Neuroskeptic

Voodoo Neuroscience Revisited

2012-01-31T08:29:00.001Z

Two years ago, neuroscientists were shaken by the appearance of a draft paper showing that half of the published work in a particular field had fallen prey to a major statistical error.

Originally called "Voodoo Correlations in Social Neuroscience", it ended up with the less snappy name of Puzzlingly high correlations in fMRI studies of emotion, personality, and social cognition. I prefer the old title.

The error in question is now known variously as the "circular analysis problem", "non-independence problem" or "double-dipping" although I still call it the "voodoo problem". In a nutshell it arises whenever you take a large set of data, search for data points which are statistically significantly different from some baseline (null hypothesis), and then go on to perform further statistics only on those significant data points.

The problem is that when you picked out the statistically significant observations, you selected the data points that were especially "good", so if you then do some more analyses only on those data, you are almost guaranteed to find something "good". To avoid this you need to make sure that your second analysis is truly independent of your first one.

Anyway, Vul and Pashler, the main authors of the original voodoo article, have just written a short piece in NeuroImage offering some reflections on the paper and the aftermath. They don't make any major new arguments but it's a good read. Particularly fun is their explanation of what inspired them to look into the voodoo problem:

In early 2005 a speaker in our department reported that BOLD activity in a small region of the brain can account for the great majority of the variance in speed with which subjects walk out of the experiment several hours later (this ﬁnding was never published as far as we know). The implications of this result struck us as puzzling, to say the least: Are walking speeds really so reliable that most of their variability can be predicted? Does a focal cortical region determine walking speeds? Are walking speeds largely predetermined hours in advance? These implications all struck us as far-fetched...

But they reveal that it was one paper in particular that set them off voodoo-hunting

Our interest in probing the matter was further whetted by an episode occurring a short while later: Grill-Spector et al. (2006) reported that individual voxels in face selective regions have a variety of stable stimulus preferences; in a critical commentary, Baker et al. (2007) found that the analysis used to ascertain this fact implicitly built these conclusions into the method, such that the same analysis applied to noise data (voxels from the nasal cavity) revealed a similar variety of stable preferences. It occurred to us that a similar circularity might underlie the puzzlingly high correlations.

To their credit, Grill-Spector et al quickly accepted Baker et al's criticism and admitted that some of their original conclusions had been wrong.

Vul, E., and Pashler, H. (2012). Voodoo and circularity errors NeuroImage DOI: 10.1016/j.neuroimage.2012.01.027

The Wriggling Brain

2012-01-28T17:03:00.002Z

What do we mean when we talk about "the brain"?

Easy, right? It's this:

Certainly, this is the image that comes to my mind.

But this is not an image of a brain. It's an image of a dead brain.

In a living brain, all kinds of interesting things are happening. Things we literally can't begin to imagine. Because these are hard to visualize, they can't enter the mental picture.

To picture the living brain as just a yellowy lump is like picturing Wikipedia as a disc. It's accurate as far as it goes, but it misses the whole point. You could download Wikipedia onto a BluRay disc, and then you could describe that disc as "Wikipedia" and you wouldn't be wrong, but Wikipedia is much more than a silver circle.

It doesn't help much that we know that there's more to the living brain than a yellowy lump. Yes, most of us know that the living brain is somehow responsible for thought, feeling, perception, and consciousness.

But we have no idea of how it does so, we don't have any feel for this relationship. We agree with the idea that brain = mind, but that's just an abstract equation. Just as most of us know that e=mc2, but only physicists understand it.

All this leads to philosophical problems. Wittgenstein wrote:

Look at a stone and imagine it having sensations. - One says to oneself: How could one so much as get the idea of ascribing a sensation to a thing? One might as well ascribe it to a number! - And now look at a wriggling fly and at once these difficulties vanish and pain seems able to get a foothold here.

What he meant is that we only feel that we can ascribe pain (or any "internal" mental state or event) to something which is behaving "externally".

Now in most cases, that's fine. Most inanimate objects really don't have mental states. But brains do. The brain, we feel, is inanimate; it's just a yellowy lump. By itself the brain is like Wittgenstein's stone - it seems.

So, we feel, the brain itself can't really have mental states, only walking, talking, behaving people can, like wriggling flies. Except we know on an abstract level that brains do have mental states; so we tie ourselves into philosophical knots about "brains" and "persons", asking whether a person is more or less or the same as a brain, and so on.

