Serotonin! What Is It Good For?

Absolutely nothing...? Not quite, but it may be good for a lot less than anyone thought. At least according to a recent paper in PLoS One describing what happens to mice given genetic knockout which left them almost completely unable to produce the neurotransmitter serotonin (5HT).

The mice lacked either one, or both, of two genes called TPH1 and TPH2, which code for two related enzymes called tryptophan hydroxylase-1 and tryptophan hydroxylase-2. These are necessary for the production of serotonin from the amino acid tryptophan (which you get from eating turkey... and also most other foods). No tryptophan hydroxylase, no serotonin.

Tryptophan hydroxylase-1 is mostly responsible for making serotonin outside the brain, while tryptophan hydroxylase-2 predominates in neurones. So the mice lacking both enzymes ("double knockouts") should have had no serotonin at all, anywhere. In fact, chemical analysis revealed a small amount present in the brains, but it was >99% less than normal, and even this may have been some kind of contaminant rather than serotonin:

Reduction of 5-HT in TPH2KO mice ranged from 67.5% (cerebellum) to 96.9% (striatum), while 5-HT reduction in DKO mice ["double knockouts" who lacked both TPH1 and TPH2] ranged from 94.4% (cerebellum) to 99.2% (cortex). 5-HT levels were lower in DKO mice than in TPH2KO mice in all brain regions examined. The percentage of 5-HIAA reduction paralleled changes in 5-HT. No generalized changes were noted in other neurotransmitter levels.

So, what happened to these serotonin-less animals? The big story is - remarkably little. They were alive, for one thing. They weren't writhing in pain thinking "Every moment I live is agony!" like that mutant on The Simpsons. The double knockout mice were slightly smaller and leaner than usual (less body fat), but only by a few % points. Otherwise, they were normal on almost every measure. This is very surprising, given that serotonin is one of the oldest neurotransmitters in evolutionary terms. Even insects use serotonin as a transmitter. Even some single-celled organisms have serotonin. There are at least 14 different types of serotonin receptor in the mouse body (same for humans). What are they all doing? Nothing especially important, clearly.

The results dramatically indicate that 5-HT is not essential for overall development and that its role in behavior is modulatory rather than essential. Initial phenotypic analysis of these mutants revealed no differences in a range of measures of physical health including assays for cardiac, immune system, endocrine, and ophthalmic function (unpublished observations).

However, that's not the end of the story. The mice were also tested in a battery of standard behavioural tests used to measure anxiety levels and such like; these are commonly used to measure the effects of antidepressants and other such drugs in rodents. Given that antidepressants such as Prozac are supposed to work by increasing serotonin levels in the brain, you'd expect that mice with no serotonin would be "depressed".

The TPH1 knockout animals showed no differences at all - no surprise since, as you'll recall, they only lacked serotonin outside the brain e.g. in the intestines, where it seems to play a role in digestion - although presumably not a vital one. So, no surprise there. The TPH2 knockouts, and the TPH1/TPH2 double knockouts were remarkably normal too, showing no differences on most of the behavioural tests

For the TPH2KO and DKO, there were no differences between the KO or DKO and WT littermate control mice in motor coordination, acoustic startle response and sensorimotor gating, tonic inflammatory pain sensitivity, and learning and memory as assessed in inverted screen, pre-pulse inhibition, formalin paw, and trace fear conditioning assays, respectively

But they did show differences in the marble burying test, the forced swim test, and the tail suspension test. The double-knockouts generally showed the most profound effects. But here's the twist - far from being "depressed", the knockout mice were less "depressed" on the forced swim test (i.e. the genetic knockout had the same effect to that seen with antidepressants.) That is, they showed more struggling and less immobility. This is the exact opposite of what you might have expected.

On the other hand, the knockouts showed increased immobility on the tail suspension test, which is generally taken to be a depressive behaviour, and they buried more marbles in the marble burying test, which is opposite to the effects of Prozac. It's not clear what if anything burying more marbles means; some have suggested that the frantically burying mice are showing OCD-like symptoms. Hmm.

So, what these results show is that a) mice can live almost normal lives without serotonin, or at best with trace amounts, and b) the main effects of having no serotonin are upon "depression-like" behaviours, but whether the knockouts are more or less depressed is unclear (the authors push the idea that they're more depressed, but really it's impossible to say.) Still, this is a bit more evidence that the serotonin hypothesis of depression isn't quite dead.

To my mind, though, the most interesting result by far is that serotonin is so dispensible. Mice can live essentially normal lives without it, which is not true for most other neurotransmitters. Bear in mind, though, that just because serotonin is not necessary for normal functioning doesn't mean that if you do have serotonin, it isn't doing anything. It might be that in the knockout mice, other systems had taken over the roles normally played by serotonin.

Finally, this study was run by Lexicon Pharmaceuticals, who use genetic knockout technology to discover new drugs. They end by saying...

Our results strongly support targeting the 5-HT system to treat affective disorders and the use of knockout mice as a tool to tease apart mechanisms involved in the etiology of these disorders.

Take that as you will.

Katerina V. Savelieva, Shulei Zhao, Vladimir M. Pogorelov, Indrani Rajan, Qi Yang, Emily Cullinan, Thomas H. Lanthorn (2008). Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants PLoS ONE, 3 (10) DOI: 10.1371/journal.pone.0003301

Seven Things You Didn't Know About Milgram

There's been a lot written about psychology professor Jerry Burger's recent replication of the famous "obedience" experiments first carried out by Stanley Milgram in the early 1960s. Here's Burger's paper in which he reports that obedience rates are almost the same today as they were nearly 50 years ago.

Wikipedia's page on this experiment has an excellent summary of the methodology and results of the original study if you're not familiar with it.

It's a testament to the importance of the original obedience experiment that many who know nothing else about psychology have at least heard of it, and it's common knowledge that Milgram found that a startlingly high proportion of ordinary volunteers were willing to administer very strong "shocks" to an innocent victim, on the orders of the experimenter. But there's much more to the "Milgram Experiment" than many people realize. So - read on. That's an order.

