Testosterone, Aggression... Confusion

Breaking news from the BBC -

Testosterone link to aggression 'all in the mind'

Work in Nature magazine suggests the mind can win over hormones... Testosterone induces anti-social behaviour in humans, but only because of our own prejudices about its effect rather than its biological activity, suggest the authors.

The researchers, led by Ernst Fehr of the University of Zurich, Switzerland, said the results suggested a case of "mind over matter" with the brain overriding body chemistry.

"Whereas other animals may be predominantly under the influence of biological factors such as hormones, biology seems to exert less control over human behaviour," they said.

Phew, that's a relief - for a minute back there I was worried we didn't have free will. But look a little closer at the study, and it turns out that all is not as it seems. The experiment (Eisenegger et al) involved giving healthy women 0.5 mg testosterone, or placebo, in a randomized double-blind manner, and then getting them to take part in the "Ultimatum Game".

This is a game for two players. One, the Proposer, is given some money, and then has to offer to give a certain proportion of it to the other player, the Receiver. If the Receiver accepts the offer, both players get the agreed-upon amount of money. If they reject it, however, no-one gets anything.

The Proposer is basically faced with the choice of making a "fair" offer, e.g. giving away 50%, or a greedy one, say offering 10% and keeping 90% for themselves. Receivers generally accept fair offers, but most people get annoyed or insulted by unfair ones, and reject them, even though this means they lose money (10% of the money is still more than 0%).

What happened? Testosterone affected behaviour. It had no effect on women playing the role of the Receivers, but the Proposers given testosterone made significantly fairer offers on average, compared to those given placebo. That's not mind over matter, that's matter over mind - give someone a hormone and their behaviour changes.

The direction of the effect is quite interesting - if testosterone increased aggression, as popular belief has it, you might expect it to decrease fair offers. Or, you might not. I suppose it depends on your understanding of "aggression". For their part, Eisenegger et al interpret this finding as suggesting that testosterone doesn't increase aggression per se, but rather increases our motivation to achieve "status", which leads to Proposers making fairer offers, so as to appear nicer. Hmm. Maybe.

But where did the BBC get the whole "all in the mind" thing from? Well, after the testing was over, the authors asked the women whether they thought they had taken testosterone or placebo. The results showed that the women couldn't actually tell which they'd had - they were no more accurate than if they were guessing - but women who believed they'd got testosterone made more unfair offers than women who believed they got placebo. The size of this effect was bigger than the effect of testosterone.

Is that "mind over matter"? Do beliefs about testosterone exert a more powerful effect on behaviour than testosterone itself? Maybe they do, but these data don't tell us anything about that. The women's beliefs weren't manipulated in any way in this trial, so as an experiment it couldn't investigate belief effects. In order to show that belief alters behaviour, you'd need to control beliefs. You could randomly assign some subjects to be told they were taking testosterone, and compare them to others told they were on placebo, say.

This study didn't do anything like that. Beliefs about testosterone were only correlated with behaviour, and unless someone's changed the rules recently, correlation isn't causation. It's like finding that people with brown skin are more likely to be Hindus than people with white skin, and concluding that belief in Brahma alters pigmentation. It could even be that the behaviour drove the belief, because subjects were quizzed about their testosterone status after the Ultimatum Game - maybe women who, for whatever reason, behaved selfishly, decided that this meant they had taken testosterone!

Overall, this study provides quite interesting data about hormonal effects on behaviour, but tells us nothing about the effects of beliefs about hormones. On that issue, the way the media have covered this experiment is rather more informative than the experiment itself.

Eisenegger, C., Naef, M., Snozzi, R., Heinrichs, M., & Fehr, E. (2009). Prejudice and truth about the effect of testosterone on human bargaining behaviour Nature DOI: 10.1038/nature08711

Memories Glow Under the Microscope

How does memory work? What changes in the brain when we learn something?


We don't know for sure. But two outstanding Nature papers have just provided an important piece of the puzzle, using a truly amazing technique which allowed them to examine the brain of a living, breathing mouse under the microscope.

The approach uses mice genetically engineered such that some of their neurons contain yellow fluorescent protein (YFP). You may have already heard of the cute glowing mice who have green fluorescent protein (GFP) in all their cells. In these YFP-H mice, only some of their neurons are fluorescent.

Two-photon microscopy uses a focused laser beam to image fluorescent tissue. The authors of these papers were able to image the brain (the cortex) after surgically thinning - but not penetrating - the mice's skulls. The bone over the brain area in question was removed until it was just 20 micrometers thick. The brain itself was not interfered with in any way, which is what makes this method so remarkable. Generally, when you put a brain under a microscope, you've had to cut slices off it first.

*

Using this transcranial two-photon microscopy, these two teams of researchers (Xu et al from Santa Cruz and Yang et al from New York) were able to directly observe the neural changes that took place following motor skill learning. Adolescent and adult mice were trained on a difficult movement task, such as the "rotarod", in which the animal has to avoid falling off a constantly rotating metal rod. With a few day's practice, most of the mouse got better at the tasks.

