How I Read Papers

Last year I blogged about how I write blog posts. I don't really have anything to add to that, so here's some advice on how I read scientific papers - both the ones I read for my day job, and the ones I blog about.


Software: If you read papers you need PubCrawler. It's free, and it's the best thing since PubMed, because it automatically searches PubMed for you and emails you the results. Second, you need a reference manager program. I use EndNote, but there are others, including various free ones. They're indispensable.

PubCrawler sends you lists of new papers you might want to read. A reference manager lets you to keep track of what you've read, and what you need to read in future; it lets you make notes on papers (see below), search them etc. and best of all it lets you insert them into Word or whatever and automatically generates a References list. If you're not using these tools, you're making life much harder than it should be.

Deciding What To Read: There are a lot of papers out there. My PubCrawler includes a search term for "antidepressants", which nets about 10 per day; one for "autism", about 5 per day; one for various brain regions I'm interested in, up to 50 per day, another for neurotransmitters I'm into, also 50...

So you need a triage system. I mentally put papers into 3 categories, based purely on the titles:

1. Irrelevant - don't even click on it. I'd say about 80% of PubCrawler hits fall into this category.
   
2. Somewhat interesting - read the abstract. 15%.
   
3. Very interesting - read the whole thing. 5%.

Reading papers: Start with the abstract. Then read the Introduction, as it's usually a pretty good summary of previous work. I'll skip this only if I know all the existing literature (very rare). Then, head to the first paragraph of the Discussion: this typically contains a summary of the main results in non-technical language.

Finally, I'll skim the Methods and the Results. If something seems unusual, dodgy, or especially interesting, I'll go back and read these fully, but most of the time I don't bother. The remainder of the Discussion is generally just speculation, and rarely worth reading.

All that applies to original experimental articles. For review papers, if I read them at all I read them straight through; a well-written review should all be useful. A bad review is no use at all. If you start reading a review, and by the end of the first page you're wondering "But what's the point of all this?", it's probably the latter.

Making notes: This is the key to memory, for me at least. If I just read something, I barely remember it the next day let alone next month. Making notes forces you to actually understand it, and then it sticks. I make notes in EndNote for every paper, and even every abstract, I read. Once you get into the swing of it it's a natural part of reading and doesn't take much time.

Here's my notes on one recent paper:

Abstract. NRG1 --> ErbB4 promotes the formation of glutamatergic --> GABA interneuron synapses via stabilizing the PSD-95 at these synapses, but NOT at other synapses i.e. glut --> glut. Therefore, NRG1 contributes to the development of inhibitory signalling. The authors say this is interesting re: SCZ [but I think it's interesting re: autism as well!]

This makes sense, if you're me. Actually, though, I rarely ever read these notes. The point is to make them. You could scribble them on toilet paper and flush them once you're finished and they'd still do their job of boosting your memory.

Here's an uncensored extract from my notes on a paper I didn't like:

Less "medication resistant" patients did better [well that's AWESOME for a treatment that's meant to be an alternative to meds isn't it, you fuck]. They admit that the actual performance was crap NNT=12, but say it would be better if concomitant meds allowed [....well yeah either that or the effect would DISAPPEAR] and that it is equivalent to what would be expected if you gave a new drug or augmentation to this population [but you DIDN'T did you, you are referring to the literature, which is shit]. There's so many conflicts of interest it's almost tragic.

It deserved it, seriously. My comments are [in brackets], obviously.

Again - when I wrote these, I didn't expect to ever read them. The point is that by writing down my comments, I forced myself to make them coherent, and hence made myself remember them. This is crucial: if you only remember what the paper said, and not the fact that when you read it, you burst out laughing in disbelief, you'll go away thinking that the paper must have been fine.

Premature Brain Diagnosis in Japan?

Nature has a disturbing article from their Asian correspondent David Cyranoski: Thought experiment. It's open access.

In brief: a number of top Japanese psychiatrists have started offering a neuroimaging method called NIRS to their patients as a diagnostic tool. They claim that NIRS shows the neural signatures of different mental illnesses.

The technology was approved by the Japanese authorities in April 2009, and since then it's been used on at least 300 patients, who pay $160 for the privilege. However, it's not clear that it works.

To put it mildly.

*

NIRS is Near Infra-Red Spectroscopy. It measures blood flow and oxygenation in the brain. In this respect, it's much like fMRI, but whereas fMRI uses superconducting magnets and quantum wizardry to achieve this, NIRS simply shines a near-infra-red light into the head, and records the light reflected back

It's a lot cheaper and easier than MRI. However, the images it provides are a lot less detailed, and it can only image the surface of the brain. NIRS has a small but growing number of users in neuroscience research; it's especially popular in Japan, for some reason, but it's also found plenty of users elsewhere.

The clinical use of NIRS in psychiatry was pioneered by one Dr Masato Fukuda, and he's been responsible for most of the trials. So what are these trials?

As far as I can see (correct me if I'm wrong), these are all the trials comparing patients and controls that he's been an author on:

• Matsuo et al (2000) n=9/10 elderly depressed/controls
• Suto et al (2004) n=10/13/16 depressed/schizophrenia/controls
• Kameyama et al (2006) n=17/11/17 bipolar/depression/controls
• Nishimura et al (2007) n=5/33 panic disorder/controls
• Takizawa et al (2008) n=55/70 schizophrenia/controls
• Uehara et al (2007) n=11/11 eating disorder/controls
• Suda et al (2010) n=27/27 eating disorder/controls

There are also a handful of Fukuda's papers in Japanese, which I can't read, but as far as I can tell they're general discussions rather than data papers.

So we have 342 people in all. Actually, a bit less, because some of them were included in more than one study. That's still quite a lot - but there were only 5 panic patients, 30 depressed (including 9 elderly, who may be different), 38 eating disordered and just 17 bipolar in the mix.

And the bipolar people were currently feeling fine, or just a little bit down, at the time of the NIRS. There are quite a lot of other trials from other Japanese groups, but sticking with bipolar disorder as an example, no trials that I could find examined people who were currently ill. The only other two trials, both very small, were in recovered people (1,2).

