of perceptual speed in which women usually excel (bottom), no relation was found between testosterone and performance.
Sex differences in problem solving have been systematically studied in adults in laboratory situations. On average, men perform better than women at certain spatial tasks. In particular, men seem to have an advantage in tests that require the subject to imagine rotating an object or manipulating it in some other way. They also outperform women in mathematical reasoning tests and in navigating their way through a route. Further, men exhibit more accuracy in tests of target-directed motor skills--that is, in guiding or intercepting projectiles. Women, on average, excel on tests that measure recall of words and on tests that challenge the person to find words that begin with a specific letter or fulfill some other constraint. They also tend to be better than men at rapidly identifying matching items and performing certain precision manual tasks, such as placing pegs in designated holes on a board. In examining the nature of sex differences in navigating routes, one study found that men completed a computer simulation of a maze or labyrinth task more quickly and with fewer errors than women did. Another study by different researchers used a path on a tabletop map to measure route learning. Their results showed that although men learned the route in fewer trials and with fewer errors, women remembered more of the landmarks, such as pictures of different types of buildings, than men did. These results and others suggest that women tend to use landmarks as a strategy to orient themselves in everyday life more than men do.
Other findings seemed also to point to female superiority in landmark memory. Researchers tested the ability of individuals to recall objects and their locations within a confined space--such as in a room or on a tabletop. In these studies, women were better able to remember whether items had changed places or not. Other investigators found that women were superior at a memory task in which they had to remember the locations of pictures on cards that were turned over in pairs. At this kind of object location, in contrast to other spatial tasks, women appear to have the advantage. It is important to keep in mind that some of the average sex differences in cognition vary from slight to quite large and that men and women overlap enormously on many cognitive tests that show average differences. For example, whereas women perform better than men in both verbal memory (recalling words from lists or paragraphs) and verbal fluency (finding words that begin with a specific letter), we find a large difference in memory ability but only a small disparity for the fluency tasks. On the whole, variation between men and women tends to be smaller than deviations within each sex, but very large differences between the groups do exist--in men's high level of visual-spatial targeting ability, for one.		Image: DOREEN KIMURA RIGHT HEMISPHERE DAMAGE affects spatial ability to the same degree in both sexes (I), suggesting that women and men rely equally on that hemisphere for certain spatial tasks. In one test of spatial-rotation performance, photographs of a three-dimensional object must be matched to one of two mirror images of the same object.
Although it used to be thought that sex differences in problem solving did not appear until puberty, the accumulated evidence now suggests that some cognitive and skill differences are present much earlier. 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.
Male and female rodents have also been found to solve problems differently. Christina L. Williams of Duke University has shown that female rats have a greater tendency to use landmarks in spatial learning tasks, as it appears women do. In Williams's experiment, female rats used landmark cues, such as pictures on the wall, in preference to geometric cues: angles and the shape of the room, for instance. If no landmarks were available, however, females used the geometric cues. In contrast, males did not use landmarks at all, preferring geometric cues almost exclusively. Hormones and Behavior Williams also found that hormonal manipulation during the critical period could alter these behaviors. Depriving newborn males of sex hormones by castrating them or administering hormones to newborn females resulted in a complete reversal of sex-typed behaviors in the adult animals. Treated males behaved like females and treated females, like males.		Image: JARED SCHNEIDMAN DESIGN APHASIAS, or speech disorders, occur most often in women when damage is sustained in the anterior of the brain. In men, they occur more frequently when damage is in the posterior region. The data presented above derive from one set of patients.
