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 Post subject: Testosterone on My Mind and in My Brain
PostPosted: Sun Jan 12, 2014 4:37 pm 
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By Simon Baron-Cohen; in Thinking: The New Science of Decision-Making, Problem-Solving, and Prediction [John Brockman]

"What I want to talk about tonight is this very specific hormone, testosterone. Our lab has been doing a lot of research to understand what this hormone does and, in particular, to test whether it plays any role in how the mind and the brain develop.

Before I get to that point, I’ll say a few words by way of background about typical sex differences, because that’s the cradle out of which this new research comes. Many of you know that the topic of sex differences in psychology is fraught with controversy. It’s an area where people, for many decades, didn’t really want to enter because of the risks of political incorrectness, and of being misunderstood.

Perhaps of all of the areas in psychology where people do research, the field of sex differences was kind of off-limits. It was taboo, and that was partly because people believed that anyone who tried to do research into whether boys and girls, on average, differ must have some sexist agenda. And so for that reason a lot of scientists just wouldn’t even touch it.

By 2003, I was beginning to sense that that political climate was changing, that it was a time when people could ask the question—Do boys and girls differ? Do men and women differ?—without fear of being accused of some kind of sexist agenda, but in a more open-minded way.

First of all, I started off looking at neuroanatomy, to look at what the neuroscience is telling us about the male and female brain. If you just take groups of girls and groups of boys and, for example, put them into MRI scanners to look at the brain, you do see differences on average. Take the idea that the sexes are identical from the neck upward, even if they are very clearly different from the neck downward: the neuroscience is telling us that that is just a myth, that there are differences, even in terms of brain volume and the number of connections between nerve cells in the brain at the structure of the brain, on average, between males and females.

I say this carefully because it’s still a field which is prone to misunderstanding and misinterpretation, but just giving you some of the examples of findings that have come out of the neuroscience of sex differences, you find that the male brain, on average, is about eight percent larger than the female brain. We’re talking about a volumetric difference. It doesn’t necessarily mean anything, but that’s just a finding that’s consistently found. You find that difference from the earliest point you can put babies into the scanner, so some of the studies are at two weeks old in terms of infants.

You also find that if you look at postmortem tissue, looking at the human brain in terms of postmortem tissue, that the male brain has more connections, more synapses between nerve cells. It’s about a 30 percent difference on average between males and females. These differences are there.

The second big difference between males and females is about how much gray matter and white matter we see in the brain: that males have more gray matter and more white matter on average than the female brain does. White matter, just to be succinct, is mostly about connections between different parts of the brain. The gray matter is more about the cell bodies in the brain. But those differences exist. Then when you probe a bit further, you find that there are differences between the male and female brain in different lobes, the frontal lobe, the temporal lobe, in terms of how much gray and white matter there is.

You can also dissect the brain to look at specific regions. Some of you will have had heard of regions like the amygdala, which people think of as a sort of emotion center, that tends to be larger in the male brain than the female brain, again, on average. There’s another region that shows the opposite pattern, larger in females than males: the planum temporale, an area involved in language. These structural differences exist, and I started by looking at these differences in terms of neuroanatomy, just because I thought at least those are differences that are rooted in biology, and there might be less scope for disagreement about basic differences.

I’ve talked a little bit about neuroanatomy, but in terms of psychology, there are also sex differences that are reported. On average, females are developing empathy at a faster rate than males. I keep using that word “on average” because none of these findings apply to all females or all males. You simply see differences emerge when you compare groups of males and females. Empathy seems to be developing faster in girls, and in contrast, in boys there seems to be a stronger drive to systemize. I use that word “systemizing,” which is all about trying to figure out how systems work, becoming fascinated with systems. And systems could take a variety of different forms. It could be a mechanical system, like a computer; it could be a natural system, like the weather; it could be an abstract system, like mathematics; but boys seem to have a stronger interest in systematic information. I was contrasting these two very different psychological processes, empathy and systemizing. And that’s about as far as I went, and that was now some 11 years ago.