Both of the papers report that the skill learning was associated with the formation of new dendritic spines in the motor cortex. The image below shows the kind of data we're talking about: this is a single neuron, and the little blobs above and below it are individual dendritic spines, or outgrowths, of the cell. The top image shows the cell before training, and the bottom image is the same cell 24 hours later, after skill learning. Several new dendritic spines have grown. Almost certainly, these spines have formed synapses with another cell.

The results of these studies show that training increases the amount of new dendritic spine formation in the motor cortex, compared to control conditions in which there is no skill learning, and that many of the new spines persist for months. Learning also seems to be associated with the removal of some already existing spines, so the overall number of spines in the brain remains roughly constant.

Overall, this is a pretty amazing set of results, and it suggests that the learning of new skills is associated not only with changes in the "strength" of existing synapses between neurons, but actually with the growth of entirely new synapses. New brain cells are not generated in the adult brain except in a couple of very specific areas, but it seems that experience causes the reshaping of existing cells.

There are lots of unanswered questions - such as whether the same process underlies other forms of learning as well as motor skill training, what triggers the formation of new dendritic spines, and how the process works in humans. But this is a very exciting first step.



Xu, T., Yu, X., Perlik, A., Tobin, W., Zweig, J., Tennant, K., Jones, T., & Zuo, Y. (2009). Rapid formation and selective stabilization of synapses for enduring motor memories Nature DOI: 10.1038/nature08389

Yang, G., Pan, F., & Gan, W. (2009). Stably maintained dendritic spines are associated with lifelong memories Nature DOI: 10.1038/nature08577

Publication Bias, 1916 Style

Whilst browsing Wikipedia, I came across a poignant early example of publication bias, the failure to make public scientific results that don't support a given hypothesis.

The Judenzählung was a census of the German military carried out in 1916, at the height of the First World War. It was designed to measure the number of Jewish soldiers in the army.

The background to this was the feeling, very powerful in Germany at that time, that the Jewish German minority were "unpatriotic" or "traitorous", and were dodging military service or avoiding front line combat.

The survey was completed, but the results were not published, apparently because they revealed that, contrary to popular belief, Jews were at least as likely as non-Jews to be serving in the army, and were overrepresented on the front lines as well. (Some of the data did emerge after the war, however, when they were criticized for being inaccurate by Jewish groups. 12,000 German Jews died in battle during the War.)

This is an exceptional example of publication bias, but in essence it's no different to what happens when academic or corporate researchers decide not to reveal data which they're not happy with, for whatever reason. The best-known culprits are pharmaceutical companies who often decline to publish data showing that their drugs don't work, but it's a problem that affects most of science, and Big Pharma are certainly not the only ones doing it.

One solution is to have scientific journals or websites dedicated to publishing "negative" results, and there are several, but this still relies on people choosing to reveal their data. It seems to me that, ultimately, the best way to combat publication bias is to require the pre-registration of studies, so that everyone knows in advance what research is being done, and "missing" results can be noticed.

Psychiatrist, Drug Thyself

Psychiatrists give their patients all kinds of drugs, but in most cases, they do so without ever taking any themselves. Some French psychiatrists found an excuse to try out some drugs in the name of science, and the results are published in a paper just out - Besnier et al's Effects of paroxetine on emotional functioning and treatment awareness.

Thirty healthy psychiatrists and clinical psychologists took paroxetine 20mg per day, or placebo pills, for 4 weeks. Paroxetine (Paxil, Seroxat) is a popular SSRI antidepressant - popular with doctors, at least. It has a bad reputation amongst users as causing serious withdrawl symptoms, even compared to other SSRIs. These psychiatrists decided to wean themselves off with a week at a reduced dose of 10mg before stopping completely - after just one month on it! Make of that what you will.

Anyway, what happened? The participants experienced no changes in mood or anxiety, although since they weren't depressed or anxious to begin with, this is not surprising. However, the people taking paroxetine did report reduced "Internal Emotional Experience" as measured with the Emotional State Questionnaire (designed by the same people who ran this study.) That means they were less likely to answer yes to questions like “Do you feel anger when faced with a familiar face with expressed anger?”

This sounds as though they experienced the "emotional blunting" reported by some people who take SSRIs, although it's not clear what exactly this questionnaire is measuring, or how powerful the effect was. The paroxetine group also reported feeling sedated and suffered many more side effects - 70% of participants presented with an adverse event for more than 3 weeks, vs 20% of placebo.

Most described adverse events were psychiatric (sleepiness disorders, libido decreased), gastrointestinal (nausea, diarrhea), or neurological signs (headache).

