ECT in Nixonland

I've just finished Nixonland, Rick Perlstein's history of the 1960s. Some things I learned: Richard Nixon was a genius, albeit an evil one; the 1960s never ended; Rick Perlstein is my new favourite political author.

The book also reminded me of a sad episode in the history of psychiatry.

George McGovern ran against Nixon as the Democratic candidate for President in 1972. He was essentially the Obama of the 60s generation: unashamedly liberal and intellectual, he unseated the "established" candidate, Hubert Humphrey, to clinch the Democrat's nomination after a bitter primary campaign thanks to his idealistic young grass-roots.

McGovern had difficulty choosing his vice-presidential running mate, and eventually chose a little-known Senator from Missouri, Thomas Eagleton (left in the photo). It seemed a safe enough choice. Until Eagleton's first press conference.

Eagleton revealed that he'd been treated in a psychiatric hospital for "exhaustion" - everyone knew he meant clinical depression - three times, and that he had received electroconvulsive therapy twice. McGovern hadn't known this when he picked him.

From there it was all downhill. McGovern initially said he backed Eagleton "1000%". But to some, the idea of putting someone who'd had shock therapy a heartbeat away from the Presidency was unacceptable, and after two weeks of gossip, McGovern dropped him from the ticket.

Perlstein notes that this move wrecked McGovern's image as the idealistic and authentic alternative to politics-as-usual. Polls showed that Americans overwhelmingly trusted Nixon over McGovern, even as the facts about Watergate were emerging. Nixon won a landslide.

The Genetics of Living To 100

Is there a gene for long life?

Boston-based group Sebastiani et al say they've found not one but two, in RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C. elegans.

They took 4 groups of "oldest old" people: from New England, Italy, and Japan, and American Ashkenazi Jews. All were aged 90 or more, and many of them were 100, centenarians. As control groups, they used random healthy people who weren't especially old. The total sample size was an impressive 2105 old vs. 3044 controls.

On the basis of a pilot study, they chose to look at two candidate genes, ADARB1 and ADARB2. Both are involved in post-transcriptional RNA editing, one of the steps in the process by which genetic material, DNA, controls protein synthesis. It's something every cell in the body needs to do in order to function.

What happened? Their abstract makes the exciting claim that

18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study ... We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity.

But read the whole paper and the picture is a little more complex. For ADARB1, they looked at 31 variants (SNPs). In the New England sample, which was the largest, 5 of them were statistically significantly more common in old people compared to the controls. However, none of these were significantly associated in any of the other samples, although for 3 of the 5 variants, there was some evidence of an effect in the same direction in the other samples.

In ADARB2, out of 114 variants, 10 were significantly associated in the New England sample. Of these, 4 were independently significant in the Italian sample, and in the combined New England/Italian sample all 10 were still associated. But the Jewish and the Japanese samples showed a rather different picture: only 1 of the 10 associations was significant in the Jews, although several were weakly associated in the same direction, and in a pooled New England/Italian/Jewish analysis 9 were still significant. In the Japanese sample, one association was replicated but another variant was associated in the wrong direction.

They also did some lab work and found that in nematode worms (C. Elegans), mutants lacking the worm equivalent of the ADARB1 and ADARB2 genes had a 50% reduced lifespan - 10 days, instead of the normal 20 - despite no obvious symptoms of illness. Hmm.


I'm not quite sure what to make of this data. They looked at 4 separate, large samples, which is an excellent size by the standards of candidate gene association studies. The evidence implicating ADARB1 and (especially) ADARB2 variants in longevity is fairly convincing, although the most consistent effects came from the European-ancestry samples, suggesting that different things might be going on in other populations. This is the first research looking at these genes; ultimately, we won't know for sure until we get more. The worm data is a nice touch, but I'd like to see evidence from animals with a bit more similarity to humans, say mice.

Still, suppose that these genes are associated with long life; suppose they they control the rate of the ageing process, protecting you from dying from "natural causes" too early. That doesn't mean that you'll live to an old age - it just makes it possible. If you get hit a truck or fall of a cliff, you're dead, anti-ageing genes or not.

Frenchwoman Jeanne Calment, born 1875, died 1997, is the oldest person on record, at 122 years. But we'll never know whether someone with the genetic potential to outlive her died in WW2, or the Cultural Revolution, or just got hit by a truck. Calment presumably had the right genes, but she was also lucky.