Given that the whole point of diagnosis is to find out what any given patient has, when they're ill, this matters to every patient. Anyone could be psychotic, or depressed, or eating disordered, or any combination thereof.

Worse yet, in many of these studies the patients were taking medications. In the 2006 depression/bipolar paper, for example, all of the bipolars were on heavy-duty mood stabilizers, mostly lithium; plus a few antipsychotics, and lots of antidepressants. The depressed people were on antidepressants.

There's a deeper problem. Fukuda says that NIRS corresponds with the clinical diagnosis in 80% of cases. Let's assume that's true. Well, if the NIRS agrees with the clinical diagnosis, it doesn't tell us anything we didn't already know. If the NIRS disagrees, who do you trust?

I think you'd have to trust the clinician, because the clinician is the "gold standard" against which the NIRS is compared. Psychiatric diseases are defined clinically. If you had to choose between 80% gold and pure gold, it's not a hard choice.

Now NIRS could, in theory, be better than clinical diagnosis: it could provide more accurate prognosis, and more useful treatment recommendations. That would be cool. But as far as I can see there's absolutely no published evidence on that.

To find out you'd have to compare patients diagnosed with NIRS to patients diagnosed normally - or better, to those randomized to get fake placebo NIRS, like the authors of this trial from last year should have done. To my knowledge, there have been no such tests at all.

*

So what? NIRS is harmless, quick, and $160 is not a lot. Patients like it: “They want some kind of hard evidence,” [Fukuda says], especially when they have to explain absences from work. If it helps people to come to terms with their illness - no mean feat in many cases - what's the problem?

My worry is that it could mean misdiagnosing patients, and therefore mis-treating them. Here's the most disturbing bit of the article:

...when Fukuda calculates his success rates, NIRS results that match the clinical diagnosis are considered a success. If the results don’t match, Fukuda says he will ask the patient and patient’s family “repeatedly” whether they might have missed something — for example, whether a depressed patient whose NIRS examination suggests schizophrenia might have forgotten to mention that he was experiencing hallucinations.

Quite apart from the implication that the 80% success rate might be inflated, this suggests that some dubious clinical decisions might be going on. The first-line treatments for schizophrenia are quite different, and rather less pleasant, than those for depression. A lot of perfectly healthy people report "hallucinations" if you probe hard enough. "Seek, and ye shall find". So be careful what you seek for.

While NIRS is a Japanese speciality, other brain-based diagnostic or "treatment personalization" tools are being tested elsewhere. In the USA, EEG has been proposed by a number of groups. I've been rather critical of these methods, but at least they've done some trials to establish whether this actually improves patient outcomes.

In my view, all of these "diagnostic" or "predictive" tools should be subject to exactly the same tests as treatments are: double blind, randomized, sham-controlled trials.

Cyranoski, D. (2011). Neuroscience: Thought experiment Nature, 469 (7329), 148-149 DOI: 10.1038/469148a

fMRI Scanning Salmon - Seriously.

Back in 2009, a crack team of neuroscientists led by Craig Bennett (blog) famously put a dead fish into an MRI scanner and showed it some pictures.



They found some blobs of activation - when they used an inappropriately lenient statistical method. Their point, of course, was to draw attention to the fact that you really shouldn't use that method for fMRI. You can read the whole paper here. The Atlantic Salmon who heroically volunteered for the study was no more than a prop. In fact, I believe he ended up getting eaten.

But now, a Japanese team have just published a serious paper which actually used fMRI to measure brain activity in some salmon: Olfactory Responses to Natal Stream Water in Sockeye Salmon by BOLD fMRI.

How do you scan a fish? Well, like this:

A total of 6 fish were scanned. The salmon were immobilized by adding an anaesthetic (eugenol) and a muscle relaxant (gallamine) to their tank of water. Then, they were carefully clamped into place to make sure they really wouldn't move, while a stream of oxygenated water was pumped through their tank.

Apart from that, it was pretty much a routine fMRI scan.

Why would you want to scan a fish? This is where the serious science comes in. Salmon are born in rivers but they swim out to live in the ocean once they reach maturity. However, they return to the river to breed. What's amazing is that salmon will return to the same river that they were born in - even if they have to travel thousands of miles to get there.

How they manage this is unclear, but the smell (or maybe taste) of the water from their birth river has long been known to be crucial at least once they've reached the right general area (see here for a good overview). Every river contains a unique mixture of chemicals, both natural and artificial (pollutants). Salmon seem to be attracted to whatever chemicals were present in the water when they were young.

In this study, the fMRI revealed that relative to pure water, home-stream water activated a part of the salmon's telencephalon - the most "advanced" part (in humans, it constitutes the vast majority of the brain; in fish, it's tiny). By contrast, a control scent (the amino acid L-serine) did not activate this area, even though the concentration of L-serine was far higher than that of anything in the home-stream water. How this happens is unclear, but further studies of the identified telencephalon area ought to shed more light on it.

So fishMRI is clearly a fast-developing area of neuroscience. In fact, as this graph shows, it's enjoying exponential growth and, if current trends continue, could become almost as popular as scanning people...

Link: Also blogged at NeuroDojo.

Bandoh H, Kida I, & Ueda H (2011). Olfactory Responses to Natal Stream Water in Sockeye Salmon by BOLD fMRI. PloS one, 6 (1) PMID: 21264223

"Packing" Autistic Kids: A French Scandal

Back in the bad old days of autism they thought it was caused by "refrigerator mothers".


Well, right now, some psychiatrists have decided that the best treatment for autism is something not that far removed from sticking them in a refrigerator - literally. Enter "Le Packing", which is the target of an unprecedented consensus statement just out from a list of 18 big-name autism experts (available free here).

This alleged therapy consists of wrapping the patient (wearing only underclothes or naked in the case of young children) several times a week during weeks or months in towels soaked in cold water (10°C to 15°C). The individual is wrapped with blankets to help the body warm up in a process lasting 45 minutes, during which time the child or adolescent is accompanied by two to four staff persons.