Since then my lab has wanted to try to understand where these sex differences come from, and now I’m fast-forwarding to tell you about the work that we’re doing on testosterone. I’m very interested in this molecule, partly because males produce more of it than females, and partly because there’s a long tradition of animal research which shows that this hormone may masculinize the brain, but there’s very little work on this hormone in humans.

Before I tell you about the testosterone work, I should just mention one somewhat controversial study that we published back in the year 2000, and that was a study of newborn babies. What we wanted to do was establish whether the sex differences that you find in behavior, or in the mind, in human beings were purely the result of culture and purely the result of postnatal experience, or whether biology might also be contributing to those differences.

We did a study that we call the Newborn Baby Study, where we studied just over 100 babies aged 24 hours old. This was a study conducted in Cambridge. The babies had just popped out of the womb. The mothers had signed a consent form, saying that they were happy for their baby to take part in research. We would have loved to study the babies as soon as they came out, but the obstetricians asked us, out of respect for mother and baby, if we would wait 24 hours, which we were happy to do; and then when the babies were settled and the mother was settled, we presented these babies with two objects: a human face or a mechanical mobile suspended above the crib. So, two very different kinds of objects, one mechanical and one animate and human. And we looked to see whether babies, aged one day old, looked longer at the human face, a social stimulus, or looked longer at the mechanical object.

The objects were presented one at a time, and we counterbalanced—that’s to say we varied the order—whether the baby saw the face first or the mechanical object first. What we found, just cutting to the chase, was that if we compared babies in terms of looking longer at a social stimulus or looking longer at a mechanical stimulus, more boys seemed to look longer at the mechanical stimulus, and more girls seemed to look longer at the social stimulus, the face. We were finding a difference that was there as early as 24 hours old; and that, to me, was pointing to biology being a contributing factor to sex differences.

People who really want to argue that all sex differences that you find in the mind and in behavior can be explained by cultural factors might still have argued that in those 24 hours, mother and baby or father and baby had been interacting, that parents may have been somehow shaping their sons and daughters to have different patterns of interest. That is just possible, because in 24 hours, people would argue, there’s plenty of room for experience. But it’s equally plausible that what we’re seeing is babies arriving on day one with slightly different patterns of interest: with girls on average being more oriented toward people, being more inquisitive about people, and boys, again on average, being slightly more oriented in their attention toward the physical environment, and patterns in the physical world.

Now we’re up to testosterone. We picked testosterone, this molecule, just because we were looking for a candidate for biological explanation or a mechanism for these sex differences we were observing. And the animal research was pointing to the fact that before birth there’s a surge in the production of testosterone. Testosterone is suddenly produced at very high quantities, and then it drops off again around birth. And the animal researchers were arguing that this surge in the production of testosterone, that the fetus is producing a lot of testosterone during fetal life, because it has some permanent and organizing effect on brain development. And they were able to show that in rats.

You can do experimental manipulations of this hormone in rats that would be completely unethical in humans: you can either deprive the animal of its testosterone, for example, by castration at birth (one source of it in males is the testes); or you can inject extra testosterone, for example, into a female rat at birth, and look at the effects of brain and behavior. And that experimental evidence was pointing to long-term “organizational” effects on brain development.

Just to take an example: if you have a female rat that’s given extra testosterone either during pregnancy or at birth, and then look at that female rat’s behavior postnatally, her behavior is much more like a typical male rat. Ways that you can test this include, for example, letting the rats run through mazes, finding their way through a maze. If you take male and female rats, usually the male rats will get through the maze faster, learning a spatial route more quickly; but female rats that have been given extra testosterone are much more like typical male rats, so their behavior has been changed. And then if you look at the postmortem rat brain, the female rats that were given extra testosterone, in terms of their neuroanatomy, the female rat’s brain looks much more like a typical male rat’s brain.