So a trait's being genetically heritable doesn't make it pre-ordained and immutable. IQ, for example, most likely has a heritability of around 50% - some people likely have a higher potential for intellectual achievement than others. But if you're born into an abusive family, or deep poverty, or you never get a chance to go to school, you may never reach that potential. There's always that truck.

Sebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S, Hartley SH, Sedgewick A, Arai Y, Bergman A, Barzilai N, Terry DF, Riva A, Anselmi CV, Malovini A, Kitamoto A, Sawabe M, Arai T, Gondo Y, Steinberg MH, Hirose N, Atzmon G, Ruvkun G, Baldwin CT, & Perls TT (2009). RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PloS one, 4 (12) PMID: 20011587

The War on "Interesting"

My New Year's Blog Resolution - no more calling things "interesting".

While writing, I sometimes find myself searching for an adjective to attach to something I've just mentioned, words to explain why I think it's relevant. It's... no... it's kind of... hmm... It's interesting, is what it is! Phew. Now I can move on. Anything can be "interesting" - a book, a blog post, an article, an event, an idea, a movement, a prediction, an argument.

Calling something interesting is effortless; easy; it's a one-size-fits-all term. If you can't think of anything else to say, you can at least say that. Which is why people do. I know I'm not alone in this.

But "interesting" is a cop-out. It adds nothing. If you're taking the trouble of writing about something, it should be taken as read that you think it's interesting. The whole point is to explain why - to tell people what's special about it. Does it present new evidence? If so, is it reliable? Does it introduce a new distinction, a new vocabulary, a new way of thinking? If so, why is it a good one?

Sadly it's easier to just call something interesting than to explain why it is. Partly this is because "interesting" (or "fascinating", "thought-provoking", "intriguing", "notable" etc.) is just one word, and it's easier to write one word than a sentence. More important is the fact that you probably don't know why you're interested by something until you do some thinking about it.

Don't duck out of doing that thinking. It's intellectual laziness. Even more so is to say that you're not sure if something is true, but it sure is interesting. "It's not necessarily true, but it's a fascinating thought" - is it? why?

Are you interested by the possibility that it's true, so if you learned that it was definitely false, it would become boring? Or is it one of those ideas that's interesting "in itself"? If so, why? Because it's an influential idea in a political or historical sense? Because it sheds light on the minds of the people who believe it? Are you sure that your interest isn't a kind of repressed belief? Are you really "only interested", or do you see something you like? If so, why not say so?

So, I'm quitting the habit, cold turkey, as of now. No more will I reach for the "interesting" button whenever I'm stuck for words. With any luck, this will make my writing a little bit more interes... hmm.

Good News for Armchair Neuropathologists

Ever wanted to crack the mysteries of the brain? Dreamed of discovering the cause of mental illness?

Well, now, you can - or, at any rate, you can try - and you can do it from the comfort of your own home, thanks to the new Stanley Neuropathology Consortium Integrative Database.

Just register (it's free and instant) and you get access to a pool of data derived from the Stanley Neuropathology Consortium brain collection. The collection comprises 60 frozen brains - 15 each from people with schizophrenia, bipolar disorder, and clinical depression, and 15 "normals".

In a Neuropsychopharmacology paper announcing the project, administrators Sanghyeon Kim and Maree Webster point out that

Data sharing has become more important than ever in the biomedical sciences with the advance of high-throughput technology and web-based databases are one of the most efficient available resources to share datasets.

The Institute's 60 brains have long been the leading source of human brain tissue for researchers in biological psychiatry. Whenever you read about a new discovery relating to schizophrenia or bipolar disorder, chances are the Stanley brains were involved. The Institute provide slices of the brains free of charge to scientists who request them, and they've sent out over 200,000 to date.

Until now, if you wanted to find out what these scientists discovered about the brains, you'd have to look up the results in the many hundreds of scientific papers where the various results were published. If you knew where to look, and if you had a lot of time on your hands. The database collates all of the findings. That's a good idea. To ensure that they get all of the results, the Institute have another good idea:

Coded specimens are sent to researchers with the code varying from researcher to researcher to ensure that all studies are blinded. The code is released to the researcher only when the data have been collected and submitted to the Institute.