Structural differences may parallel behavioral ones. Lucia F. Jacobs, while at the University of Pittsburgh, discovered that the hippocampus--a region thought to be involved in spatial learning--is larger in several male species of rodents than in females. At present, there are insufficient data on possible sex differences in hippocampal size in human subjects. One of the most compelling areas of evidence for hormonally influenced sex differences in humans comes from studies of girls exposed to excess androgens in the prenatal or neonatal stage. The production of abnormally large quantities of adrenal androgens can occur because of a genetic defect in a condition called congenital adrenal hyperplasia (CAH). Before the 1970s a similar condition also unexpectedly appeared in the offspring of pregnant women who took various synthetic steroids. Although the consequent masculinization of the genitals can be corrected by surgery and drug therapy can stop the overproduction of androgens, the effects of prenatal exposure on the brain are not reversed. Sheri A. Berenbaum, while at Southern Illinois University at Carbondale, and Melissa Hines, then at the University of California at Los Angeles, observed the play behavior of CAH girls and compared it with that of their male and female siblings. Given a choice of transportation and construction toys, dolls and kitchen supplies, or books and board games, the CAH girls preferred the more typically masculine toys--for example, they played with cars for the same amount of time that boys did. Both the CAH girls and the boys differed from unaffected girls in their patterns of choice. Berenbaum also found that CAH girls had greater interest in male-typical activities and careers. Because there is every reason to think parents would be at least as likely to encourage feminine preferences in their CAH daughters as in their unaffected daughters, these findings suggest that these preferences were altered by the early hormonal environment. Other researchers also found that spatial abilities that are typically better in males are enhanced in CAH girls. But in CAH boys the reverse was reported. Such studies suggest that although levels of androgen relate to spatial ability, it is not simply the case that the higher the levels, the better the spatial scores. Rather studies point to some optimal level of androgen (in the low male range) for maximal spatial ability. This finding may also hold for men and math reasoning; in one study, low-androgen men tested higher. The Biology of Math Such findings are relevant to the suggestion by Camilla P. Benbow, now at Vanderbilt University, that high mathematical ability has a significant biological determinant. Benbow and her colleagues have reported consistent sex differences in mathematical reasoning ability that favor males. In mathematically talented youth, the differences were especially sharp at the upper end of the distribution, where males vastly outnumbered females. The same has been found for the Putnam competition, a very demanding mathematics examination. Benbow argues that these differences are not readily explained by socialization. It is important to keep in mind that the relation between natural hormone levels and problem solving is based on correlational data. Although some form of connection between the two measures exists, we do not necessarily know how the association is determined, nor do we know what its causal basis is. We also know little at present about the relation between adult levels of hormones and those in early life, when abilities appear to become organized in the nervous system. One of the most intriguing findings in adults is that cognitive patterns may remain sensitive to hormonal fluctuations throughout life. Elizabeth Hampson of the University of Western Ontario showed that women's performances at certain tasks changed throughout the menstrual cycle as levels of estrogen varied. High levels of the hormone were associated not only with relatively depressed spatial ability but also with enhanced speech and manual skill tasks. In addition, I have observed seasonal fluctuations in spatial ability in men: their performance is better in the spring, when testosterone levels are lower. Whether these hormonally linked fluctuations in intellectual ability represent useful evolutionary adaptations or merely the highs and lows of an average test level remains to be seen through further research. A long history of studying people with damage to one half of their brain indicates that in most people the left hemisphere of the brain is critical for speech and the right for certain perceptual and spatial functions. Researchers studying sex differences have widely assumed that the right and left hemispheres of the brain are more asymmetrically organized for speech and spatial functions in men than in women. This belief rests on several lines of research. Parts of the corpus callosum, a major neural system connecting the two hemispheres, as well as another connector, the anterior commissure, appear to be larger in women, which may permit better communication between hemispheres. Perceptual techniques that measure brain asymmetry in normal-functioning people sometimes show smaller asymmetries in women than in men, and damage to one brain hemisphere sometimes has less of an effect in women than the comparable injury in men does. My own data on patients with damage to one hemisphere of the brain suggest that for functions such as basic speech and spatial ability, there are no major sex differences in hemispheric asymmetry, although there may be such disparities in certain more abstract abilities, such as defining words. If the known overall differences between men and women in spatial ability were related to differing dependence on the right brain hemisphere for such functions, then damage to that hemisphere might be expected to have a more devastating effect on spatial performance in men. My