1. There wasn't just one experiment In 1974, Milgram discussed the results and implications of his research in a book, Obedience to Authority: An Experimental View. (The cover is rather amusing). In it he describes no fewer than 19 different experiments, not including pilot studies. Most of the studies included 40 participants, although some of the later ones used 20. The basic nature of the experimental situation was the same in each case, but important factors were varied between expriments, offering some insight into the conditions which drive obedience (see below). All of this work was performed at or near Yale between 1960 and 1963. Milgram also refers to later replication studies carried out in"Princeton, Munich, Rome, South Africa and Australia" where "the level of obedience was invariably somewhat higher than that found [in the Yale studies]". So, whatever was going on in the Milgram experiments, it wasn't unique to the USA, and the fact that Jerry Burger has just obtained very similar results shows that it wasn't unique to the 1960s either (although, to look at it the other way, the USA today is not especially conformist.)
2. Subjects were paid $4 each Milgram's book is full of details such as this, including plenty of photos and drawings illustrating what happened. The picture here shows the designated "victim" in most of the experiments - James McDonough, "a 47-year old accountant, trained for the role; he was of Irish-American descent and most observers found him mild-mannered and affable". This is the face that launched a thousand shocks - seeing it, for me, brought home the results of the obedience studies very starkly. How could anyone shock that guy? Another important detail is that rather than recruiting undergraduate students, as most psychology experiments do, Milgram placed adverts in local newspapers and, when that only got a few hundred volunteers, resorted to cold-calling names in the New Haven telephone directory. This meant that the participants were (as far as possible) representative of the normal population - a crucial point.
   
3. Milgram was an Evolutionary Psychologist Well, sort of. He was into Evolutionary Psychology before it became a buzzphrase - indeed, before the term had been coined. In his book, Milgram notes that "the formation of hierarchically organised groupings lends enormous advantage to those so organized in coping with dangers of the physical environment, threats posed by competing species, and potential disruption from within." In other words, an animal which has the ability to submit to authority when necessary might be more likely to survive than one which was stubbornly individualistic. He goes on to theorize that humans have evolved a psychological mechanism for obedience, which he calls the "Agentic State", a special state of mind in which our normal moral inhibitions are bypassed and we become an agent of an authority. I'm not sure many people would buy this as a good explanation, and it isn't clear if Milgram's evolutionary logic relies on Group Selection theory, but it's certainly interesting.
   
4. It was stressful Most of the subjects were acutely distressed during the procedure - hardly surprising given the screams and protests of their "victim". Some subjects shook with tension; one started laughing whenever they had to give a shock. Yet most of them continued to give the shocks despite being tangibly upset about it. They didn't want to hurt the "victim" - but they did. This inner conflict suffered by the subjects comes across vividly in Milgram's writing, and it led to some fascinating behaviour. In Experiment 7, in which the "experimenter" giving orders left the room and spoke to the subjects by telephone, many subjects continued to give shocks but gave much milder shocks than they were supposed to. In other words, they were unwilling to hurt the victim but also unwilling to openly disobey (although in this case, 80% of subjects eventually did). Most people also seemed to try to keep the shocks as short as possible, and tried to minimize the number of punishments by helping the victim to give the right answers. Milgram argued that this ruled out the view that his experiment showed people to be "aggressive" or "sadistic" - rather, people were naturally averse to causing harm, but the situation they found themselves in led them to do so anyway. As he put it "The social psychology of this century reveals a major lesson: often it is not so much the kind of person a man as the kind of situation in which he finds himself that determines how he will act."
   
5. There was follow-up Milgram's sometimes accused of being a cavalier or even callous researcher who exposed his volunteers to emotional harm. In fact although, as the cliche goes, Milgram's studies would never pass an ethics committee today, he seems (at least on his own account) to have gone to great effort to ensure that his participants were not traumatized and to record how they felt about the experiment. Immediately after the experiment was finished the subjects were "debriefed" and told what had really happened; if they had been obedient, they were reassured that this was normal behaviour (true, of course). Then, a few weeks later, they were sent a write-up of the results of the research and an explanation of the rationale. A questionairre asked how they felt about the study overall; 43% said they were very glad to have done it, 40% said they were glad, and just 1.3% were sorry or very sorry to have done it; there was little difference between those who obeyed and those who didn't. Commenting on the fact that people seemed remarkably relaxed about what they had done, in retrospect, Milgram wryly noted "The same mechanisms that allow the subject to perform the act...continue to justify his behaviour for him".
   
6. Not everyone obeyed You probably already know this, but you think of it as less exciting than the fact that most people did. In the best known version of the experiment (Experiment 5), 35% of people refused to administer the highest shock level, and some of those came close to it. In other experimental set-ups, obedience rates were different - when the study was carried out in a run-down city apartment, rather than in the presitgous surroundings of Yale, obedience rates dropped (but were still 47.5%). When the subjects did not have to administer the shocks themselves but simply sit by and take notes while someone else did, almost everyone complied (92.5%). Yet there were no clear explanations for why some individuals obeyed and some did not. Some people were chillingly obedient, others were boldly defiant, but it's not clear why. Age, religion (Catholic vs. Protestant), and political affiliation did not seem to matter. Most of the studies used male volunteers only, for some reason, but Experiment 8 used women; compared to Experiment 5 the results were pretty much identical. In the early experiments there were some indications that better educated and higher-status men were more defiant, but this did not seem to hold for all of the studies.
   
7. This actually happened Again, you already knew this, but it's worth taking a moment to remember it. This really happened and it's been replicated ad nauseum; so far as I can see, no-one has succesfully criticized the basic assumptions of the paradigm (although if anyone has please let me know.) Milgram's faith in humanity seems to have been shaken by his research - his book contains case studies of individual participants which are are cynical to the point of misanthropy, even down to the level of the physical appearance and personality of the participants ("Mr Batta is a 37-year old welder...he has a rough-hewn face that conveys a conspicuous lack of alertness. His overall appearance is somewhat brutish...[during the experiment] what is remarkable is his total indifference to the learner; he hardly takes cognizance of him as a human being...the scene is brutal and depressing...at the end of the session he tells the experimenter how honored he has been to help him.") The subjects who disobeyed authority get a slightly better treatment, but not much better. Yet who can blame Milgram for this? It's worth bearing in mind also that Milgram was Jewish. His text is full of references to Nazi Germany, Hannah Arendt, the Vietnam War and the Mai Lai massacre. The hero of the book, if there is one, seems to be the young man who took part in the experiment and, as a result, decided to apply for Conscientous Objector status to avoid being sent to Vietnam. He got it.
   

Links: Dr Thomas Blass's StanleyMilgram.com - excellent.
Dr Blass's review paper on the Milgram paradigm.

Encephalon #61 is up

The 61st edition of neuroscience/psychology-based blog carnival, Encephalon, is up at Sharpbrains. I'm in it, twice, but don't let that stop you - the rest of it is pretty good...

John F. Kennedy, speed freak?

In his book In Sickness and In Power, the former British politician and doctor David Owen (sorry - Lord Owen) discusses the physical and mental health of various 20th century leaders.(*) The chapter on John F. Kennedy is extremely interesting. The most popular President of the century was both seriously ill and a big drug user.

Although he denied it at the time, to the point of lying, it's now known that Kennedy suffered from Addison's disease, a serious chronic condition leading to a lack of the steroid hormone cortisol, and in his case, also of thyroid hormone. As a result he required daily hormone treatments of cortisone , tri-iodothyronine and testosterone to stay alive. Kennedy also suffered from several other health problems such as chronic back pain following a World War 2 injury (his boat was rammed by a Japanese submarine and sank), and came close to death at least twice.