The alleged goal of this technique is to “allow the child to rid him- or herself progressively of its pathological defense mechanisms against archaic anxieties,” by achieving “a greater perception and integration of the body, and a growing sense of containment.”

No, really. Frankly, they could have stopped there, because the description is condemnation enough, but they go on to write:

We have reached the consensus that practitioners and families around the world should consider this approach unethical. Furthermore, this “therapy” ignores current knowledge about autism spectrum disorders; goes against evidence-based practice...and, in our view, poses a risk of preventing these children and adolescents from accessing their basic human rights to health and education.

Le Packing, as the name suggests, originated in France, and its use seems to be confined to France and other French-speaking areas. This is the first I'd ever heard of it. Little has been written about it in English (though see this long article and this piece from 2007) so here's my loose translation of the the article on the French Wikipedia:

• Packing is used in children with autism, but also in others: psychotic adults (specifically when they're recovering from an acute psychotic episode), in the elderly, etc.
• It's intended to restore "awareness of the body image".
• It's extremely controversial. Well, duh.
• The technique was invented, in France, by a "controversial American psychiatrist" called M. A. Woodburry. It was intended for the treatment of severely autistic children and adolescents, especially those with severe behavioural problems such as self-harm, aggression, and refusal to eat.
• The patient is wrapped in towels covered in cold water: two towels for the torso, and one for each arm and leg. They're then additionally wrapped in a sheet and then blankets, over the towels. The cold water quickly warms up thanks to body heat: the child is never actually hypothermic.
• After this session, the child is "frictionné" (I guess this means massaged) and taken to their living quarters and offered a snack "in a friendly atmosphere".
• Le Packing is intended to recover a physical sense of their own body. It should be used as part of a wider package of care, and only with the consent of the patient's parents.
• The cold water is optional; some, e.g. a Dr A. Gillis, use warm water nowadays. The key point is the restraint, i.e. the fact that their attempts to move their body are restricted temporarily. Hence "le packing", huh.
  
• The scientific status of Le Packing is controversial. A group called "Léa pour Samy" say it should be banned, and replaced by the (much more orthodox) method of ABA. However, in 2007, authorities approved a randomized controlled trial led by a "Dr Goeb" of the CHU hospital in Lille.
• Critics accuse Le Packing of being an unethical, inhuman and degrading treatment, maybe even torture. There are allegations of cases in which the towels were much colder than 10°C, e.g. straight out of the freezer.
• There are also allegations of its use without parental consent. A Professor Pierre Delion, of the CHU in Lille, reportedly defended this in remarks to The Lancet "if a child is in danger following a road accident, you do not wait for the parents' agreement to give him a transfusion." But this is actually a misquote. In the Lancet piece, he was referring to the patient's consent and said parental consent was always sought.
  
• In 2009 a government minister told the French Senate that Le Packing should only be used under strictly controlled conditions according to a protocol - but others, e.g. the "Léa pour Samy" group, want it banned altogether.
  

This rather speaks for itself, but I'll say this. If someone is suffering these kinds of severe behavioural disturbances, the temptation to do something dramatic must be intense. Indeed, if someone's disturbed to the point of trying to mutilate themselves, or refusing to eat, almost by definition you're going to have to restrain them, either physically or with sedatives, temporarily. While Le Packing may be a French peculiarity, it's not like psychiatrists in other countries never resort to drastic measures.

Amaral D, Rogers SJ, Baron-Cohen S, Bourgeron T, Caffo E, Fombonne E, Fuentes J, Howlin P, Rutter M, Klin A, Volkmar F, Lord C, Minshew N, Nardocci F, Rizzolatti G, Russo S, Scifo R, & van der Gaag RJ (2011). Against le packing: a consensus statement. Journal of the American Academy of Child and Adolescent Psychiatry, 50 (2), 191-2 PMID: 21241956

When "Healthy Brains" Aren't

There's a lot of talk, much of it rather speculative, about "neuroethics" nowadays.

But there's one all too real ethical dilemma, a direct consequence of modern neuroscience, that gets very little attention. This is the problem of incidental findings on MRI scans.

An "incidental finding" is when you scan someone's brain for research purposes, and, unexpectedly, notice that something looks wrong with it. This is surprisingly common: estimates range from 2–8% of the general population. It will happen to you if you regularly use MRI or fMRI for research purposes, and when it does, it's a shock. Especially when the brain in question belongs to someone you know. Friends, family and colleagues are often the first to be recruited for MRI studies.

This is why it's vital to have a system in place for dealing with incidental findings. Any responsible MRI scanning centre will have one, and as a researcher you ought to be familiar with it. But what system is best?

Broadly speaking there are two extreme positions:

1. Research scans are not designed for diagnosis, and 99% of MRI researchers are not qualified to make a diagnosis. What looks "abnormal" to Joe Neuroscientist BSc or even Dr Bob Psychiatrist is rarely a sign of illness, and likewise they can easily miss real diseases. So, we should ignore incidental findings, pretend the scan never happened, because for all clinical purposes, it didn't.
2. You have to do whatever you can with an incidental finding. You have the scans, like it or not, and if you ignore them, you're putting lives at risk. No, they're not clinical scans, they can still detect many diseases. So all scans should be examined by a qualified neuroradiologist, and any abnormalities which are possibly pathological should be followed-up.

Neither of these extremes is very satisfactory. Ignoring incidental findings sounds nice and easy, until you actually have to do it, especially if it's your girlfriend's brain. On the other hand, to get every single scan properly checked by a neuroradiologist would be expensive and time-consuming. Also, it would effectively turn your study into a disease screening program - yet we know that screening programs can cause more harm than good, so this is not necessarily a good idea.

Most places adopt a middle-of-the-road approach. Scans aren't routinely checked by an expert, but if a researcher spots something weird, they can refer the scan to a qualified clinician to follow up. Almost always, there's no underlying disease. Even large, OMG-he-has-a-golf-ball-in-his-brain findings can be benign. But not always.

This is fine but it doesn't always work smoothly. The details are everything. Who's the go-to expert for your study, and what are their professional obligations? Are they checking your scan "in a personal capacity", or is this a formal clinical referral? What's their e-mail address? What format should you send the file in? If they're on holiday, who's the backup? At what point should you inform the volunteer about what's happening?