There's a twist, though, in that while 20 of the subjects got placebo or paroxetine in a double-blind manner (10 each), the other 10 got paroxetine unblinded, i.e. they knew they were not going to get placebo. Strangely, the unblinded group experienced much weaker effects than the double-blind paroxetine group, including many fewer side effects. What's up with that? It's hard to say. It doesn't make much sense. To be honest, with just 10 people in each group, any or all of these results could be random chance anyway.

Still, I do like the idea of psychiatrists self-experimenting. Sadly we're not told whether they were more or less likely to prescribe paroxetine after taking it themselves! Still, I have a bit of anecdotal evidence here. I was talking to a French psychiatrist a while ago who said he'd self-prescribed the SSRI antidepressant citalopram and thought it was brilliant. But one day he accidentally picked up a box of chlorpromazine instead (they were next to each other on the shelf) and that wasn't much fun at all...

Freudian psychoanalysis requires trainee therapists to undergo a full course of therapy themselves before they get to inflict it on their patients. Maybe psychiatrists should have to take courses of antidepressants and antipsychotics as part of their training? Or as the psychopathic bounty hunter said to the doctor in Joss Whedon's Firefly -

Jubal Early: You ever been shot?
Dr Simon Tam: No.
Jubal Early: You oughta be shot. Or stabbed. Lose a leg. To be a surgeon, you know? Know what kind of pain you're dealing with. They make psychiatrists get psychoanalyzed before they can get certified, but they don't make a surgeon get cut on. That seem right to you?
- Firefly

Besnier N, Cassé-Perrot C, Jouve E, Nguyen N, Lançon C, Falissard B, & Blin O (2009). Effects of paroxetine on emotional functioning and treatment awareness: a 4-week randomized placebo-controlled study in healthy clinicians. Psychopharmacology PMID: 19826792

Big Pharma Drama in Iceland

Icelandic academic and Neuroskeptic reader Steindór J. Erlingsson reports that thanks to his efforts, pharmaceutical company GlaxoSmithKlein (GSK) has stopped distributing a booklet promoting the monoamine hypothesis of depression to pharmacies and doctors offices in Iceland.

His report is here, and it has links to more details on the story, although these are in Icelandic, a language I'm unfortunately not familiar with. In a nutshell, Erlingsson says he spoke to the Icelandic Medical Director of Health who, after some back-and-forth and consultations with psychiatrists, contacted GSK.

On September 29th GSK announced that they

have received information that its information booklet on depression needs to be improved. The company views favorably well argued suggestions and as a result it is going to review the booklet.

They went on to say that the booklet, which had been around since 1999, should no longer be distributed. According to Erlingsson, the booklet made three claims:

1. An imbalance in the neurotransmitter serotonin causes depression. 2. SSRIs treat depression by correcting the serotonin imbalance. 3. Psychological treatment is ineffective in treating the serotonin imbalance.

Coincidentally, GSK are the manufacturers of paroxetine (Paxil, Seroxat), one of the best-selling SSRIs. Iceland, like most countries (except the US and New Zealand), bans direct-to-consumer advertising for drugs, but this kind of thing is not covered by such laws.

Personally I believe that serotonin probably is involved in some cases of depression. My views on the serotonin hypothesis of depression are therefore more favorable than those of many critics for whom the whole idea is a myth. But even so, I'm happy that to hear that this booklet has been withdrawn. Drug companies have no business promoting the serotonin hypothesis to the public.

First off, because it's controversial science. There's no "smoking gun" proof linking serotonin to depression. There's a lot of circumstantial evidence, but we don't really know how antidepressants work, or indeed how well they work, at all. For once, we should be "Teaching the Controversy". Most of the time when people say that, they're wrong, because they're talking about science which is rock solid, like the theory of evolution. The monoamine theory, however actually is controversial, which is why there are articles in major scientific journals criticizing it and others defending it.

Second, because the monoamine theory is certainly not true in any simple sense. Low serotonin levels cannot be the sole cause of depression because you can temporarily deplete someone's serotonin with a technique called tryptophan depletion and for most people, this does nothing at all to their mood. On the other hand about 50% of people who have suffered from depression in the past do get depressed again after tryptophan depletion, which is why I think there is some truth in the serotonin theory, but this shows that it's not a straightforward picture.

Third, the idea that only drugs can correct the "chemical imbalance" and psychotherapy can't is simply wrong. I don't know what the wording of GSK's booklet was, but from Erlingsson's summary, it sounds like it was giving people medical advice - you won't benefit from therapy - via leaflet, which is very irresponsible. Only a clinician with personal experience of an individual patient can say what treatment is best for them. Some people benefit from therapy, others do well on medication, and some people get better with no treatment at all. It sounds like GSK is behaving just as Oliver James did when he used the Guardian to recommend Freudian psychoanalysis over drugs and other kinds of therapy for postnatal depression. They're both wrong.

On the other hand, information leaflets telling people about depression and encouraging sufferers to seek professional help sound like a great idea to me, because many people with depression go undiagnosed and untreated and that's a real tragedy. But drug companies are unlikely to be the best people to provide such information.