There was a hypothesis from animal research that testosterone was this special molecule that masculinizes the brain, and it was looking clearer and clearer in other species, but no one had found a way to demonstrate it in humans. What we’ve been doing over the last decade is to try to find a way to test it in humans. And the way that we settled on was to look at women in pregnancy who were having a procedure called amniocentesis. Many of you will have heard of this: this is where a pregnant woman has a long needle introduced into the womb, the baby is in the womb surrounded by amniotic fluid, and the needle goes in as part of a medical, clinical procedure, to take some of that fluid. That’s called amniocentesis, where you take some of the amniotic fluid that surrounds the baby. Usually this is done because there’s some suspicion that the baby might have Down syndrome, and the doctor wants to analyze the amniotic fluid for chromosomal abnormalities, as a test of whether the baby will indeed go on to have Down syndrome.

These women were having this procedure, and the research had been telling us that if you wanted to look at hormones like testosterone, in terms of their potential influence on the human brain, you’d need to find a way of measuring it during pregnancy. We put these two things together and asked these women, if you’re having an amniocentesis anyway, can we take some of the fluid, with your consent, and analyze it for testosterone levels that you find in the fluid? This is when the baby is sometime between 12 and 19 weeks of pregnancy. It’s a little window when amniocentesis takes place. If you think of pregnancy as 40 weeks normally, nine months, roughly 40 weeks, this is at the end of the first trimester, the first third of pregnancy, and just going into the second trimester, the middle of pregnancy.

We were getting this opportunity to measure hormones, but particularly testosterone, whilst the baby was still growing, at a point when the brain is developing very rapidly. And then the design of our research was that we would then store the fluid in our deep freeze, wait for the baby to be born, and follow up the babies after they were born to see if there was any correlation between their testosterone levels in the womb and how they turned out as children.

I should say one other thing, which is that this was premised on the idea that children are more different to each other than they are similar. Those of you who are parents know this very well: that you might have two or three kids and despite the fact that they’ve grown up in the same home, they’ve got the same parents, they seem to have very different personalities, very different patterns of interest, and very different rates of development. Part of the challenge, scientifically, was also to try to understand this variability in development, individual differences in development, and we were anchoring our research by looking at one factor, testosterone, which varies, with some people being very low in testosterone, other people being average or very high in testosterone, and seeing whether that scale of individual differences had anything to do with individual differences we see postnatally—for example, in rates of language development, in how sociable children are, and on other dimensions.

The study was that the woman had her amniocentesis while she was pregnant, we then waited for the baby to be born, and we’ve invited these babies in pretty much every year since their birth. We started off with about 500 of these babies—that’s the cohort— where their testosterone levels are known, and we’ve been following them and they’re now about 12 years old. So it’s a story that’s been unfolding whilst we’ve been able to measure the behavior as they grow, and see whether it has anything to do with their testosterone prenatally.

At their first birthday, we looked at eye contact. And I was particularly interested in this, because my main area of research is autism, and children with autism make very little eye contact. Their eye contact is at the extreme, showing very little interest in faces. But we’d already heard from that newborn baby study that there seems to be, on average, a sex difference in how interested people are in faces, and making eye contact, with girls being, on average, more interested in faces than boys, but there’s a whole spectrum of individual differences. And what we found was that the higher the baby’s prenatal testosterone, the less eye contact they made at their first birthday. That was simply measured by inviting the toddler into our lab, videotaping them, and then later coding those videotapes for how many times the baby looked up at their mother’s face. That was at the first birthday.

At the second birthday we looked at language development. We got parents to fill in a checklist of how many words does your child know, and how many words can your child produce. We were looking at the size of children’s vocabularies. What we found, which was quite striking to us, was that by two years old, there were some children who had very small vocabularies, only about 10 or 20 words, they were kind of at the low edge of normal development; and there were some kids who were really chatty and had 600 words. So the size of the differences in vocabulary was immense. And then we could look back at their testosterone levels. And once again, we found a significant correlation: that the higher the child’s prenatal testosterone, the smaller their vocabulary at two years old. So this same hormone seemed to be related not only to patterns of social interest—whether you look at faces—but also to communication—how talkative you are and your rate of language development.

