boys' brains, girls' brains

Fri Apr 29 12:48:40 UTC 2005

April 25, 2005

His Brain, Her Brain

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.
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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.

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