This is quite interesting in itself, but especially so since both cortisone and testosterone can alter mood and behaviour. In high doses, cortisone can produce mood swings, agitation and mania, and with prolonged use, depression; while testosterone... well, it's testosterone. In theory, Kennedy only needed to take enough of these hormones to achieve normal levels, but in fact, Owen says, for long periods of his Presidency he was taking much more than that, partly because doctors in the 1960s tended to use higher doses than would now be considered wise, and partly because he was being simultanously treated by a number of doctors who didn't always know what the others were doing (seriously.) Allegedly, some photos of Kennedy show symptoms of excessive cortisol levels ("Cushingoid features") such as a puffy face, although I haven't checked this. (This picture shows signs of Addison's disease - low weight and dark skin - before he was treated).

Most interestingly for drug fans, Owen says that Kennedy was a regular user of amphetamine ("speed"), which he was given by Dr Max "Dr Feelgood" Jacobson, who was essentially a high-class quack, although a very popular one. Jacobson was a methamphetamine user himself and he was eventually banned from practicing medicine in 1975. Jacobson gave Kennedy injections of amphetamine and steroids, and probabky also gave him vials of drugs to inject himself with; on at least one occasion he probably gave him methamphetamine. All of this was perfectly legal, but it was medically unnecessary, and maybe downright dangerous. Kennedy also had injections of Demerol (pethidine) for chronic back pain, a powerful painkiller which pharmacologically is rather like a cross between morphine and cocaine. Fun stuff. Jacobson, however, disappoved of this.

Owen speculates that Kennedy's medication, as well as his general health, contributed to his erratic performance during the first half of his presidency - hence the Bay of Pigs fiasco, and an embarrasingly poor form during a summit with the Soviet leader Khrushchev. Later on, when Kennedy's health situation had improved and he had cut back on the speed and steroids, he was able to handle the Cuban Missile Crisis very effectively and, probably, saved the world. A skeptic would say that Kennedy might have just learned from his mistakes of course, but Owen's theory is certainly possible, and it's worth bearing in mind when thinking about the possibility of the widespread use of "cognitive enhancers" - most of these drugs are stimulants with effects on mood and judgement. So remember - unless you want to preside over an abortive, ill-planned invasion of a small third-world country, keep away from speed.

(*)Mini-book-review: In Sickness and in Power is interesting but badly flawed; it mixes sound history with fluffy speculation seemingly at random. Would French President Mitterand have acted differently on the War in Yugoslavia if he hadn't had cancer? Would the Shah of Iran have been forced to step down earlier if he had admitted to having leukemia? Possibly - but we really don't know. Owen spends a lot of time wondering about such hypothetical questions. He has also invented a new psychiatric diagnosis, "hubris syndrome", complete with a DSM-IV style symptom checklist, with which he proceeds to diagnose people like Tony Blair and George Bush on the basis that they made bad decisions about Iraq. Fair enough, but I've have preferred to hear more about Nixon and Bush's alcoholism or about Winston Churchill's depression, which are discussed, but only briefly.

A Gene for Power-Line Leukemia?

Some people believe that living near high-voltage power lines raises the risk of childhood cancer. Most people are skeptical. A Chinese group have just published a paper in the journal Leukemia and Lymphoma, claiming that a genetic polymorphism in the XRCC1 gene, which has been previously linked to various cancers, raises the risk of electromagnetic field (EMF)-related leukemia. People who believe in EMF-related leukemia are happy. The Daily Mail report on this study quoting no less than three such people.

What's the real story? The authors took 123 childhood leukemia patients living near Shanghai. They took blood samples for DNA analysis and asked the parents to report on a wide range of possible environmental risk factors, not just EMF:

The mothers of the patients were interviewed at the hospital by specifically trained medical doctors using a questionnaire. Visits to the present (or previous) residential areas of 66 cases were arranged, and the actual values of magnetic field intensities were measured using an EMF detector (TriField Meter, AlphaLab, USA). Questionnaires covered information about the parents’ sociodemographic characteristics, the children’s pre and postnatal characteristics and the familial history of cancer and autoimmune diseases. The questions related to environmental exposure covered pregnancy and the period from birth to diagnosis and detailed information including: Was there a television set/refrigerator/ microwave oven in the children’s rooms? Did you regularly use insecticides at home? Did you use gardening chemicals such as, fertilisers, herbicides, insecticides, fungicides, others? Were there chemical factories/telecommunication transmitters/electric transformers/power lines around your house?

Relying on self-report like this raises the risk of recall bias, but to be honest, this doesn't seem like a major problem. Certainly there is a much bigger problem with this study (see below). The authors genotyped the children for six different SNPs (genetic variants) which have been previously implicated in cancer

The MassARRAY technology platform (Sequenom, San Diego, California, USA) was used to detect the SNPs in hMLH1 Ex8–23A4G (rs1799977), APEX1 Ex5þ5T4G (rs1130409), MGMTEx7þ 13A4G (rs2308321), XRCC1 Ex9þ16G4A (rs25489), XPD Ex10–16G4A (rs1799793) and XPD Ex23þ61 T4G (rs13181)

See the problem that's developing here? Six SNPs, who knows how many different environmental factors (the paper isn't clear, but it seems to be at least seven, see below) - that's a textbook example of multiple comparisons. Any statistical comparison has a chance of giving a positive result just by chance. If you do enough comparisons, you will find something, just by chance.

The authors do not report making an attempt to correct for this (although there are plenty of ways of doing so). They never even acknowledge the problem. They simply report on their only positive result - an association between the XRCC1 risk allele and "proximity to electrical transformers and power lines" - and relegate all the negative results to a brief summary

No significant interactions between the proximity of the electric transformers and power lines and other genotypes were observed. No significant interactions were observed between genotypes and the presence of television sets, refrigerators or microwave ovens in children’s rooms, pesticides use or the presence of chemical factories or telecommunication transmitter within 500 m of the houses.

The positive result was that out of the children with leukemia, those living within 100m of electrical transformers and power lines were more likely to carry the XRCC1 risk allele than those not living within this proximity. Those living within 50m were slightly more likely than that. Under the assumption that genotype is not correlated with environment in the general population (a reasonable assumption, and they did test this in a control sample), this indicates a G x E interaction for leukemia / lymphoma risk, with p below 0.01.

One such result from what seems like at least 42 such comparisons is not especially impressive. It's certainly not proof of an interaction between XRCC1 and EMF, it's not even "suggestive evidence", it's at best a prompt for further research. Even being generous, and assuming that they would not have reported on an association with any risk factor other than proximity to power lines, this is still 6 comparisons with different polymorphisms (more if you count the fact that children living at differing distances from power lines were tested seperately).