The data we're provided about the brains is quite exciting, if you like molecules, comprising 1749 markers from 12 different parts of the brain. Markers include levels of proteins, RNA, and the number and shape of various types of cells.

It's easy to use. While waiting for my coffee to brew, I compared the amount of the protein GFAP76 in the frontal cortex between the four groups. There was no significant difference. I guess GFAP76 doesn't cause mental illness - darn. So much for my Nobel Prize winning theory. But I did find that levels of GFAP76 were very strongly correlated with levels of another protein, "phosphirylated" (I think they mean "phosphorylated") PRKCA. You read it here first.

In the paper, Kim and Webster used the Database to find many differences between normal brains and diseased brains, including increased levels of dopamine in schizophrenia, and increased levels of glutamate in depression and bipolar. And decreased GAD67 proteins in the frontal cortex in bipolar and schizophrenia. And decreased reelin mRNA in the frontal cortex and cerebellum in bipolar and schizophrenia. And...

This leaves open the vital questions of what these differences mean, as I have complained before. And the problem with giving everyone in the world the results of 1749 different tests, and letting us cross-correlate them with each other and look for differences between 4 patient groups, is that you're making possible an awful lot of comparisons. With only 15 brains per group, none of the results can be considered anything more than provisional, anyway - what we really need are lots more brains.

But this database is still a welcome move. This kind of data pooling is the only sensible approach to doing modern science, and it's something people are advocating in other fields of neuroscience as well. It just makes sense to share results rather than leaving everyone to do there own thing in near-isolation from each other, now that we have the technology to do so. In fact, I'd say it's a... no-brainer.

Kim, S., & Webster, M. (2009). The Stanley Neuropathology Consortium Integrative Database: a Novel, Web-Based Tool for Exploring Neuropathological Markers in Psychiatric Disorders and the Biological Processes Associated with Abnormalities of Those Markers Neuropsychopharmacology, 35 (2), 473-482 DOI: 10.1038/npp.2009.151

The Guineapigs

Before waterboarding, there was wall standing.

The Guineapigs is a book by John McGuffin. It was published in 1974, at the height of "The Troubles" in Northern Ireland, and banned in Britain almost immediately.

The "guineapigs" in question were 14 men from Northern Ireland detained by British security forces during the 1971 campaign of internment of suspected Irish Republican Army militants and sympathizers. The book details the treatment they experienced in the week after their detention, specifically "sensory deprivation".

The men were forced to stand up against a wall, with a black hood over their head, in a room into which a loud noise - described as something like a jet engine or gushing water - was played. If they fell or otherwise moved from this stance, they were forced back up. This went on for up to 48 hours, during which time they were given neither food nor sleep.

After this the treatment became a bit less harsh, and they were interrogated at various intervals. After about a week, they were released into a "normal" prison, and the story came out. A government inquiry, the Compton Report, followed, confirming that the "Questioning in Depth" had occurred but denying that it constituted "brutality".

The Guineapigs contains first person accounts from several of the men, describing the disorientation, hallucinations and terror they experienced during the procedure, and also details the psychological after-effects they reportedly suffered, including several cases of mental illness and at least psychiatric hospitalization.

McGuffin's most controversial claim was that the whole thing was a psychological experiment. It could not, he said, have been meant to gather useful information per se, because the 14 "subjects" were not especially high-value suspects; they seemed to have been chosen at random from the hundreds interned. Instead, he said, it was a research project, a trial of the technique of sensory deprivation as torture.

During the 1960s and 1970s there was lots of academic research on sensory deprivation, in which volunteers often reported hallucinations, paranoia, mood changes and other "psychotic" symptoms after being deprived of sight, sound and touch stimuli for a few hours. According to McGuffin, the British government decided to "field test" to procedure to see whether the same thing happened in "real life" with test subjects who weren't willing volunteers.

I'm not sure whether to believe this explanation of what happened; McGuffin was hardly an unbiased observer - he was himself interned in 1971, although he wasn't amongst the guineapigs - and he was a lifelong opponent of British rule in Northern Ireland. We'll probably never know for sure. But maybe it's as convincing as any other explanation.

Links: Lots of the book is online here. Mind Hacks on a recent sensory deprivation study, and a documentary about s.d. interrogation during WW2. I found a paper by T Shallice (1972) on The Ulster depth interrogation techniques and their relation to sensory deprivation research, but I haven't been able to access it yet. John McGuffin obits.

