[Paleopsych] Scientific American: His Brain, Her Brain

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His Brain, Her Brain
http://www.sciam.com/print_version.cfm?articleID=000363E3-1806-1264-980683414B7F0000

    April 25, 2005

    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

    On a gray day in mid-January, Lawrence Summers, the president of
    Harvard University, suggested that innate differences in the build of
    the male and female brain might be one factor underlying the relative
    scarcity of women in science. His remarks reignited a debate that has
    been smoldering for a century, ever since some 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.
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    Several intriguing behavioral studies add to the evidence that some
    sex differences in the brain arise before a baby draws its first
    breath.
      _________________________________________________________________

    That view, however, has now been knocked aside by a surge of findings
    that highlight the influence of sex on many areas of cognition and
    behavior, including memory, emotion, vision, hearing, the processing
    of faces and the brain's response to stress hormones. This progress
    has been accelerated in the past five to 10 years by the growing use
    of sophisticated noninvasive imaging techniques such as
    positron-emission tomography (PET) and functional magnetic resonance
    imaging (fMRI), which can peer into the brains of living subjects.

    These imaging experiments reveal that anatomical variations occur in
    an assortment of regions throughout the brain. Jill M. Goldstein of
    Harvard Medical School and her colleagues, for example, used MRI to
    measure the sizes of many cortical and subcortical areas. Among other
    things, these investigators found that parts of the frontal cortex,
    the seat of many higher cognitive functions, are bulkier in women than
    in men, as are parts of the limbic cortex, which is involved in
    emotional responses. In men, on the other hand, parts of the parietal
    cortex, which is involved in space perception, are bigger than in
    women, as is the amygdala, an almond-shaped structure that responds to
    emotionally arousing information--to anything that gets the heart
    pumping and the adrenaline flowing. These size differences, as well as
    others mentioned throughout the article, are relative: they refer to
    the overall volume of the structure relative to the overall volume of
    the brain.

    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.

    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.