Postscript: I hope that I'm wrong about this. It would be great if XRCC1 raised the risk of childhood cancer, because it would mean that we could prevent some childhood cancers by keeping at-risk children away from power-lines. This post is just something I hacked together in an hour and a half on a Sunday morning, and I'm not a statistician - it would be awful if I've just spotted a serious problem with an important paper which went un-noticed by journal editors and peer reviewers. So if someone wants to disagree with me please, please do - I'll provide the PDF of the paper on request if you need it. Until then, I think that this is especially bad example of the problem of multiple comparisons and a tragic case of sloppy science which could end up having serious consequences for health, in terms of acting as a red herring distracting from more valuable research.

[BPSDB]

You Yang, Xingming Jin, Chonghuai Yan, Ying Tian, Jingyan Tang, Xiaoming Shen (2008). Case-only study of interactions between DNA repair genes (hMLH1, APEX1, MGMT, XRCC1 and XPD) and low-frequency electromagnetic fields in childhood acute leukemia Leukemia and Lymphoma, 49 (12), 2344-2350 DOI: 10.1080/10428190802441347

The Lonely Grave of Galileo Galilei

Galileo would be turning in his grave. His achievement was to set science on the course which has made it into an astonishingly successful means of generating knowledge. Yet some people not only reject the truths of the science that Galileo did so much to advance; they do it in his name.

Intro: In Denial?

Scientific truth is increasingly disbelieved, and this is a new phenomenon, so much so that new words have been invented to describe it. Leah Ceccarelli defines manufacturoversy as a public controversy over some question (usually scientific) which is not considered by experts on the topic to be in dispute; the controversy is not a legitimate scientific debate but a PR tool created by commercial or ideological interests.

Probably the best example is the attempts by tobacco companies to cast doubt on the association between tobacco smoking and cancer. The techniques involved are now well known. The number of smokers who didn't quit smoking because there was "doubt" over the link with cancer is less clear. More recently, there have been energy industry-sponsored attempts to do the same to the science on anthropogenic global warming. Other cases often cited are the MMR-autism link, Intelligent Design, and HIV/AIDS denial, although the agendas behind these "controversies" are less about money and more about politics and cultural warfare.

Many manufacturoversies are also examples of denialism, which Wikipedia defines as

the position of governments, political parties, business groups, interest groups, or individuals who reject propositions on which a scientific or scholarly consensus exists

although the two terms are not synonymous; one could be a denialist without having any ulterior motives, while conversely, one could manufacture a controversy which did not involve denying anything (e.g. the media-manufactured MMR-causes-autism theory, while completely wrong, didn't contradict any established science, it was just an assertion with no evidence and plenty of reasons to think it was wrong.) Denialism is very often accompanied by invokations of Galileo (or occasionally other "rebel scientists"), in an attempt to rhetorically paint the theory under attack as no more than an established dogma.

Just a caveat: in the wrong hands, the concepts of manufacturoversy and denialism could become a means of rubbishing legitimate dissent. The slogan of the denialism blog is "Don't mistake denialism for debate", but the line is sometimes very fine(*). For example, I'm critical of the idea that psychiatric medications and electroconvulsive therapy are of little or no benefit to patients. If one wanted to, it would be possible to make a coherent-sounding case as to why this debate was a manufacturoversy on the part of the psychotherapy industry to undermine confidence in a competing form of treatment which is overwhelmingly supported by the scientific evidence. This would be wrong (mostly).

A History of Error

Anyway. What's interesting is that the idea of inappropriate or manufactured doubt about scientific or historical claims is a very new phenomenon. Indeed, it's very hard to think of any examples before 1950, with the possible exception of the first wave of Creationism in the 1920s. Leah Ceccarelli points out that many of the rhetorical tricks used go back to the Greek Sophists but until recently the concept of denialism would have been almost meaningless, for the simple reason that this requires a truth to be inappropriately called into question and before about the 19th century, to a first approximation, we didn't have access to any such truths.

It's easy to forget just how ignorant we were until recently. The average schoolkid today has a more accurate picture of the universe than the greatest genius of 500 years ago, or of 300 years ago, and even of 100 years ago (assuming that the schoolkid knows about the Big Bang, plate tectonics, and DNA - all 20th century discoveries).

To exaggerate, but not very much: until the last couple of centuries of human history, no-one correctly believed in anything, and people had many beliefs that were actively wrong - they believed in ghosts, and witches, and Hiranyagarbha, and Penglai. People erred by believing. Those who disbelieved were likely to be right.

Things have changed. There is more knowledge now; today, when people err, it is increasingly because they reject the truth. No-one in the West now believes in witches, but hundreds of millions of us don't believe that the visible universe originated in a singularity about 13.5 billion years ago, although this is arguably a much bigger mistake to make. In other words, whereas in the past the main problem was belief in false ideas ("dogma"); increasingly the problem is doubting true ones ("denialism").

Myths & Legends of Science

The problem is that the way most people think about science hasn't caught up with the pace of scientific change. In just a couple of hundred years, science has gone from being an assortment of separate, largely bad notions, to being a vast construct of interlinking and mutually supporting theories, the foundations of which are supported by mountains of evidence. Yet all of our most popular myths about science are Robin Hood stories - the hero is the underdog, the rebel, the Maverick who stands up to authority, battles the entrenched beliefs of the Establishment, and challenges dogma. In other words, the hero is a denialist - albeit one who turns out to be right.

Once, this was realistic. Galileo was an Aristotelean cosmology denier; Pasteur was a miasma theory denier; Einstein was a Newtonian physics denier. (In fact, the historical facts are a bit more complicated, as they often are, but this is true enough.) But these stories are out of date. Thanks to the great deniers of the past, there are few, if any, inappropriate dogmas in mainstream science. There, I said it. Thanks to the efforts of scientists past and present, science has become a professional activity with, generally, a very good success rate.

The HIV/AIDS hypothesis and anti-retroviral drugs were developed by orthodox career scientists with proper qualifications working within the mainstream of biology and medicine. They probably wore boring, conventional white coats. There were no exciting paradigm shifts in HIV science. There was no Galileo of HIV; there was Robert Gallo. Yet orthodox science has been successful in delivering treatments for HIV and understanding of the disease (anti-retrovirals are not perfect, but they're a hell of a lot better than untreated AIDS, and just 20 years ago that was what all patients faced.) The skeptics, the rebels, the Robin Hoods of HIV/AIDS - they have been a disaster. If global warming deniers succeed, the consequences will be much worse.

Of coure, we do still need intelligent rebels. It would be a foolhardy person(**) who predicted that there will never be another paradigm shifts in science; neuroscience, at least, is due at least one more and there are parts of the remoter provinces of science, such as behavioural genetics, which are in serious need of a critical eye. But the vast majority of modern science, unlike the science of the past, is actually quite good. Hence, rebels are most likely wrong. To make a foolhardy prediction: there will never be another Galileo in the sense of a single figure who denies the scientific consensus and turns out to be right. There can only be a finite number of Galileos in history - once one succeeds in reforming some field, there is no need for another - and we may well have run out. My previous post on this topic included the bold claim that

if most scientists believe something you probably should believe it, just because scientists say so.