The whole problem could be removed, I think, if instead of a yellowy lump, we could picture the living brain in all its active complexity; if we could talk about "the brain", not as an inanimate object, but as the most animate thing in the world.

In the brain there are hundreds of billions of cells, and each one is a hive of movement - not visible to the naked eye or even to a microscope, but the movement of ions and neurotransmitters and ultimately information.

I think many philosophical puzzles would lose their edge if we could somehow get a feel for all that; if we could replace the accurate, but misleading, yellowy lump picture of "the brain" with one that captures the complexity and dynamism of the thing: a city, a hive of insects, a vast machine.

Take Your Placebos, Or Die

2012-01-26T08:02:00.002Z

People who take their medication as directed are less likely to die - even when that "medication" is just a sugar pill.

This is the surprising finding of a paper just published, Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST).

BEST was a clinical trial of beta blockers, drugs used in certain kinds of heart disease. The patients were aged about 60 and they all suffered from heart failure. Everyone was randomly assigned to get a beta blocker or placebo, then followed up for 3 years to see how they did.

Here's the big finding: in the placebo group of 1174 patients, the people who took all of their placebo pills on time (the good adherers), were significantly less likely to die than the patients who missed lots of doses. People who took over 75% as directed were 40% less likely to die than those with less than 75% adherence:

That's pretty interesting. The pills were placebos - they can't have had any benefit. So what's going on?

It gets even better. You might be tempted to write off these results as obvious: "Clearly, people who follow the study instructions are just 'healthy' people in other ways - maybe they take more exercise, eat better, etc. and that's what protects them."

Certainly, that's what I'd have said.

But what's remarkable is that when the authors corrected the statistics for all the confounding variables they measured - including things like age, gender, ethnicity, smoking, body mass index and blood pressure - it barely changed the effect. Some of the factors did correlate with adherence, but not in a way that it could explain the adherence effect on mortality.

This isn't the first study to find this effect. The authors themselves have already reported it, as have other researchers going back decades (many of which also tried, and failed, to explain it through confounding factors.) They say that it's unlikely to be a case of publication bias.

So what we have is a large effect, which cannot be causal, yet which can't be explained by any obvious confounds. Logically then, it must be the result of a confound (or more than one) that aren't obvious.

This is an important lesson. It's common for someone to do a study and find an interesting / scary / controversial correlation between two things. Often one is some kind of lifestyle factor, diet, environmental exposure, or whatever, and the other is some nasty disease. "And it wasn't explained by confounds!", such studies often conclude.

What the placebo adherence effect demonstrates is that there may be confounds no-one has thought of. They might even be impossible to measure. And if these mystery confounds can literally kill you, they can probably cause all kinds of other effects too.

In other words this illustrates the truism that correlation is not causation - not even when you're really sure it is...

Pressman, A., Avins, A., Neuhaus, J., Ackerson, L., and Rudd, P. (2012). Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST) Contemporary Clinical Trials DOI: 10.1016/j.cct.2011.12.003

The Hidden Face Within

2012-01-25T08:59:00.001Z

One of these two images contains a hidden picture of a face. Which one?

This was the question faced by participants in a remarkable psychology experiment just published, Measuring Internal Representations from Behavioral and Brain Data.

Five healthy volunteers were presented with a series of random black and white grid patterns. Each grid square was either black or white, and this was randomly determined on each trial.

There was no pattern to the images, they were completely random. But the subjects were told that half of the patterns contained a hidden face, and that their job was to work out which ones did. Each subject saw over 10,000 random images and they took about 1 second to judge each one.

The volunteers "detected" a face in 44% of the images. Somehow, all five of them convinced themselves that they were seeing faces in many of the grids. The authors say that

Upon completion of the experiment we debriefed observers, and all expressed shock that no face was ever presented.

That's strange enough in itself, but here's the really clever bit. The authors compared the patterns which were declared to contain a face, to the ones that were reported as empty. The image below shows the average "face" grid, minus the average "non face" grid, for each individual subject:

As you can see, this reveals...a face! Kind of. The top half shows the raw average; the bottom half shows the statistically significant differences from random noise.