Like fire escapes, these things are incredibly boring, until the day when they're suddenly not.

A new paper from the University of California Irvine describes a computerized system that made it easy for researchers to refer scans to a neuroradiologist. A secure website was set up and publicized in University neuroscience community.

Suspect scans could be uploaded, in one of two common formats. They were then anonymized and automatically forwarded to the Department of Radiology for an expert opinion. Email notifications kept everyone up to date with the progress of each scan.

This seems like a very good idea, partially because of the technical advantages, but also because of the "placebo effect" - the fact that there's an electronic system in place sends the message: we're serious about this, please use this system.

Out about 5,000 research scans over 5 years, there were 27 referrals. Most were deemed benign... except one which turned out to be potentially very serious - suspected hydrocephalus, increased fluid pressure in the brain, which prompted an urgent referral to hospital for further tests.

There's no ideal solution to the problem of incidental findings, because by their very nature, research scans are kind of clinical and kind of not. But this system seems as good as any.

Cramer SC, Wu J, Hanson JA, Nouri S, Karnani D, Chuang TM, & Le V (2011). A system for addressing incidental findings in neuroimaging research. NeuroImage PMID: 21224007

Democrats vs. Dictators

What makes a government democratic?

The obvious answer is: people voted it into power. But that's completely wrong.

People voted Hitler into power. The Nazi party won by far the biggest single share of the vote in the 1932 elections, which were as "free and fair" as any in the world at that time. The next election was less free, but only thanks to a, technically constitutional, emergency Decree. Hitler's assumption of all executive and legislative powers was aided by dirty tricks, but it was pretty much above board.

The current provisional government of Tunisia has not won any elections. The overthrown dictatorship won many, though they weren't free because most opposition was banned. The current government, however, is seen as more democratic, because its role is to facilitate free and fair elections. It will then dissolve and give power to whoever wins them.

Maybe the provisional government of Tunisia isn't entirely democratic. But it's clearly more democratic than Hitler, even though Hitler won more elections.

So being elected into power has nothing to do with being a democrat or a dictator. Don't forget that. What is a democratic regime, then? I think it's this: a regime is democratic if it would peacefully hand over power were it to lose an election. If and only if you respect the people's choice to kick you out, you're a democrat. It's not about winning elections, it's about losing them.

Dictators aren't dictators because their people don't like them. It's because they're going to rule whether or not people like them. They rule: that's the basic political fact. If the people agree, great - and many are genuinely popular. If not, too bad.

What we've seen in the Ivory Coast recently, and in Zimbabwe over the past few years, is what happens when elected dictators lose elections: they don't accept it, and blood flows. If you want a soundbite: a dictator is someone who's willing to get blood on their hands, if it meant they keep a grip on power.

Retract That Seroxat?

Should a dodgy paper on antidepressants be retracted? And what's scientific retraction for, anyway?


Read all about it in a new article in the BMJ: Rules of Retraction. It's about the efforts of two academics, Jon Jureidini and Leemon McHenry. Their mission - so far unsuccesful - is to get this 2001 paper retracted: Efficacy of paroxetine in the treatment of adolescent major depression.

Jureidini is a member of Healthy Skepticism, a fantastic Australian organization that Neuroskeptic readers have encountered before. They've got lots of detail on the ill-fated "Study 329", including internal drug company documents, here.

So what's the story? Study 329 was a placebo-controlled trial of the SSRI paroxetine (Paxil, Seroxat) in 275 depressed adolescents. The paper concluded: that "Paroxetine is generally well tolerated and effective for major depression in adolescents." It was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP).

There's two issues here: whether paroxetine worked, and whether it was safe. On safety, the paper concluded that "Paroxetine was generally well tolerated...and most adverse effects were not serious." Technically true, but only because there were so many mild side effects.

In fact, 11 patients on paroxetine reported serious adverse events, including suicidal ideation or behaviour, and 7 were hospitalized. Just 2 patients in the placebo group had such events. Yet we are reassured that "Of the 11, only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment."

The drug company argue that it didn't become clear that paroxetine caused suicidal ideation in adolescents until after the paper was published. In 2002, British authorities reviewed the evidence and said that paroxetine should not be given in this age group.

That's as maybe; the fact remains that in this paper there was a strongly raised risk. However, in fairness, all that data was there in the paper, for readers to draw their own conclusions from. The paper downplays it, but the numbers are there.

*

The efficacy question is where the allegations of dodgy practices are most convincing. The paper concludes that paroxetine worked, while imipramine, an older antidepressant, didn't.

Jureidini and McHenry say that paroxetine only worked on a few of the outcomes - ways of measuring depression and how much the patients improved. On most of the outcomes, it didn't work, but the paper focusses on the ones where it did. According to the BMJ

Study 329’s results showed that paroxetine was no more effective than the placebo according to measurements of eight outcomes specified by Martin Keller, professor of psychiatry at Brown University, when he first drew up the trial.

Two of these were primary outcomes...the drug also showed no significant effect for the initial six secondary outcome measures. [it] only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used... Fifteen other new secondary outcome measures failed to throw up positive results.

Here's the worst example. In the original protocol, two "primary" endpoints were specified: the change in the total Hamilton Scale (HAMD) score, and % of patients who 'responded', defined as either an improvement of more than 50% of their starting HAMD score or a final HAMD of 8 or below.

On neither of these measures did paroxetine work better than placebo at the p=0.05 significance level. It did work if you defined 'responded' to mean only a final HAMD of 8 or below, but this was not how it was defined in the protocol. In fact, the Methods section of the paper follows the protocol faithfully. Yet in the Results section, the authors still say that:

Of the depression-related variables, paroxetine separated statistically from placebo at endpoint among four of the parameters: response (i.e., primary outcome measure)...

It may seem like a subtle point. But it's absolutely crucial. Paroxetine just did not work on either pre-defined primary outcome measure, and the paper says that it did.