Neuroskeptic Gets "Cited"

...kind of. Last week, I blogged about a Nature paper, Eisenegger et al, reporting that giving women testosterone makes them behave more generously in a money-sharing procedure called the Ultimatum Game.

But just a few days later, PLoS ONE published a paper, Zak et al, finding exactly the opposite result - testosterone decreased generosity in the Ultimatum Game - although that was in men, rather than women. The lead author of the PLoS paper, Paul J. Zak, then "cited" my blog post in an online comment attached to his article, as part of a discussion of the differences between his paper and Eisenegger et al's. This is not a proper citation of course, but it's a start. At least I like to think so.

PLoS have a brilliant policy of having a blog-style comment thread attached to every paper. This is a far better system than the traditional academic policy of allowing comments only in the form of formal "Letters to the Editor" of the journal. This made sense in the days before the internet, but it's long outlived its usefulness.

A Letter has to be approved by the editor of the journal to get published at all. For reasons of space, if nothing else, the number which get printed is small. Even if your Letter does see the light of day, it will be, at minimum, a couple of months after the original paper was published, by which time most readers of the original will have forgotten what the fuss was about. If the original authors reply to your Letter, and you want to reply to their reply, it'll be another couple of months before you can, assuming you still care about it by this point. And so on.

An online comment thread, on the other hand, is "peer review" in its purest form. The key difference is speed - replies take place in real time or close to it, which makes a genuine conversation possible. The fact that anyone on the internet can comment might not seem to be a good thing; the internet makes you stupid, after all. But the standard of comments on PLoS papers is generally very high; I don't know if this is because of a moderation policy, or just because PLoS readers are sensible folk.

A few other journals have adopted a similar commenting system, notably Nature (although apparently not other Nature group journals like Nature Neuroscience), but this is something I'd like to see all journals adopt. Ultimately, I'd like to see the boundaries between the "official" academic literature and "informal" online discussion such as blogs blurred further; PLoS seem to be leading the way in this regard too with their recently announced integration with ResearchBlogging.org although Nature also have a blog section. Exciting times.

Two Drugs Are Better Than One?

According to a study just out in the American Journal of Psychiatry, starting depressed people on two antidepressants leads to much better results than starting them on just one - Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder. But how reliable is it?

Currently accepted practice is to prescribe one antidepressant to begin with, and if the patient doesn't feel better after about 6 weeks, to either change to a different antidepressant (switching) or add a second drug while continuing the first (augmentation).

But in clinical trials and also in "real life", the proportion of depressed people who achieve "remission", meaning that they're fully or almost fully recovered, with their first antidepressant is rarely more than 1 in 3. Some antidepressants may be slightly better than others as first-line treatments, but any such differences are small.

Do two mediocre drugs combined add up to one good treatment? In this study, Blier et al. took 105 depressed people and gave them either one antidepressant or two. The one antidepressant was fluoxetine (Prozac) 20mg, and the two was mirtazapine 30mg and either fluoxetine 20mg, venlafaxine 225mg, or buproprion 150mg. The study was double-blind; patients didn't know which drug(s) they were on. There was no placebo group, however.

Mirtazapine (Remeron) is an antidepressant which is commonly used as an add-on treatment in depression, because it can be safely combined with most other drugs. So it makes sense to use mirtazapine in research like this, but take note: this study was "supported by Organon Pharmaceuticals", who make... mirtazapine.

What happened? All three combinations of two antidepressants were equally effective, and all three were considerably better than just Prozac alone, in the initial 6 week phase of the trial. The difference was massive by the standards of antidepressants - about 5 Hamilton scale points, considerably larger than the average benefit of an antidepressant over placebo.

There was also a 6 month follow-up phase to the study in which everyone who had been taking two antidepressants had one of them replaced by placebos, so everyone ended up only taking one drug (either fluoxetine or mirtazapine). Discontinuing one antidepressant seemed to cause relapse in about 40-50% of the people who were taking two, as opposed to a 25% relapse rate in the people who started on just fluoxetine and kept taking it. If you believe it, this is further evidence that two drugs are better than one, although the total sample size was just 66 for this bit, and I'm not sure I do.