I don’t want to go through all the steps, but we’ve also looked, when they were four years old, at empathy, finding that prenatal testosterone is negatively correlated with empathy. So again, it’s the same pattern we were just hearing about: that if you were higher in testosterone during the pregnancy, it meant that you were slower to develop empathy as a four-year-old. And again, there are different ways that you can measure that. You can ask parents to fill in questionnaires about their child’s empathy. You can actually get the child to take various empathy tests, or you can also get information about how easily the child mixes in school with other children. But the hormone, once again, was showing relationships with social behavior at school age.

We were also interested in that concept of systemizing, how strong a child’s interest was in systems of different kinds. Was this a child who liked to collect things, to have the complete set, for example, that makes up a system? Was this a child who loved to take things apart and put them back together again? So, very much interested in construction and assembly and figuring out how things work? Was this a child who spotted the small differences between different makes of cars, or little toy cars, and could tell you the differences between different varieties of system? Again, what we found (but this time the correlation was flipped over), was a positive correlation with prenatal testosterone. The higher the child’s prenatal testosterone, the more interested they were in systems of one kind or another.

When they were about eight years old, we figured it was time to invite these kids into the MRI scanner, so that we could look directly at the question of whether testosterone is actually changing the way the brain is developing. Up until now we’d only done what’s called behavioral studies, where we could find relationships between testosterone and behavior. But by eight years old a child is old enough to stay still, which is essential in a brain scan, because if the child squirms and moves around too much, then you can’t interpret the results. These children, by eight, were able to tolerate having an MRI scan, and we were able to look at the structure of the brain and see if it had any relationship to prenatal testosterone. And in fact, there are lots of interesting relationships.

As I mentioned, one region of the brain that differs between males and females is that region called the planum temporale, a language area, and that’s related to prenatal testosterone. The hormone is having an effect on the way the brain is growing, just looking at the volume of different regions in the brain. We looked at one other region, which is the corpus callosum. Some of you will have heard of this: it’s the connective tissue between the two hemispheres, and the hormone was correlated with the asymmetry of one part of the corpus callosum, just toward the back of that structure. This was the first evidence that the hormone in humans is having an effect on brain structure, brain development, and it was mirroring what the scientists who do animal research had been telling us all along, but we needed to demonstrate it in humans.

I want to bring this back to my interest in autism: autism is a neurological disability, and it affects boys much more than girls, and we were interested in the possibility that that same hormone, prenatal testosterone, might be a risk factor, or might be playing some role in the outcome of autism. I told you that the sample of children we were studying was about 500 kids. And autism is a relatively rare condition. It affects about one percent of the population. What that means is within 500 kids, there might be five children who have autism, which would be way too small a number to be able to draw any inferences about prenatal testosterone and association with this medical diagnosis.

We’ve been tackling the problem in two different ways. The first way is that within these 500 children we’ve used a dimensional measure of autism, rather than looking at whether the child has autism or not. We’ve been looking at the dimension of autistic traits, where you can look at the number of autistic traits a child has. The assumption is that we all have some autistic traits and that autism isn’t categorically different to the rest of the population. It’s simply at an extreme of a bell curve, a normal distribution of autistic traits. There are ways to measure autistic traits. Most of them are questionnaires. You get the parents to fill out a questionnaire, which is basically a way of describing how many autistic traits their child has, and then independently, you can look at their prenatal testosterone and see if there’s any correlation.

What we found—maybe some of you have anticipated the result of this particular stage of the research—is that the higher the child’s prenatal testosterone, the more autistic traits they were showing at different stages in development, at two years old, and we’ve repeated that at four years old. That’s telling us about prenatal testosterone and autistic traits. But what we’d really like to do, and this is bringing you right up to date with where our research is, is to see whether there’s any relationship between prenatal testosterone and actually developing autism.