In Subjects 1 and 2, the face is pretty clear, with eyes, a nose and a mouth. For 3 and 4, it's less coherent, but you might be able to see it if you look hard enough. For Subject 5, not really.

What this means is that people (at least, most of them) were not just seeing faces in any noise. They tended to see faces when the random patterns happened to resemble a kind of primitive face, but it was a different face for each person. The authors say that these strange faces correspond to the individual's internal representations, or models, of "a face", that each subject was "seeing" in the noise.

Finally, the whole experiment was conducted while EEG data was being recorded from the participant's brains. The EEG results revealed that there was a clear difference in the neural activity associated with "face" compared to "nonface" stimuli - except in Subject 5, who you'll remember had the least coherent "internal face".

What's exciting about this approach is that it investigates perception in a purely "top down" way. Normally, when we look at anything, what we end up perceiving is a product of "bottom up" influences - the raw data - and "top down" ones - what we expect to see. In this experiment, there was no real "bottom up" data; it was all "top down".

This is a form of pareidolia - perceiving familiar things in random stimuli. Seeing the face of Jesus in your sock, that kind of thing. It works for sounds too: in the famous White Christmas Experiment, people report "hearing" music in pure white noise - when told to expect it. Real-life examples of this include the "Islam Is The Light" doll, and my personal favorite, the singing paedophile Christmas mouse.

Finally, I wonder what embodied cognition theorists make of this paper. Because this paper claims to be "Measuring Internal Representations from Behavioral and Brain Data"; embodied cognition (at least the radical kind) is the theory that "internal representations" either don't exist, or at least don't explain anything about human cognition.

Smith, M., Gosselin, F., and Schyns, P. (2012). Measuring Internal Representations from Behavioral and Brain Data Current Biology DOI: 10.1016/j.cub.2011.11.061

The Trojan Horses of Medicine

2012-01-21T17:23:00.003Z

Dodgy science is being smuggled into medical journals thanks to a loophole in the regulations, say Italian psychiatrists Barbui and Cipriani in an important article.

They focus on agomelatine, a recently-approved antidepressant. But their point applies to all of medicine, not just psychiatry.

Here's the problem. Nowadays, major medical journals have rules governing systematic reviews and meta-analyses of clinical trial data. If you want to review the evidence about how well a certain drug works, or its safety, you've got to do it properly. You have to consider all of the data, not just focus on the results that suit you. And so on.

However, these rules don't apply to "narrative" review papers, which is a broad term meaning any kind of article meant to give a discussion of the pharmacology, history, chemistry etc. behind a particular drug. For a narrative review, there are no rules.

In particular, you can write about the clinical trial data in such articles with no restrictions. Unlike in a proper systematic review, you can cherry-pick trials and so on to your heart's content. Some narrative reviews have so much clinical data in them that they end up being, in effect, a bad systematic review. One that would never have been deemed acceptable as a systematic review.

Barbui and Cipriani argue that narrative reviews are often used in this way, namely to paint drugs in a positive light. In the case of agomelatine, they mention a number of recent narrative reviews which were supposedly about the drug's mechanism of action, but which actually contained extensive (but biased) reviews of the clinical trial data.

It's not hard to see how pharmaceutical companies might take advantage of this process.

However, the problem is surely not limited to agomelatine. It's a loophole that affects every branch of medicine:

Most medical journals require adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). It is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses. Adherence to PRISMA is not required in review articles dealing with basic science issues as these articles are not focused on clinical trials.

In practice, however, the agomelatine case indicates that clinical data are regularly included and reviewed with no reference to the rigorous requirements of the PRISMA approach. These articles have this way became a modern Trojan horse for reintroducing the brave old world of narrative-based medicine into medical journals.

How do we stop this? It's simple, the authors say: just make all references to clinical data subject to PRISMA, or other accepted regulations, whatever the supposed 'primary focus' of the paper:

We argue that medical journals should urgently apply this higher standard of reporting, which is already available, easy to implement and inexpensive, to any form of clinical data presentation.

Of course, there are plenty of good narrative reviews that really do cover the pharmacology or other science in a useful way. The problem is not narrative reviews as such, but the way they're used.