What are we to make of all this? This study joins a previous one finding that mirtazapine plus paroxetine is better than either drug alone as a starting treatment. But that paper was also by Blier et al and it was "fully funded by Organon Pharmaceuticals" although apparently "The sponsor had no role in the study design, in the collection and interpretation of the data, in the preparation of this report, and in the decision to publish this manuscript".

Personally, I'm not so much troubled by the industry sponsorship in these studies as I am by the nature of the add-on treatment, mirtazapine. Mirtazapine is an unusual drug, with a pharmacological profile very different to that of most antidepressants. Notably, it's a powerful hypnotic - it makes you sleep - and it increases appetite. Patients on mirtazapine in the present study put on over 2kg in 6 weeks.

Why does this matter? Because the two scales used to rate depression in this study, the Hamilton Scale and the Montgomery-Asberg Scale, both count reduced appetite and sleeplessness as symptoms of depression. If you're on mirtazapine, you're unlikely to have either problem - you'll be more worried about the exact opposite, insatiable hunger and drowsiness. So mirtazapine could reduce your total score on these scales even if it didn't change your mood. I have no idea to what extent this is a factor in these results, but it could be important.

So, are two drugs better than one? Should antidepressants come with a side-order of mirtazapine as standard? Maybe. But it's far from proven.

Blier, P., Ward, H., Tremblay, P., Laberge, L., Hebert, C., & Bergeron, R. (2009). Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study American Journal of Psychiatry DOI: 10.1176/appi.ajp.2009.09020186

Gamma Knives Out

The Guardian covers contemporary psychosurgery - in their "Life and Style" section, believe it or not -

A radical treatment for Obsessive-compulsive disorder patients

The treatment being "gamma knife" lesions in OCD. Surgeons use a gamma knife to destroy part of the brain by aiming several beams of gamma rays at it from different angles. At the point of the target the beams overlap, and the total radiation level is intense enough to kill cells. Other parts of the brain only get hit by one beam, which is, hopefully, harmless. It's quite a clever technique, although it's not exactly brain surgery. (Sorry...)

Unlike actual surgery, the gamma knife doesn't involve cutting holes in people. This makes it safer, because any neurosurgery carries risks of infection or haemorrhage. But functionally, it's exactly the same as physically removing the tissue with a scalpel. It's hardly "non-invasive", which is what the Guardian call it (twice). Maybe technically, in the sense that it doesn't break the skin, but it does permanently destroy a substantial part of the brain. That's rather more invasive than, say, getting a tattoo, if you ask me.

Lesioning the brain to treat severe OCD has a long history. In the past couple of decades, it's been done on some dozens of patients at a few hospitals such as the Karolinska Institute in Sweden, Brown University in the US, Spain, China and South Korea.

Does it work? Some reports say that about 60% of OCD patients experience a good response others put the rate at more like 40%. So it doesn't work for everyone although given that the patients who get psychosurgery are severely ill and have not benefited from other treatments (medication and therapy), it's not so bad. But it's impossible to know how much of the improvement is a placebo effect, because there's never been a placebo controlled trial of any kind of psychosurgery for OCD, including gamma knife. This is something that the Guardian unfortunately doesn't mention.

*

Newspapers at the moment are pretty keen on neurosurgery for mental illness. Deep brain stimulation (DBS) has been getting positive coverage for years, and psychosurgery is also becoming popular nowadays. The NYT recently ran a cautious, but generally positive, piece on it.

There seems to be an unwritten rule that every such article has to include a bit reassuring us that today's psychosurgery is Not Like In One Flew Over the Cuckoo's Nest. Hence The Guardian:

The technique certainly could not be further from the brutal lobotomies made famous by Ken Kesey's novel, One Flew Over the Cuckoo's Nest. While the frontal lobotomy essentially destroys part of the brain, Gamma Knife is highly accurate and non-invasive, damaging only a minute area - 100 millimeters square - of brain tissue. It is usually done as an out-patient procedure. Some might experience a mild headache afterwards, but most report no physical problems at all.

And the NYT:

In the early days of psychosurgery doctors published scores of papers detailing how lobotomy relieved symptoms of mental distress. But careful follow-up painted a darker picture: of people who lost motivation, who developed the helpless indifference dramatized by the post-op rebel McMurphy in Ken Kesey’s novel “One Flew Over the Cuckoo’s Nest”... The newer operations pinpoint targets on specific, precisely mapped circuits, whereas the frontal lobotomy amounted to a crude slash into the brain behind the eyes, blindly mangling whatever connections and circuits were in the way.