As I’ve already explained, having a sample of 500 kids doesn’t allow us to answer that question, so we’ve been collaborating with scientists in Copenhagen, Denmark, at the Biobank there, because in Denmark they’ve been collecting amniotic fluid from women who have amniocentesis there. But they’ve been collecting those samples since 1980, so they have 100,000 samples sitting in their deep freeze. And for a scientist, that’s a wonderful opportunity. The other thing that Denmark has is a national register for psychiatric diagnosis. Every time anyone in Denmark develops any kind of psychiatric condition, they’re put into a central database, and so we know across the whole of Denmark who has autism. We can go to the Biobank and fish out their amniotic fluid if it’s in there, to analyze it for prenatal testosterone.

Whereas in our normative study of 500 children, we were dependent on doing the first measure of the hormones in pregnancy and then waiting for life to unfold over a ten-year period, in this new study, we can work backward. We can say we know who’s got autism, and we can look to see whether their amniotic fluid is still in the deep freeze. That then gives us, if you like, a fossil record of what their hormones were like, what their levels of testosterone were like when they were in the womb. It’s reverse engineering the problem. And to just tell you where we’re up to, we’ve just completed that study. The analysis is going on as we speak, so we hope to publish the results of that study later this year. Effectively, that will tell us whether testosterone levels are elevated prenatally in children who go on to receive a diagnosis of autism.

This is a hormone that has fascinated me. It’s a small molecule that seems to be doing remarkable things. The variation we see in this hormone comes from a number of different sources. One of those sources is genes. Many different genes can influence how much testosterone each of us produces, and I just wanted to share with you my fascination with this hormone, because it’s helping us take the science of sex differences one step further, to try to understand not whether there are sex differences, but what are the roots of those sex differences. Where are they springing from? And along the way we’re also hoping that this is going to teach us something about those neurodevelopmental conditions like autism, like delayed language development, which seem to disproportionately affect boys more than girls, and potentially have us understand the causes of those conditions.

Q & A

TOM STANDAGE: What’s the thing that determines the level of the testosterone in the womb? What’s the next step along the path?

BARON-COHEN: I mentioned that there are at least 25 different genes that can influence how much testosterone any of us produces. If we had been in that study, if we were part of that cohort, it’s our genetic makeup in part that influences how much testosterone each of us produces. And these are genes that are common genes, they’re not rare mutations, they’re common genes we all have, but it just depends on which version of the gene you have. They’re polymorphic genes, different versions of the same gene. So that’s one possible source of variation in testosterone levels, but there may be other sources too.

PHILIP CAMPBELL: Are the animal models telling us about what the testosterone is actually doing, that’s in the brain development?

BARON-COHEN: Yes. I didn’t mention that, but I’m really glad you’ve raised it. Testosterone by itself doesn’t really do anything, but for testosterone to do its work it has to bind to androgen receptors. There are these receptors that are just waiting for testosterone, and when testosterone is bound to the receptors, then it can start influencing all sorts of other processes. Androgen receptors are all over the body, but they’re also in the brain and in some of those regions like the amygdala or the planum temporale. These regions are sexually dimorphic: they’re different in one sex or another, and they’re very rich in these androgen receptors. We know that from animal work, and people are beginning to create maps of androgen receptors across the brain. It’s all about the hormone binding to these receptors.

Once it’s bound, the hormone can do all sorts of things. It can, for example, modulate neurotransmitters. There’s one called serotonin. There’s another one called GABA. And testosterone seems to modulate how those neurotransmitters work. Testosterone also seems to affect connections that neurons make with each other. There’s a process called apoptosis that some of you will have heard of, which is selective cell death, where neurons, or nerve cells in the brain, are pruned, so that we lose certain connections. Testosterone seems to affect the rate at which we lose those connections."


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