Yet this wasn't always true. To pluck a nice round number out of the air, I'd say that science has only been this trustworthy for 50 years. Most of our myths and ideas about science date from before that era. Science has moved on since the time of Galileo, thanks to his efforts and those of they who came after him, but he is still invoked as a hero by those who deny scientific truth. He would be turning in his grave, in the earth which, as we now know, turns around the sun.

(*) and of course as we know, "it's such a fine line between stupid and clever".
(**) As foolhardy as Francis Fukuyama who in 1989 proclaimed that history had ended and that the world was past the era of ideological struggles.

[BPSDB]

We Really Are Sorry, But Your Soul is Still Dead

Over the past few weeks, Christian neurosurgeon Michael Egnor, who writes on Evolution News & Views, and atheist neurologist Steve Novella (Neurologica) have been having an, er, vigorous debate about what neuroscience can tell us about materialism and the soul. As reported in New Scientist, this is part of an apparant attempt to undermine the materialist position (that all mental processes are the product of neural processes), on the part of the same people who brought you Intelligent Design. Many are calling it the latest front in the Culture War.

A couple of days ago Denyse O'Leary, a Canadian journalist who writes the blog Mindful Hack(*), posted some comments from Egnor about the great Wilder Penfield and his idea of "double consciousness" (my emphasis)

[By stimulating points on the cerebral cortex with electrodes during surgery] Penfield found that he could invoke all sorts of things- movements, sensations, memories. But in every instance ... the patients were aware that the stimulation was being done to them, but not by them. There was a part of the mind that was independent of brain stimulation and that constituted a part of subjective experience that Penfield was not able to manipulate with his surgery.... Penfield called this "double consciousness", meaning that there was a part of subjective experience that he could invoke or modify materially, and a different part that was immune to such manipulation.

I generally find arguing about religion boring, and I've no wish to enlist in any Culture Armies (I'm British - we're a nation of Culture Pacifists), but I'm going to say something about this, because it's just bad neuroscience. Maybe there are good arguments against materialism, but this isn't one.

Unfortunately, neither O'Leary nor Egnor allow comments on their blogs, but immediately after posting this I emailed them both with a link to this post. We'll see what happens.

Anyway, Penfield, whom you can read about in great detail at Neurophilosophy, was a pioneer in the functional mapping of the cerebral cortex. He was a neurosurgeon, and as part of his surgical procedures he would systematically stimulate different points of the cerebral cortex with an electrode, so as to locate which areas were responsible for important functions and avoid damaging them. Michael Egnor, following Penfield, is correct that this kind of point stimulation of the cortex tends to evoke sensations or motor responses which are experienced by the patient as external. Point stimulation is not reported to be able to effect our "higher" mental faculties such as our beliefs, desires, decisions, and "will"; it might evoke a movement of the arm, say, but the subject will report that this felt like an involuntary reflex, not a willed action.

However, to take this as evidence for some kind of a dualism between a form of conciousness which can be manipulated via the brain and another, non-material level of conciousness which can't (the "soul" in other words), is like saying that because hammering away at one key of a piano produces nothing but an annoying noise, there must be something magical going on when a pianist plays a Mozart concerto. Stimulating a single small part of the brain is about the crudest manipulation imaginable; all we can conclude from the results of point-stimulation experiments is that some kinds of mental processes are not controlled by single points on the cortex. This should not be surprising, since the brain is a network of 100 billion cells; what's interesting, in fact, is that stimulating a few million of these cells with the tip of an electrode can do anything.

Neuroskeptic is frequently critical of fMRI, but one of my favorite papers is an fMRI study, Reading Hidden Intentions in the Human Brain. In this experiment the authors got volunteers to freely decide on one of two courses of action several seconds before they were required to actually do the chosen act. (It was deciding betweening adding vs. subtracting two numbers on a screen.) They discovered that it was possible to determine (albeit with less than 100% accuracy) what subjects were planning to do on any given trial, before they actually did it, through an analysis of the pattern of neural activity across a large area of the medial prefrontal cortex.

The green area on this image shows the area over which activity predicts the future action. Importantly, no one point on the cortex is associated with one choice over another, but the combination of activity across the whole area is (once you put it through some brilliant maths).

Based on this evidence, it's reasonable to suppose that we could manipulate human intentions if, instead of just one electrode, we had several thousand (or million), and if we knew exactly which pattern of stimulation to apply. Or to run with the piano analogy: we could play a wonderful tune if we were skilled enough to play the right notes in the right combinations in the right order.

In fact, there are plenty of things which already are known to alter "higher" processes. At the correct doses, acetylcholine receptor antagonists such as scopolamine and atropine can produce a state of delerium with hallucinations which are experienced as being indistingishable from reality. Someone might talk to a non-existent friend or try to smoke a non-existent cigarette, without any knowledge of having taken a drug at all. Erowid has many first-hand accounts from people who have taken such drugs "recreationally" (a very bad idea, as you'll gather if you read a few.)

Then there's psychiatric illness. Someone who's psychotic may hear voices and believe them to be real communications from God, or the dead, or a radio transmitter in his head. A bipolar patient in a manic state may believe herself to have incredible talents or supernatural powers and dismiss as nonsense any suggestion that this is a result of her illness. In general those suffering from acute abnormal mental states may behave in a manner which is completely out of character, or think and talk in bizarre ways, without being aware of doing so. This is called "lacking in insight".

We don't yet know the neurobiological basis of these states, but that they (often) have one is beyond doubt; give the appropriate drugs - or use electricity to induce seizures - and they (usually) vanish. Many people in the advanced phases of dementia, especially Alzheimer's disease, as a result of neurodegeneration, are similarly unaware of being ill - hence the sad sight of formerly intelligent men and women wandering the streets, not knowing how they got there. Brain damage, or stimulation of deep brain structures (not the cortex which Penfield studied), can lead to profound alterations in personality and emotion. To summarize - if you seek the soul in the data of neuroscience, you will need to look harder than Penfield did.

Links : Sorry, But Your Soul Just Died - Tom Wolfe. A classic.

(*) - Mindful Hack - not to be confused with Mind Hacks.

[BPSDB]

No ventral prefrontal cortex? No problem!

Brain damage - it's not much fun when it's your brain, but for science, it's often good news. While neuroimaging can find the neural correlates of mental processes - areas of the brain which become active during the experience of an emotion, say - lesion studies are often necessary to establish the direction of causality. Just because somewhere in the brain is activated during the experience of fear, for example, doesn't mean that this area is responsible for our feelings of fright; it might just happen to be lighting up as a side effect. Neuroimaging can't tell the difference, but if someone suffers damage to some part of the brain and then becomes fearless, it becomes possible to establish which parts do what. Localizing a function to a certain region of the brain is not the same as understanding it, of course, but it's a start.