Barbui, C., and Cipriani, A. (2012). Agomelatine and the brave old world of narrative-based medicine Evidence-Based Mental Health, 15 (1), 2-3 DOI: 10.1136/ebmh.2011.100485

The Age (Cohort) of Autism

2012-01-20T18:31:00.006Z

New data shed light on the recent mysterious rise in the number of kids being diagnosed with autism.

The new research doesn't explain the increase, but it tells us more about it. It shows that the rise in Californian autism diagnoses (reported to the state DDS) over the period 1996 to 2005 was a cohort effect, meaning that the rates of diagnosis have got higher, the later a child was born.

A child who's 10 today (born 2002) has double of the chance of having a recorded diagnosis compared to a 14-year-old born just four years earlier, in 1998.

"That doesn't tell us anything new!" you might object (I did at first). "All that means is that rates have risen, and we knew that already". But actually it does tell us something important. Because the data could have turned out differently; rates could have risen without a cohort effect, if, in recent years, lots of diagnoses were being handed to children regardless of their age.

That didn't happen. Almost all children in California who get a diagnosis, get it at age 3 or 4. In more recent years, the average age at diagnosis actually fell slightly. The peak used to be age 4, it's now 3.

So it's not that children in general have been getting diagnosed with autism more. It's that young children are getting diagnosed more; children aren't being diagnosed "retrospectively", as it were.

Another interesting finding is that the rise in rates of 'high-functioning' autism has been much bigger than the rise in low-functioning autism (i.e. autism alongside intellectual disability), although that has risen as well. Edit: but note that their defintion of 'functioning' is rather unique; see the comments.

So what does this mean?

These data are consistent with various interpretations. It could be that rates of autism have really risen in California over this time period. But it could also be that people are getting more likely to detect and diagnose it - in young children.

Keyes, K., Susser, E., Cheslack-Postava, K., Fountain, C., Liu, K., and Bearman, P. (2011). Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California International Journal of Epidemiology DOI: 10.1093/ije/dyr193

Challenging the Antidepressant Severity Dogma?

2012-01-19T08:33:00.003Z

Regular readers will be familiar with the idea that "antidepressants only work in severe depression".

A number of recent studies have shown this. I've noted some important questions over how we ought to define "severe" in this context, and see the comments here for some other caveats, but I'm not aware of any studies that directly contradict this idea.

Until now. A new paper has just come out which seeks to challenge this dogma - not the author's term, but I think it's fair to say that the severity theory is becoming a dogma, even if it's an evidence-based one (but then, all dogmas start out seeming reasonable).

However, while the new paper is interesting, I think the dogma survives intact.

The authors went through the archives of all of the trials of antidepressants for depressive disorders conducted at the famous New York State Psychiatric Institute for the past 30 years. They excluded any patients who were severely depressed, and just looked at the milder cases. The drugs were mostly the older tricyclic antidepressants.

With a mean HAMD17 score of about 14, the patients they looked at were certainly mild. By comparison, most trials today have a mean of well over 20, and according to the main studies supporting the severity dogma, you need a score of about 25ish to benefit substantially:

So what happened? They reanalyzed 6 trials with over 800 patients. Overall there was a highly significant effect of antidepressants over placebo in mild depression, with an effect size d=0.52, or about 3.5 HAMD points. This is actually better than most other studies have found in "severe" depression. If valid, these results would torpedo the severity theory.

This seems very interesting... but. There's a big but (I cannot lie). Although the authors say they wanted to include all the relevant trials from the NYSPI, they only had access to the data from 6. There were another 6 projects, but they were "pharmaceutical company studies from which data were not released to the investigators."

This pretty much wrecks the whole deal. If those 6 studies all found no benefit of the drug, the overall average results would be much less impressive. We have no way of knowing what those studies found, but I'd wager that most of them were negative, because of publication bias - we know that drug companies tend to publish positive studies and bury negative ones. Or at least they did, at the time these studies took place (there are better regulations now).

By contrast, severity dogma classic Kirsch et al (2008) avoided publication bias by looking at unpublished data. Fournier et al (2010), the other major severity study, didn't but the data were very similar to Kirsch et al so it's not hard to believe them.

So in my view, until we know what happened in the other 6 trials, we can't really interpret these results, and the severity theory stands.