laboratory has studied the ability of patients with damage to one hemisphere of the brain to visualize the rotation of certain objects. As expected, for both sexes, those with damage to the right hemisphere got lower scores on these tests than those with damage to the left hemisphere did. Also, as anticipated, women did not do as well as men on this test. Damage to the right hemisphere, however, had no greater effect on men than on women. The results of this study and others suggest that the normal differences between men and women on rotational and line orientation tasks need not be the result of different degrees of dependence on the right hemisphere. Some other brain systems may be mediating the higher performance by men. Patterns of Function Another brain difference between the sexes has been shown for speech and certain manual functions. Women incur aphasia (impairment of the power to produce and understand speech) more often after anterior damage than after posterior damage to the brain. In men, posterior damage more often affects speech. A similar pattern is seen in apraxia, difficulty in selecting appropriate hand movements, such as showing how to manipulate a particular object or copying the movements of the experimenter. Women seldom experience apraxia after left posterior damage, whereas men often do. Men also incur aphasia from left hemisphere damage more often than women do. One explanation suggests that restricted damage within a hemisphere after a stroke more often affects the posterior region of the left hemisphere. Because men rely more on this region for speech than women do, they are more likely to be affected. We do not yet understand the effects on cognitive patterns of such divergent representation of speech and manual functions. Although my laboratory has not found evidence of sex differences in functional brain asymmetry with regard to basic speech, movement or spatial-rotation abilities, we have found slight differences in some verbal skills. Scores on a vocabulary test and on a verbal fluency test, for instance, were slightly affected by damage to either hemisphere in women, but such scores were affected only by left hemisphere damage in men. These findings suggest that when using some more abstract verbal skills, women do use their hemispheres more equally than men do. But we have not found this to be true for all word-related tasks; for example, verbal memory appears to depend just as much on the left hemisphere in women as in men. In recent years, new techniques for assessing the brain's activity--including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), when used during various problem-solving activities--have shown promise for providing more information about how brain function may vary among normal, healthy individuals. The research using these two techniques has so far yielded interesting, yet at times seemingly conflicting, results. Some research has shown greater differences in activity between the hemispheres of men than of women during certain language tasks, such as judging if two words rhyme and creating past tenses of verbs. Other research has failed to find sex differences in functional asymmetry. The different results may be attributed in part to different language tasks being used in the various studies, perhaps showing that the sexes may differ in brain organization for some language tasks but not for others. The varying results may also reflect the complexity of these techniques. The brain is always active to some degree. So for any activity, such as reading aloud, the comparison activity--say, reading silently--is intended to be very similar. We then 'subtract' the brain pattern that occurs during silent reading to find the brain pattern present while reading aloud. Yet such methods require dubious assumptions about what the subject is doing during either activity. In addition, the more complex the activity, the more difficult it is to know what is actually being measured after subtracting the comparison activity. Looking Back To understand human behavior--how men and women differ from one another, for instance--we must look beyond the demands of modern life. Our brains are essentially like those of our ancestors of 50,000 and more years ago, and we can gain some insight into sex differences by studying the differing roles men and women have played in evolutionary history. Men were responsible for hunting and scavenging, defending the group against predators and enemies, and shaping and using weapons. Women gathered food near the home base, tended the home, prepared food and clothing, and cared for small children. Such specialization would put different selection pressures on men and women. Any behavioral differences between individuals or groups must somehow be mediated by the brain. Sex differences have been reported in brain structure and organization, and studies have been done on the role of sex hormones in influencing human behavior. But questions remain regarding how hormones act on human brain systems to produce the sex differences we described, such as in play behavior or in cognitive patterns. The information we have from laboratory animals helps to guide our explanations, but ultimately these hypotheses must be tested on people. Refinements in brain-imaging techniques, when used in conjunction with our knowledge of hormonal influences and with continuing studies on the behavioral deficits after damage to various brain regions, should provide insight into some of these questions.
The Author(s): DOREEN KIMURA studies the neural and hormonal basis of human intellectual functions. She is visiting professor in psychology at Simon Fraser University in British Columbia and a fellow of the Royal Society of Canada.
MORE TO EXPLORE: Sex on the Brain: The Biological Differences between Men and Women. Deborah Blum. Viking Press, 1997.
Reformatted from: http://www.sciam.com/article.cfm?articleID=00018E9D-879D-1D06-8E49809EC588EEDF