Finally, there were also issues of ghostwriting. I've never been that concerned by this in itself. If the science is bad, it's bad whoever wrote it. Still, it's hardly a good thing.

*

Does any of this matter? In one sense, no. Authorities have told doctors not to use paroxetine in adolescents with depression since 2002 (in the UK) and 2003 (in the USA). So retracting this paper wouldn't change much in the real world of treatment.

But in another sense, the stakes are enormous. If this paper were retracted, it would set a precedent and send a message: this kind of p-value fishing to get positive results, is grounds for retraction.

This would be huge, because this kind of fishing is sadly very common. Retracting this paper would be saying: selective outcome reporting is a form of misconduct. So this debate is really not about Seroxat, but about science.


There are no Senates or Supreme Courts in science. However, journal editors are in a unique position to help change this. They're just about the only people (grant awarders being the others) who have the power to actually impose sanctions on scientists. They have no official power. But they have clout.

Were the JAACAP to retract this paper, which they've so far said they have no plans to do, it would go some way to making these practices unacceptable. And I think no-one can seriously disagree that they should be unacceptable, and that science and medicine would be much better off if they were. Do we want more papers like this, or do we want fewer?

So I think the question of whether to retract or not boils down to whether it's OK to punish some people "to make an example of them", even though we know of plenty of others who have done the same, or worse, and won't be punished.

My feeling is: no, it's not very fair, but we're talking about multi-billion pound companies and a list of authors whose high-flying careers are not going to crash and burn just because one paper from 10 years ago gets pulled. If this were some poor 24 year old's PhD thesis, it would be different, but these are grown-ups who can handle themselves.

So I say: retract.

Newman, M. (2010). The rules of retraction BMJ, 341 (dec07 4) DOI: 10.1136/bmj.c6985

Keller MB, et al. (2001). Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry, 40 (7), 762-72 PMID: 11437014

Psychoanalysis: So Bad It's Good?

Many of the best things in life are terrible.


We all know about the fun to be found in failure, as exemplified by Judge A Book By Its Cover and of course FailBlog. The whole genre of B-movie appreciation is based on the maxim of: so bad, it's good.

But could the same thing apply to psychotherapies?

Here's the argument. Freudian psychoanalysis is a bit silly. Freud had pretensions to scientific respectability, but never really achieved it, and with good reason. You can believe Freud, and if you do, it kind of make sense. But to anyone else, it's a bit weird. If psychoanalysis were a person, it would be the Pope.

By contrast, cognitive-behavioural therapy is eminently reasonable. It relies on straightforward empirical observations of the patient's symptoms, and on trying to change people's beliefs by rational arguments and real-life examples ("behavioural experiments"). CBT practitioners are always keen to do randomized controlled trials to provide hard evidence for their success. CBT is Richard Dawkins.

But what if the very irrationality of psychoanalysis is its strength? Mental illness is irrational. So's life, right? So maybe you need an irrational kind of therapy to deal with it.

This is almost the argument advanced by Robert Rowland Smith in a short piece In Defence of Psychoanalysis:

...The irony is that in becoming more “scientific”, CBT becomes less therapeutic. Now, Freud himself liked to be thought of as a scientist (he began his career in neurology, working on the spinal ganglia), but it’s the non-scientific features that make psychoanalysis the more, not the less, powerful.

I’m referring to the therapeutic relationship itself. Although like psychoanalysis largely a talking cure, CBT prefers to set aside the emotions in play between doctor and patient. Psychoanalysis does the reverse. To the annoyance no doubt of many a psychoanalytic patient, the very interaction between the two becomes the subject-matter of the therapy.

The respected therapist and writer Irvin Yalom, among others, argues that depression and associated forms of sadness stem from an inability to make good contact with others. Relationships are fundamental to happiness. And so a science that has the courage to include the doctor’s relationship with the patient within the treatment itself, and to work with it, is a science already modelling the solution it prescribes. What psychoanalysis loses in scientific stature, it gains in humanity.

Rowland Smith's argument is that psychoanalysis offers a genuine therapeutic relationship complete with transference and countertransference, while CBT doesn't. He also suggests that analysis is able to offer this relationship precisely because it's unscientific.

Human relationships aren't built on rational, scientific foundations. They can be based on lots of stuff, but reason and evidence ain't high on the list. Someone who agrees with you on everything, or helps you to discover things, is a colleague, but not yet a friend unless you also get along with them personally. Working too closely together on some technical problem can indeed prevent friendships forming, because you never have time to get to know each other personally.

Maybe CBT is just too sensible: too good at making therapists and patients into colleagues in the therapeutic process. It provides the therapist with a powerful tool for understanding and treating the patient's symptoms, at least on a surface level, and involving the patient in that process. But could this very rationality make a truly human relationship impossible?

I'm not convinced. For one thing, there can be no guarantee that psychoanalysis does generate a genuine relationship in any particular case. But you might say that you can never guarantee that, so that's a general problem with all such therapy.

More seriously, psychoanalysis still tries to be scientific, or at least technical, in that it makes use of a specialist vocabulary and ideas ultimately derived from Sigmund Freud. Few psychoanalysts today agree with Freud on everything, but, by definition, they agree with him on some things. That's why they're called "psychoanalysts".

But if psychoanalysis works because of the therapeutic relationship, despite, or even because, Freud was wrong about most things... why not just chat about the patient's problems with the minimum of theoretical baggage? Broadly speaking, counselling is just that. Rowland Smith makes an interesting point, but it's far from clear that it's an argument for psychoanalysis per se.

Note: A truncated version of this post briefly appeared earlier because I was a wrong-button-clicking klutz this morning. Please ignore that if you saw it.

Autistic Children In The Media

Emory University's Jennifer Sarrett offers an interesting although sadly brief analysis of the way in which autism is treated in the mass media: Trapped Children.

She examines media depictions of children with autism, first in the 1960s, and then today. In those 40 years, professionals radically changed their minds about autism: in the 60s, a lot of people thought it was caused by emotionally distant refrigerator mothers; nowadays, we think it's a neural wiring disorder caused by deleted genes.