The main problem with lesion studies is that there aren't enough of them. Because of those pesky ethical considerations, you can't just go around poking holes in people's brains - you have to wait until damage occurs naturally. In many interesting parts of the brain, localized damage is frustratingly uncommon.

Yet good things come to those who wait. The Journal of Neuroscience have just published a landmark lesion study by Koenigs et. al.(*) who studied two separate, large groups of people who had suffered brain damage to a range of areas - Vietnam veterans with combat head injuries, and Iowa citizens who had suffered tumors, strokes, and other medical conditions. In both samples they measured symptoms of depression and attempted to correlate them with the location of the lesions.

They succeeded. In both samples, patients who had suffered damage to the ventro-medial prefrontal cortex (vmPFC), which sits a few inches behind the center of the forehead, seemed to be protected against depression. Compared to people who had suffered lesions to all of the other parts of the brain, people with vmPFC damage on both sides of the brain were rated as having fewer depressive symptoms, both according to their own report and the observations of the experimenters. In particular, they reported being almost completely free of emotional or subjective symptoms such as feelings of guilt, sadness, or self-dislike. For illustration, they describe the incredible (and ironic) case of a woman with a self-inflicted vmPFC lesion:

We identified one patient in the Iowa registry who represents an intriguing case of an apparent alleviation of severe depression after a bilateral vmPFC lesion. ... per secondary report the patient was being treated for depression when she attempted suicide 11 years ago by means of a gunshot to the head. The gunshot destroyed most of ventral PFC, including vmPFC bilaterally, but left intact most of dorsal PFC. The patient’s neuropsychologist, neurosurgeon, and long-term boyfriend all remarked that her depression was markedly diminished after the brain injury (boyfriend, speaking 16 months after the injury: “no sign of depression whatsoever since the accident”; neuropsychologist: “she never shows distress, worry, or anger”).

Overall, these results are exciting, but unsurprising - the vmPFC is commonly thought of as being involved in emotion and emotional decision making; Antonio Damasio famously inferred this from the case of Phineas Gage, who after losing his medial prefrontal cortex to an iron rod, became impulsive, reckless, and unconcerned for himself or others. It's not difficult to see that someone with such characteristics might be resistant to such emotional difficulties as depression, or, say, post-traumatic stress - and indeed Koenigs et. al. previously reported that such lesions also protect against PTSD in combat veterans.

Fascinatingly, old-fashioned psychosurgery frequently ended up destroying much the same areas of the brain; the desired result, sometimes achieved, was a patient who no longer cared or worried about anything - which was thought preferable to someone paralyzed by despair or anxiety. The point is that the vmPFC is not specifically a "depression area of the brain" - although these results suggest that it is necessary for the experience of depression, it is probably also responsible for a broad range of other emotions, and patients lacking a vmPFC clearly lack more than just sadness. (If there is a "depression area", which is possible, my money's on the subgenual cingulate cortex.)

The paper also reported that damage to another part of the brain, the dorsal prefrontal cortex (bilateral), seemed to cause depression - however, there were only 5 patients with this kind of damage, of whom 2 were clinically depressed, so it's harder to interpret this result:

The proportion of individuals meeting DSM-IV criteria for "current" MDD was significantly greater for the dorsal PFC lesion group (2 of 5) than for the non-PFC lesion group (1 of 101; p = 0.005) or non-brain-damaged group (0 of 54; p = 0.006). Thus, bilateral dorsal PFC lesions were associated with a relatively high prevalence of subsequent major depression.

A few things to note: Case histories are anecdotes, not data - and the brain of the woman described above is extensively abnormal; CT scans, not for the squeamish. The total number of vmPFC patients here was just twenty. This is the largest group of these patients studied so far, because this kind of injury is very rare, but this is still a smallish sample. Most importantly, levels of depression in the control groups in this study were fairly low. The vmPFC group showed essentially zero depressive symptoms, but even the control patients only showed mild symptoms on average, and only a couple of them were diagnosed with actual clinical depression. So the between-group differences were, while statistically significant, modest.

(*) Annoyingly, pretty much every paper from Mike Koenigs is a landmark lesion study. It's always the same lesion patients. Not that this is a major problem, I'm just annoyed that he gets to study them and not me.

M. Koenigs, E. D. Huey, M. Calamia, V. Raymont, D. Tranel, J. Grafman (2008). Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression Journal of Neuroscience, 28 (47), 12341-12348 DOI: 10.1523/JNEUROSCI.2324-08.2008

New Deep Brain Stimulation Blog

Via Dr Shock, there's a new blog just been started by an anonymous American man who will soon be undergoing deep brain stimulation (DBS) for clinical depression, as part of a blinded trial.

It sounds like it's going to be fascinating reading - to my knowledge this is the first blog of its kind. I've always been a big believer in the important of first-hand reports in psychiatry and neurology, but sadly these are often in short supply compared to the huge proliferation of MRI scans, graphs and clinical rating scales. Sometimes, you just need to listen to people.

The study, called 278-005, also known as BROADEN, will involve electrical stimulation of the subgenual cingulate cortex ("Area 25"), the most commonly chosen target for DBS in depression. The preliminary reports from subgenual cingulate DBS have been extremely positive, but there have been no large scale clinical trials to date.

Lessons from the Placebo Gene

Update: See also Lessons from the Video Game Brain

The Journal of Neuroscience has published a Swedish study which, according to New Scientist (and the rest) is something of a breakthrough:

First 'Placebo Gene' Discovered

I rather like the idea of a dummy gene made of sugar, or perhaps a gene for being Brian Moloko, but what they're referring to is a gene, TPH2, which allegedly determines susceptibility to the placebo effect. Interesting, if true. Genetic Future was skeptical of the study because of its small sample size. It is small, but I'm not too concerned about that because there are, unfortunately, other serious problems with this study and the reporting on it. I should say at the outset, however, that most of what I'm about to criticize is depressingly common in the neuroimaging literature. The authors of this study have done some good work in the past and are, I'm sure, no worse than most researchers. With that in mind...

The study included 25 people diagnosed with Social Anxiety Disorder (SAD). Some people see the SAD diagnosis as a drug company ploy to sell pills (mainly antidepressants) to people who are just shy. I disagree. Either way, these were people who complained of severe anxiety in social situations. The 25 patients were all given placebo pill treatment for 8 weeks.