This old bad, new good message is simplistic and misleading. The old (1930s-1940s) psychosurgery didn't consist of "blindly mangling" the brain. At least at first, it was targeted as precisely as the technology and neuroanatomy at the time allowed. And although some psychosurgeons used it in a cavalier way, there is no doubt that it often seemed to produce dramatic benefits; the contemporary testimonials of patients and their families are proof of that.

Today's surgery allows more accurate (and smaller) lesion placement, thanks to advances in stereotactic techniques and now the gamma knife. But we still have no solid understanding of the brain circuits underlying mental illness. We still don't know why destroying certain frontal white matter pathways in the brain alleviates symptoms. We still don't know why it works in some people and not others.

There's not even much agreement on which parts of the brain to hit; the most popular surgical target for OCD is the anterior limb of the internal capsule (capsulotomy) although cingulotomy has also been used, and for depression there are a handful. To say that "The newer operations pinpoint targets on specific, precisely mapped circuits" is true only in the sense that if a modern surgeon tries to destroy the anterior limb of the internal capsule, they will probably do it.

None of this means that psychosurgery doesn't work. It probably does - or rather, it certainly does, and it's probably not just a placebo. (For one thing the fact that accidental brain damage to the same regions also seems to reduce emotional distress is very promising.) But it's not so different to what was going on in the 1930s. It's still, basically, a stab in the dark.

Link: The Lobotomist and Last Resort are excellent books on the history of psychosurgery.

In the Brain, Acidity Means Anxiety

According to Mormon author and fruit grower "Dr" Robert O. Young, pretty much all diseases are caused by our bodies being too acidic. By adopting an "alkaline lifestyle" to raise your internal pH (lower pH being more acidic), you'll find that

if you maintain the saliva and the urine pH, ideally at 7.2 or above, you will never get sick. That’s right you will NEVER get sick!

Wow. Important aspects of the alkaline lifestyle include eating plenty of the right sort of fruits and vegetables, ideally ones grown by Young, and taking plenty of nutritional supplements. These don't come cheap, but when the payoff is being free of all diseases, who could complain?

Young calls his amazing theory the Alkavorian Approach™, aka the New Biology™. Almost everyone else calls it quack medicine and pseudoscience. Because it is quack medicine and pseudoscience. But a paper just published in Cell suggests an interesting role for pH in, of all things, anxiety and panic - The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior.

The authors, Ziemann et al, were interested in a protein called Acid Sensing Ion Channel 1a, ASIC1a, which as the name suggests, is acid-sensitive. Nerve cells expressing ASIC1a are activated when the fluid around them becomes more acidic.

One of the most common causes of acidosis (a fall in body pH) is carbon dioxide, CO2. Breathing is how we get rid of the CO2 produced by our bodies; if breathing is impaired, for example during suffocation, CO2 levels rise, and pH falls as CO2 is converted to carbonic acid in the bloodstream.

In previous work, Ziemann et al found that the amygdala contains lots of ASIC1a. This is intriguing, because the amygdala is a brain region believed to be involved in fear, anxiety and panic, although it has other functions as well. It's long been known that breathing air with added CO2 can trigger anxiety and panic, especially in people vulnerable to panic attacks.

What's unclear is why this happens; various biological and psychological theories have been proposed. Ziemann et al set out to test the idea that ASIC1a in the amygdala mediates anxiety caused by CO2.

In a number of experiments they showed that mice genetically engineered have no ASIC1a (knockouts) were resistant to the anxiety-causing effects of air containing 10% or 20% CO2. Also, unlike normal mice, the knockouts were happy to enter a box with high CO2 levels - normal mice hated it. Injections of a weakly acidic liquid directly into the amygdala caused anxiety in normal mice, but not in the knockouts.

Most interestingly, they found that knockout mice could be made to fear CO2 by giving them ASIC1a in the amygdala. Knockouts injected in the amygdala with a virus containing ASIC1a DNA, which caused their cells to start producing the protein, showed anxiety (freezing behaviour) when breathing CO2. But it only worked if the virus was injected into the amygdala, not nearby regions.