Yet, she says, while theories about the causes have changed, the media's view of what autism is hasn't, and assumptions from the 60s are still around (even amongst professionals). She identifies two enduring themes:

Fragmentation. The child with autism is somehow not a whole person; they are fundamentally "broken". And the family with an autistic child is emotionally shattered, too. In the 60s, the theory was that the broken family caused the autism. Nowadays, it's the other way round: having an autistic child stresses family relationships to breaking-point.

Imprisonment. The child with autism is at heart "normal", but their autism has them trapped, blocked-off from the world. Bruno Bettelheim, a leading champion of the refrigerator mother theory, called his major book The Empty Fortress. Either professionals, or parents, need to "break through" the autism to contact the "real" child imprisoned by the disorder. Likewise, this real child is eager to get out, but this is very difficult: they are crying out for help. In the 60s, it was psychoanalysis that could free the child. Today, it's anything from Prozac to chelation and other quack "biomedical" cures.

The problem with these kinds of articles is that you can really make up any themes you want, and find examples to fit. That doesn't mean it's a pointless exercise, it just means that the examples can't prove the analysis right. You need to ask yourself: does this, in general, ring true?

Sarrett's analysis does ring true for me, especially the theme of imprisonment, which is almost never made explicit, but it seems to lurk in the background of a lot of modern thought about autism. The autistic isn't really autistic. Their autism is something external - if only we could reach the normal child underneath! Every attempt to "cure" or "rescue" the autistic child relies on this belief.

I said that this paper is sadly brief. There's so much more to say on this topic; in particular, we need to compare representations of autism to those of other developmental disorders like Down's syndrome, in order to work out what's specific to autism as opposed to just general "disability" or "disorder".

However, I think if you did this, you'd probably end up agreeing with the paper. I can't remember Down's syndrome being portrayed as a kind of self-fragmentation or imprisonment; this article seems quite typical.

Sarrett recommends accounts by authors who have autism themselves for an alternative and more valid view of autism: people like Temple Grandin and Daniel Tammet:

autistic voices can promote a much needed faithfulness and tolerance to future representations of autism and those diagnosed with autism.

Although she admits that these authors only speak for a subset of those with "high-functioning" autism or Asperger's, and that

there remains a population of people with autism who are not writing, speaking and reading, making the representations advanced by these narratives subject to questions about generalizability.

Sarrett JC (2011). Trapped Children: Popular Images of Children with Autism in the 1960s and 2000s. The Journal of medical humanities PMID: 21225325

Two Blogs and a Public Service Announcement

First up, here are two new(ish) blogs which have been consistently excellent since I started reading them:

• Neurobonkers (see e.g. this post)
  
• Psych Gripe (e.g. this post)

Second, an announcement: Blogger has a spam filter for comments.

It's rubbish.

It seems to think that any comment containing more than one hyperlink is spam. Actually, all the spam I get contains one link, and hence makes it through, while the real comments with multiple links, which are usually interesting and sensible, get blocked. A Mr. "Generic Viagra" (no really) can leave 20 comments in 5 minutes with impunity, but more than one link, and you're out.

I would love to turn it off, but you can't. Thanks Google. My comment policy is, as it's always been, that all comments except spam are welcome. So if your comment hasn't appeared, it's not that I've deleted it, it's the spam filter.

I check the spam folder as often as I can, and allow the proper comments through, but you might want to avoid comments with more than one link. Maybe split them into multiple comments. It's not ideal but, as I said, it's not my filter.

A Brief Guide to Being Shot in the Head

You know what this is about. I don't have anything especially useful to say about the recent tragedy, or the question of crazy vs. political: at this stage, it's all speculation. Let's wait for the trial.
But anyway, the incredible thing is that Rep. Gabrielle Giffords survived a bullet to the head. How?

One of the amazing things about the brain is that almost all of it is unnecessary. The bullet passed through Gifford's left cerebral cortex, various parts of which are responsible for moving the right side of the body, seeing and hearing things from the right, and, in most people, language. But the only part of the brain which you actually need in order to live is the brainstem, which forms the top of the spinal cord.

The main reason you need your brainstem is that it controls breathing. It also controls your heart rate and blood pressure, but your heart pumps itself, without any input from the brain: the brain just does the fine tuning. Breathing, however, is controlled directly by several brainstem nuclei, and if you stop breathing, your blood will run out of oxygen and you'll die (without artificial ventilation.)

Damage to any other part of the brain is survivable. Of course, you might just bleed to death from the head injury, or get an infection; there's also the risk of brain swelling which can be fatal by compressing the brainstem (amongst other problems). This is why doctors have removed a large part of Gifford's skull, to give the brain room.

But the brainstem can do a surprising amount on its own. In the early days of neuroscience, there was a bit of a fad for decerebrating animals, essentially removing everything except the brainstem. These animals were still "alive", at least in the sense that they weren't corpses; decerebrate cats can walk and run.

They don't walk to anywhere, but this shows that the spinal cord and brainstem can control movement and respond to sensory feedback. It's even on YouTube. The famous headless chicken that lived for over a year - that really happened, it's no myth - is another such case.

Fat Genes Make You Happy?

Does being heavier make you happier?

An interesting new paper from a British/Danish collaboration uses a clever trick based on genetics to untangle the messy correlation between obesity and mental health.

They had a huge (53,221) sample of people from Copenhagen, Denmark. It measured people's height and weight to calculate their BMI, and asked them some simple questions about their mood, such as "Do you often feel nervous or stressed?"

Many previous studies have found that being overweight is correlated with poor mental health, or at least with unhappiness ("psychological distress"). And this was exactly what the authors found in this study, as well.

Being very underweight was also correlated with distress; perhaps these were people with eating disorders or serious medical illnesses. But if you set those small number of people aside, there was a nice linear correlation between BMI and unhappiness. When they controlled for various other variables like income, age, and smoking, the effect of BMI became smaller but it was still significant.

But that's just a correlation, and as we all know, "correlation doesn't imply causation". Actually, it does; something must be causing the correlation, it didn't just magically appear out of nowhere. The point is that shouldn't make simplistic assumptions about what the causal direction is.