Before and after the treatment they each got an [H2
15O] PET scan, which measures regional blood flow (rCBF) in the brain, something that is generally assumed to correlate with neural activity. It's a bit like fMRI, although the physics are different. During the scans the subjects had to make a brief speech in front of 6 to 8 people. This was intended to make them anxious, as it would do. The patient's self-reported social anxiety in everyday situations was also assessed every 2 weeks by questionaires and clinical interviews.

The patients were then split into two groups based upon their final status: "placebo responders" were those who ended up with a "CGI" rating of 1 or 2 - meaning that they reported that their anxiety had got a lot better - and "placebo nonresponders" who didn't. (You may take issue with this terminology - if so, well done, and keep reading). Brain activation during the public speaking task was compared between these two groups. The authors also looked at two genes, 5HTTLPR and TPH2. Both are involved in serotonin signalling and both have been associated (in some studies) with vulnerability to anxiety and depression.

The results: The placebo responders reported less anxiety following treatment - unsurprisingly, because this is why they were classed as responders. On the PET scans, the placebo responders showed reduced amygdala activity during the second public speaking task compared to the first one; the non-responders showed no change. This is consistent with the popular and fairly sensible idea that the amygdala is active during the experience of emotion, especially fear and anxiety. However, in fact, this effect was marginal, and it was only significant under a region-of-interest analysis i.e. when they specifically looked at the data from the amygdala; in a more conservative whole-brain analysis they found nothing (or rather they did, but they wrote it off as uninteresting, as cognitive neuroscientists generally do when they see blobs in the cerebellum and the motor cortex):

PET data: whole-brain analyses
Exploratory analyses did not reveal significantly different treatment-induced patterns of change in responders versus nonresponders. Significant within-group alterations outside the amygdala region were noted only in nonresponders, who had increased (pre < post) rCBF in the right cerebellum ... and in a cluster encompassing the right primary motor and somatosensory cortices...

As for the famous "placebo gene", they found that two genetic variants, 5HTTLPR ll and TPH2 GG, were associated with a bigger drop in amygdala activity from before treatment to after treatment. TPH2 GG was also associated with the improvement in anxiety over the 8 weeks.

In a logistic regression analysis, the TPH2 polymorphism emerged as the only significant variable that could reliably predict clinical placebo response (CGI-I) on day 56, homozygosity for the G allele being associated with better outcome. Eight of the nine placebo responders (89%), for whom TPH2 gene data were available, were GG homozygotes.

You could call this a gene correlating with the "placebo effect", although you'd probably be wrong (see below). There are a number of important lessons to take home here.

1. Dr Placebo, I presume? - Be careful what you call the placebo effect

This study couldn't have discovered a "placebo gene", even if there is one. It didn't measure the placebo effect at all.

You'll recall that the patients in this study were assessed before and after 8 weeks of placebo treatment (sugar pills). Any changes occuring during these 8 weeks might be due to a true "placebo effect" - improvement caused by the patient's belief in the power of the treatment. This is the possibility that gets some people rather excited: it's mind over matter, man! This is why the word "placebo" is often preceded by words like "Amazing", "Mysterious", or even "Magical" - as if Placebo were the stage-name of a 19th century conjuror. (As opposed to the stage name of androgynous pop-goth Brian Moloko ... I've already done that one.)

But, as they often do, more prosaic explanations suggest themselves. Most boringly, the patients might have just got better. Time is the greater healer, etc., and two months is quite a long time. Maybe one of the patients hooked up with a cute guy and it did wonders for their self-confidence. Maybe the reason why the patients volunteered for the study when they did was because their anxiety was especially bad, and by the time of the second scan it had returned to normal (regression towards the mean). Maybe the study itself made a difference, by getting the patients talking about their anxiety with sympathetic professionals. Maybe the patients didn't actually feel any better at all, but just said they did because that's what they thought were expected to say. I could go on all day.

In my opinion most likely, the patients were just less anxious having their second PET scan, once they had survived the first one. PET scans are no fun: you get a catheter inserted into your arm, through which you're injected with a radioactive tracer compound. Meanwhile, your head is fixed in place within big white box covered in hazard signs. It's not hard to see that you'd probably be much more anxious on your first scan than on your second time around.

So, calling the change from baseline to 8 weeks a "placebo response", and calling the people who got better "placebo responders", is misleading (at least it misled every commentator on this study so far). The only way to measure the true placebo effect is to compare placebo-treated people with people who get no treatment at all. This wasn't done in this study. It rarely is. This is something which confuses an awful lot of people. When people talk about the placebo effect, they're very often referring to the change in the placebo group, which as we've seen is not the same thing at all, and has nothing even vaguely magical or mysterious about it. (For example, some armchair psychiatrists like to say that since patients in the placebo group in antidepressant drug trials often show large improvements, sugar pills must be helpful in depression.) Although that said there was another study in the same issue of the same journal which did measure an actual placebo effect.

2. Beware Post Hoc-us Pocus

From the way it's been reported, you would probably assume that this was a study designed to investigate the placebo effect. However, in the paper we read:

Patients were taken from two previously unpublished RCTs that evaluated changes in regional cerebral blood flow after 56 d of pharmacological treatment by means of positron emission tomography. ... The clinical PET trials ... included a total of 108 patients with SAD. There were three treatment arms in the first study and six arms in the second. ... Only the pooled placebo data are included herein, whereas additional data on psychoactive drug treatment will be reported separately.

Personally, I find this odd. Why have so many groups if you're interested in just one of them? Even if the data from the drug groups are published, it's unusual to report on some aspect of the placebo data in a seperate paper before writing up the main results of an RCT. To me it seems likely that when this study was designed, no-one intended to search for genes associated with the placebo effect. I suspect that the analysis the authors report on here was post-hoc; having looked at the data, they looked around for any interesting effects in it.

To be clear, there's no proof that this is what happened here, but anyone who has worked in science will know that it does happen, and to my jaded eyes it seems probable that this is a case of it. For one thing, if this was a study intended to investigate the placebo effect, it was poorly designed (see above).

There's nothing wrong with post-hoc findings. If scientists only ever found what they set out to look for, science wouldn't have got very far. However, unless they are clearly reported as post-hoc the problem of the Texas Sharpshooter arises - findings may appear to be more significant than they otherwise would. In this case, the TPH2 gene was only a significant predictor of "placebo response" with p=0.04, which is marginal at the best of times.

The reason researchers feel the need to do this kind of thing is because of the premium the scientific community (and hence scientific publishing) places on getting "positive results". Plus, no-one wants to PET scan over 100 people (they're incredibly expensive) and report that nothing interesting happened. However, this doesn't make it right (rant continues...)

3. Science Journalism Is Dysfunctional

Sorry to go on about this, but really it is. New Scientist's write up of this study was, relatively speaking, quite good - they did at least include some caveats ("The gene might not play a role in our response to treatment for all conditions, and the experiment involved only a small number of people.") Although, they had a couple of factual errors such as saying that "8 of the 10 responders had two copies [of the TPH2 G allele], while none of the non-responders did" - actually 8 of the 15 non-responders did - but anyway.