This is a nice series of experiments which shows convincingly that ASIC1a mediates acidosis-related anxiety, at least in mice. What's most interesting however is that it also seems to involved in other kinds of anxiety and fear. The ASIC1a knockout mice were slightly less anxious in general; injections of an alkaline solution prevented CO2-related anxiety, but also reduced anxiety caused by other scary things, such as the smell of a cat.

The authors conclude by proposing that amygdala pH might be involved in fear more generally

Thus, we speculate that when fear-evoking stimuli activate the amygdala, its pH may fall. For example, synaptic vesicles release protons, and intense neural activity is known to lower pH.

But this is, as they say, speculation. The link between CO2, pH and panic attacks seems more solid. As the authors of another recent paper put it

We propose that the shared characteristics of CO2/H+ sensing neurons overlap to a point where threatening disturbances in brain pH homeostasis, such as those produced by CO2 inhalations, elicit a primal emotion that can range from breathlessness to panic.

Ziemann, A., Allen, J., Dahdaleh, N., Drebot, I., Coryell, M., Wunsch, A., Lynch, C., Faraci, F., Howard III, M., & Welsh, M. (2009). The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior Cell, 139 (5), 1012-1021 DOI: 10.1016/j.cell.2009.10.029

That Sinking Feeling?

Sinking and Swimming is a paper just out from the Young Foundation, a British think-tank. It "explores how psychological and material needs are being met and unmet in Britain." I'm not sure how useful their broad concept of "unmet needs" is, but there's some rather interesting data in this report.

On page 238, and prominently in the executive summary, we find the following terrifying graph, which comes with warnings like "anxiety and depression looks set to double during the course of a single generation..."

The % of the population self-reporting suffering from depression or anxiety seems to have been consistently rising since 1990, from less than 6% to almost 10% today. And the line continues ever upwards. Eeek!

Is Britain really becoming more depressed and anxious? No, and that's what makes this graph terrifying. According to the large government Adult Psychiatric Morbidity Survey, the prevalence of self-reported depression and anxiety symptoms rose slightly from 1993 to 2000 (15.5% to 17.5%) and then stayed level up to 2007 (17.6%). Not very scary. Even the Young Foundation note (on page 80) that when you look at "well-being"

analysis of the English health survey that uses a variation of GHQ [General Health Questionnaire] suggested that the proportion of the working age population with poor psychological well-being decreased from 17% in 1997 to 13% in 2006.

On that measure, we're getting happier. And the rate of new diagnoses of clinical depression fell over the past decade.

So what about that ominous line? Well, that graph was based on "self-reported anxiety or depression", but in a specific sense. People were not reporting feeling scared or unhappy (see above for the data on that), but rather, reporting having anxiety or depression as medical disorders. Curiously the % of people reporting having every other sort of health problems (except with vision) increased from 1991 to 2007 as well:


What seems to be happening is that British people are becoming more willing to label our problems as medical illnesses, although in fact our mental health has not changed much over the past two decades, and may even have improved slightly. This is what's terrifying, because medicalizing emotional issues is a bad idea.

Mental illness does exist, and medicine can help treat it, but medicine can't resolve non-medical problems even if they're labelled as illnesses. Antidepressants, for example, are (imperfectly) effective for severe clinical depression but probably not for "mild depression"; much of what is labelled "mild depression" is probably not, in any meaningful sense, an illness.

Why does this matter? Drugs have side effects, and psychotherapy is expensive. The cost-benefit profile of any treatment is obviously negative when there are no benefits because the treatment is being used inappropriately. My biggest concern, though, is that if someone is unhappy because of tensions in their marriage or because they're in the wrong job, they don't need treatment, they need to do something about it. Labelling a problem as an illness and treating it medically may, in itself, make that problem harder to overcome.

[BPSDB]

Neuro4Kids Stuff

Neuroscience For Kids is a long-standing website hosted by the University of Washington and run by Dr. Eric H. Chudler.


It's extremely good, and even if you're no longer a kid you'll find it an interesting resource - I'm not ashamed to admit that I learned stuff from pages like this one on ancient Egyptian brain damage or the questions and answers section.

Anyway, Dr Chudler has just launched the Neuro4Kids.com store where you can buy brain-based items. I particularly like the Stroop effect bag (also t-shirt) and the "I misplaced my brain" late-birthday cards...

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.

[BPSDB]

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.

[BPSDB]

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