It would be easy to make these assumptions. Maybe being miserable makes you fat, due to comfort eating. Or maybe being fat makes you miserable, because overweight is considered bad in our society. Or both. Or neither. We don't know.

Finding this kind of correlation and then speculating about it is where a lot of papers finish, but for these authors, it was just the start. They genotyped everyone for two different genetic variants known, from lots of earlier work, to consistently affect body weight (FTO rs9939609 and MC4R rs17782313).

They confirmed that they were indeed associated with BMI; no surprise there. But here's the surprising bit: the "fat" variants of each gene were associated with less psychological distress. The effects were very modest, but then again, their effects on weight are small too (see the graph above; the effects are in terms of z scores and anything below 0.3 is considered "small".)

The picture was very similar for the other gene.

This allows us to narrow down the possibilities about causation. Being depressed clearly can't change your genotype. Nothing short of falling into a nuclear reactor can change your genotype. It also seems unlikely that genotype was correlated with something else which protects against depression. That's not impossible; it's the problem of population stratification, and it's a serious issue with multi-ethnic samples, but this paper only included white Danish people.

So the author's conclusion is that being slightly heavier causes you to be slightly happier, even though overall, weight is strongly correlated with being less happy. This seems paradoxical, but that's what the data show.

That conclusion would fall apart, though, if these genes directly effect mood, and also, separately, make you fatter. The authors argue that this is unlikely, but I wonder. Both FTO and MC4R are active in the brain: they influence weight by making you eat more. If they can affect appetite, they might also affect mood. A quick PubMed search only turns up a couple of rather speculative papers about MC4R and its possible links to mood, so there's no direct evidence for this, but we can't rule it out.

But this paper is still an innovative and interesting attempt to use genetics to help get beneath the surface of complex correlations. It doesn't explain the observed correlation between BMI and unhappiness - it actually makes it more mysterious. But that's a whole lot better than just speculating about it.

Lawlor DA, Harbord RM, Tybjaerg-Hansen A, Palmer TM, Zacho J, Benn M, Timpson NJ, Smith GD, & Nordestgaard BG (2011). Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults. Journal of internal medicine PMID: 21210875

The Wheel of Peer Review

In the spirit of the 9 Circles of Scientific Hell, and inspired by the evidence showing that scientific peer reviewers agree only slightly more often than they would by chance, here's a handy tool for randomly generating your review.

Feel free to print it out and throw darts at it, or maybe make a roulette wheel kind of thing, or perhaps a ouija board. It seems to be in widespread use already, so there must be an easy way to use it.


1. The Power of Love: You love this paper! Well, you love the author. Maybe it's a romantic thing, maybe they once saved your ass by lending you their expertise/equipment/data, or maybe they bought you a drink once at a conference. Either way, they're awesome, so their paper must be fine.

2. Bee-in-your-Bonnet: You don't really care about this paper, but you do care, very strongly, about something else which is vaguely related. Many say that you're obsessed by it, though not to your face, because that would start you off talking about it. The problem with this paper is that it doesn't cover your pet idea. If the authors want it published, they'll need to change that, pronto. Major revisions are called for.

3. The Pedant: The paper is atrocious and doesn't deserve to be written on a scrap of toilet paper let alone submitted to this great Journal... in terms of spelling and formatting. Scientifically, you think it's probably pretty good, but it was hard to tell because of the amount of red ink you put all over it. English isn't the author's first language? That's their problem. Isn't that what "minor corrections" are for? No! That's what the bin is for.

4. Cite Me, Me, Me!: The problem with this paper is that it doesn't reference the right previous work... yours. Unless the authors change it to cite everything you've written in the past 10 years, they can get lost. If they do, the paper will be immediately accepted - to reject it would harm your citation count.

5. The Tortoise: You'll review this paper when you get back from holiday. And finished writing your own paper. After that conference. When you've finished your teaching for the year. Maybe. Until you submit your review, the authors are stuck in a horrible limbo, but luckily you're anonymous so they won't know who to send hate mail to.

6. The Cheerleader: This paper is awesome because it supports something that you yourself are about to publish. It's full of methodological holes? Never mind, that will only make your paper better by comparison. It's barely readable? Suggest edits to make it just about comprehensible so people can tell how well it supports you. Then accept a.s.a.p.

7. Wrong End of the Stick: You think you understand this paper, but actually you don't. So your review completely misses the point. When the authors point this out, you have two options: a) blame the paper for being confusing, and chuck it out or b) decide the whole thing is much too complicated to spend time over, and accept it.

8. The Perfect Reviewer: You are an intelligent, informed expert, new enough to the field that you have no axe to grind, and you take the time to read the paper fully, and return a constructive, perceptive review within a couple of weeks. Well done. Unfortunately, there are 1 or 2 other reviewers, and there's only a 1 in 8 chance they'll be like you...

Antidepressants Still Don't Work In Mild Depression

A new paper has added to the growing ranks of studies finding that antidepressant drugs don't work in people with milder forms of depression: Efficacy of antidepressants and benzodiazepines in minor depression.


It's in the British Journal of Psychiatry and it's a meta-analysis of 6 randomized controlled trials on three different drugs. Antidepressants were no better than placebo in patients with "minor depressive disorder", which is like the better-known Major Depressive Disorder but... well, not as major, because you only need to have 2 symptoms instead of 5 from this list.

They also wanted to find out whether benzodiazepines (like Valium) worked in these people, but there just weren't any good studies out there.

The results look solid, and they fit with the fact that antidepressants don't work in people diagnosed with "major" depression, but who fall at the "milder" end of that range, something which several recent studies have shown. Neuroskeptic readers will, if they've been paying attention, find this entirely unsurprising.

But in fact, it's not just not news, it's positively ancient. 50 years ago, at the dawn of the antidepressant era, it was commonly said that most antidepressants don't work in everyone with "depression", they work best in people with endogenous depression, and less well, or not at all, in those with "neurotic" or "reactive" depressions (see, e.g. 1, 2, 3, but the literature goes back even further).