The main point is that they didn't pick up on the fact that this experiment didn't measure the placebo effect at all, which makes their whole article misleading. (The newspapers generally did an even worse job.) I was able to write this post because I had nothing else on this weekend and reading papers like this is a major part of my day job. Ego aside, I'm pretty good at this kind of thing. That's why I write about it, and not about other stuff. And that's why I no longer read science journalism (well, except to blog about how rubbish it is.)

It would be wrong to blame the journalist who wrote the article for this. I'm sure they did the best they could in the time available. I'm sure that I couldn't have done any better. The problem is that they didn't have enough time, and probably didn't have enough specialist knowledge, to read the study critically. It's not their fault, it's not even New Scientist's fault, it's the fault of the whole idea of science journalism, which involves getting non-experts to write, very fast, about complicated issues and make them comprehensible and interesting to the laymen even if they're manifestly not. I used to want to be a science journalist, until I realised that that was the job description.

T. Furmark, L. Appel, S. Henningsson, F. Ahs, V. Faria, C. Linnman, A. Pissiota, O. Frans, M. Bani, P. Bettica, E. M. Pich, E. Jacobsson, K. Wahlstedt, L. Oreland, B. Langstrom, E. Eriksson, M. Fredrikson (2008). A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety Journal of Neuroscience, 28 (49), 13066-13074 DOI: 10.1523/JNEUROSCI.2534-08.2008

Alas, Poor Noradrenaline

Previously I posted about the much-maligned serotonin theory of depression and tentatively defended it, while making it clear that "low serotonin" was certainly not the whole story. Critics have noted that the serotonin-is-happiness hypothesis has become folk wisdom, despite being clearly incomplete, and this is generally ascribed to the marketing power of the pharmaceutical industry. What's also interesting is that a predecessor and rival to the serotonin hypothesis, the noradrenaline theory, failed to achieve such prominence.

Everyone's heard of serotonin. Only doctors and neuroscientists have heard of noradrenaline (called norepinephine if you're American), which is another monoamine neurotransmitter. Chemically the two molecules are rather different, but they both play roughly parallel roles in the brain, in the sense that both are released from a small number of cells originating in the brain stem onto areas throughout the brain in what's often described as a "sprinkler system" arrangement.

Forty years ago, noradrenaline was seen by most psychopharmacologists as being the key chemical determinant of mood, and the leading theory on the cause of depression was some kind of noradrenaline deficiency. At this time, serotonin was generally seen as being at best of uncertain importance. In 1967 two superstars of psychopharmacology, Joseph Schildkraut and Seymour Kety, wrote a review article in Science in which they summarized the evidence for a noradrenaline theory of depression. It still makes quite convincing reading, and since 1967, more evidence has come to light; reboxetine, which selectively inhibits the reuptake of noradrenaline, is at least as effective as Prozac, which is selective for serotonin. Although it's slightly controversial, it also seems as though antidepressants which target both monoamines are slightly more effective than those which only target either.

So what happened to the noradrenaline theory? If pressed, most experts will admit that there must be something in it, and it is still discussed - but noradrenaline just doesn't get talked about as much as serotonin in the context of depression and mood. So far as I can see there is little good reason for this - given that both serotonin and noradrenaline seem to be involved in mood, the best thing would be to study both, and in particular to study their interactions. Yet this is not what most scientists are doing. Noradrenaline has just dropped off the scientific radar.

Because everyone likes graphs, and because I had nothing better to do today, I knocked together a couple to show the rise and fall of noradrenaline. The first shows the total number of PubMed entries for each year from 1969 to 2007, containing hits in the Title or Abstract for [noradrenaline OR norepinephrine] AND [depression OR depressive OR antidepressant OR antidepressants OR antidepressive] vs. [Serotonin OR 5HT OR 5-hydroxytryptamine] AND [depression OR depressive OR antidepressant OR antidepressants OR antidepressive]. As you can see, the two lines track each other very closely until about 1990, when interest in serotonin in the context of depression / antidepressants suddenly takes off, leaving noradrenaline languishing far behind.

What's fascinating is that the total amount of published research about noradrenaline also peaked around 1990 and has since declined markedly, while publications about serotonin and dopamine (another monoamine neurotransmitter) have been steadily growing.

What happened around 1990? Prozac, the first commercially successful selective serotonin reuptake inhibitor (SSRI), was released onto the U.S. market in late 1987. Bearing in mind that science generally takes a year or so to make it from the lab to the journal page, it's tempting to see 1990 as the year of the onset of the "Prozac Effect". Prozac notoriously achieved a huge amount of publicity, far more than was granted to older antidepressants such as imipramine, despite its probably being less effective. Could this be one reason why serotonin has eclipsed noradrenaline in the eyes of scientists?

A couple of caveats: All I've shown here are historical trends, which is not in itself proof of causation. Also, the fall in the total number of publications mentioning noradrenaline is much too large to be directly due to the stall in the number of papers about noradrenaline and depression / antidepressants. However, there could be indirect effects (scientists might be less interested in basic research on noradrenaline if they see it as having no relevance to medicine.)

Note 16/12/08: I've realized that it would have been better to include the term "5-HT" in the serotonin searches as this is a popular way of referring to it. I suspect that had I done this the serotonin lines would have been higher, but the trends over time would be the same.

J. J. Schildkraut, S. S. Kety (1967). Biogenic Amines and Emotion Science, 156 (3771), 21-30 DOI: 10.1126/science.156.3771.21

That esteemed journal, Viz

Viz is a British institution. One of the funniest magazines ever printed, and utterly unique; the most obvious comparison, although it's a bad one, is MAD Magazine, but I've always found Viz much more entertaining.

Just about everything in Viz is a parody - most commonly the taregt is British comic strips, but most issues have parodies of newspapers as well. Although almost everything in the magazine is full of nudity, profanity, or both, Viz features often have a (semi)serious message. There's a long-running series poking fun at religion and pseudoscience; a few months ago there was a strip about "Dr" Gillian McKeith and her Giant Pile of Bollocks, and recently they ran a contest, in association with Ben Goldacre, in which you could win a free PhD - perfect for cranks who need to add a little academic credibility. In fact Ben has said that he aims for his columns to be something of a cross between Viz and the British Medical Journal.

So, inspired by some Viz fun on ScienceBlogs, I thought I'd post a classic bit of parody neuro-journalism from a few years back. Or is it a parody? You'll learn more about the brain reading this than you will from any number of writeups of fMRI studies.

I'm big in Vietnam

Apparently. Thanks to whoever posted a link to Neuroskeptic on this Vietnamese forum! As they comment, wisely:

To be well informed about science, ignore everything you read about it in newspapers. Then read some science books if you like, but ignoring journalists is the important thing.