"Endogenous" is not strictly the same as "severe", however, in practice, these two concepts have never really been clearly seperated, and they're largely equivalent today, because the leading measure of "severity", the Hamilton Scale, measures symptoms, and arguably these symptoms are mostly (though not entirely) the symptoms of the old concept of endogenous depression. The Hamilton Scale was formulated in 1960 when modern concepts of "minor depressive disorder" and "major depressive disorder" were unknown.

Why then are we only now working out that antidepressants only work in some people? There's one obvious answer: Prozac, which arrived in 1987. Before Prozac, antidepressants were serious stuff. They could easily kill you in overdose, and they had a lot of side effects. Many of them even meant that you couldn't eat cheese. As a result, they weren't used lightly.

Prozac and the other SSRIs changed the game completely. They're much less toxic, the side effects are milder, and you can eat as much cheese as you want. So it's very easy to prescribe an SSRI - maybe it won't work, but it can't hurt, so why not try it...?

As a result, I think, the concept of "depression" broadened. Before Prozac, depression was inherently serious, because the treatments were serious. After Prozac, it didn't have to be. Drug company marketing no doubt helped this process along, but marketing has to have something to work with. Over the past 25 years, terms like "endogenous", "neurotic" etc. largely disappeared from the literature, replaced by the single construct of "Major Depression".

For nearly 1,000 years, the great scientific and philosophical work of the ancient Greeks and Romans were lost to Europeans. Only when Christian scholars rediscovered them in the libraries of the Islamic world did Europe begin to remember what it had forgotten. We call those the Dark Ages. Will the past 25 years be remembered as psychiatry's Dark Age?

Barbui, C., Cipriani, A., Patel, V., Ayuso-Mateos, J., & van Ommeren, M. (2011). Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis The British Journal of Psychiatry, 198 (1), 11-16 DOI: 10.1192/bjp.bp.109.076448

A Grand Unified Theory of Autism?

A physicist famously wanted to find the grand unifying equation behind the laws of nature, in a form that you could put on a t-shirt.


Neuroscientists Kamilla and Henry Markram have proposed a grand unifying theory of autism, and the key to it is in this picture. I wouldn't want to be seen wearing it quite yet, but if the theory pans out, I'm sure we could come up with a more torso-friendly diagram.

So what does this mean? The Markrams call their idea the Intense World Theory. Essentially, they propose that all of the diverse symptoms of autism are direct or indirect consequences of the autistic brain's being hyper-responsive to stimuli. (They published an earlier version of this theory in 2007).

Not the brain as a whole, and not each individual cell, either. Rather, they say that the abnormality lies in local microcircuits. The best known of these are the cortical columns and minicolumns. Neurons in any given microcircuit are connected both with their neighbors, and with more distant cells. A bit like a large company with offices in different cities: people within each office talk to each other, but they also phone and email the other branches.

The theory goes that the autistic brain has too many connections within any given microcircuit. So, when the circuit is activated, it reactivates itself too strongly, and shows a stronger, and longer, excitation. A bit like if the offices were open-plan, so everyone can overhear everyone else, and it all gets very noisy.

So what's the evidence for this? There's circumstantial support. It "makes sense", if you're willing to accept an analogy between hyperactive local neural circuits and hyper-intense psychological phenomena.

We know that a given cortical minicolumn responds to a particular type of stimulus, or aspect of a stimulus; there are minicolumns for horizontal lines, for lines at 10 degrees to the horizontal, and so on. People with autism are often fixated on little details. It's a leap, but not an impossible one, to see these as related.

But the only really direct biological evidence is from rats. The story starts with valproate (VPA), an effective anticonvulsant also widely used in bipolar disorder. VPA has to be used with extreme caution in women because of the risk of birth defects.

Children whose mothers take VPA (and to various degrees other similar drugs) during pregnancy often suffer various physical and behavioural problems, the fetal anticonvulsant syndrome. Sadly, this happened quite a lot in the past, before the risks were appreciated. The key point is that autistic symptoms extremely common in children exposed to high-dose VPA.

Markram (and other people) have studied rats exposed to valproate in the womb. They found that, well, they're weird. Proponents would say that they behave a lot like how an "autistic" rat would: they are less sociable, prone to repetitive behaviours, highly anxious, etc.

Can a rat "have autism"? That's one to ponder. On the one hand, rats are surprisingly smart, sociable animals. For every human brain region, there's a rat equivalent in roughly the same place, which does roughly the same thing. They have cortical columns and minicolumns like ours (we just have more of them). They even "laugh" when you tickle them. On the other hand... they're rats. They run around gutters eating trash.

The t-shirt image at the top of this post is based on Markram and colleagues work on the cortical network properties of VPA-exposed rats (e.g. this and several other studies). These studies revealed hyper-connectivity within local microcircuits, and have also shown that circuits from VPA-exposed rats "learn" faster: they form new synaptic connections via the process of LTP at an accelerated rate, likely due to over-expression of NMDA glutamate receptors.

They admit that it's a big leap from that to human autism. But it's not an impossible leap. As they say:

This provided the potential cellular and circuit explanation for how an autistic brain could be easily trapped in a painfully intense world, potentially explaining a broad range of common autistic symptoms such as sensory sensitivity, withdrawal, repetitive behavior, idiosyncrasies, and even exceptional talents.

The major attraction of the theory is that it is a unified one: it seems to explain everything about autism, although maybe it's just vague enough to be stretched to cover anything. For example, Markram attributes the social awkwardness of autistic people to an overactive amygdala, which makes them extremely anxious in social situations, especially when meeting people's gaze; this, he says, means that they quickly learn to avoid other people in an attempt to cope with this Intense World.

Henry Markram is best known as the leader of the Blue Brain Project, which aims to simulate a brain using supercomputers. So he's no stranger to big ideas. Whether this idea is as solid as it is big remains to be seen, but I think he's to be applauded for at least having a crack at a unified account of autism, something which, as far as I know, no-one else has had the guts to try yet (Edit: But see the comments for a debate on that question)...

Markram K, & Markram H (2010). The intense world theory - a unifying theory of the neurobiology of autism. Frontiers in human neuroscience, 4 PMID: 21191475