Stewart, J., Deliyannides, D., Hellerstein, D., McGrath, P., and Stewart, J. (2011). Can People With Nonsevere Major Depression Benefit From Antidepressant Medication? The Journal of Clinical Psychiatry DOI: 10.4088/JCP.10m06760

Neuroskeptic In The Papers

2012-01-18T08:35:00.000Z

Two more academic papers have appeared that refer to this blog:

The Openness of Illusions is a philosophy piece about the epistemological implications of optical illusions. It cites my post about a paper dealing with the spooky Hollow Face Illusion. Long-time readers will remember this, but most of you probably won't, so here it is again; it truly is weird:

In my view, an even better demonstration of the same effect is the incredible magic dragon:

You can make your own dragon by printing it out from this helpful page. It takes like 5 minutes to make and it'll provide hours of philosophical fun.

Meanwhile, Stereotypes and stereotyping: What's the brain got to do with it? takes a neuro-skeptical look at the psychology and neuroscience of prejudice. It flatters me with a mention:

It should go without saying that activity in the brain does not indicate in any way whether a mental act is hard-wired (Beck, 2010). It is equally absurd to argue that the amygdala is on anyone’s team or feels occasionally upset. Alas, non-experts should not be expected to spot such fundamental ﬂaws in reasoning without help.

Thus scientists using neuroscientiﬁc methods to study phenomena of social relevance are not only expected to be particularly critical towards over-interpreting their own ﬁndings, but also to monitor the ways in which their and other researchers’ data are reported in the media. Courageous attempts to counter overblown neuroscience-based claims in non-scientiﬁc outlets have so far resulted in numerous critical blogs (e.g., http://www.talkingbrains.org; http://neuroskeptic.blogspot.com) as well as in the publication of counterstatements in popular magazines (e.g., Aron et al., 2007).

Dolphins who Dream of Whales

2012-01-13T08:02:00.003Z

Once in a while you come across a paper that can only be described as lovely. This is one: Do dolphins rehearse show-stimuli when at rest?

Five dolphins lived in a certain aquarium in France. Every day, they put on shows for people - jumping around, that kind of thing. One day the aquarium started playing a 20-minute clip of "intro music" for the show. This consisted of various oceanic sounds including sea birds, dolphin noises and some whale-song.

What happened next was amazing. About a month about they brought in the intro sounds, the researchers noticed some odd sounds coming from the dolphins, late at night. It turned out that the dolphins had started making whale noises.

They only did this at night, mostly between 1 am and 3 am, when they were resting, possibly even sleeping. No-one trained them to do this. The "atypical vocalizations" were much lower than the dolphin's normal whistles, and also lasted longer.

Unfortunately, it wasn't possible to tell how many of the dolphins did this.

The authors recorded the dolphin's whale impressions with an underwater microphone, and played them back to a sample of 20 biologists, who weren't told the hypothesis of the study. Many of them thought they were whale-song, especially when the clips were slowed down to half-speed, dolphin's voices being "higher" than whales'.

Why the dolphins did this is a mystery. All of them had been born in captivity, so they'd never encountered a real whale. One theory is that they were mentally rehearsing the events of the day to come. Maybe they were even dreaming about them and "talking in their sleep" - although this is unclear, because it's not known whether dolphins dream; don't exactly sleep in the same way we do.

The paper's open access and it even comes with some audio clips of the dolphins, although unless you're familiar with what they sound like normally these aren't very meaningful.

Kremers D, Jaramillo MB, Böye M, Lemasson A, & Hausberger M (2011). Do dolphins rehearse show-stimuli when at rest? Delayed matching of auditory memory. Frontiers in Psychology, 2 PMID: 22232611

Do Brain Scans Sway Juries?

2012-01-11T20:40:00.002Z

Does seeing a criminal's brain affect jury decisions?

Edith Greene and Brian Cahill ask this question in a new study which put volunteers in the position of jurors in a murder trial. The 'defendant' was guilty, but the question was: should they get life in prison, or death?

It turned out that seeing brain scans didn't have much of an effect - but it's not clear how far the results would generalize.

208 mock-jurors were randomly assigned to get different kinds of mitigationinformation about the accused. Sometimes, all they were told was that he had been diagnosed with schizophrenia, depression and a substance misuse disorder. Others were also given neuropsychological test scores showing that he did poorly on various tests of reasoning and cognition. Finally, some were shown brain scans on top of all that, scans which were described as showing left frontal lobe damage.

All these materials were based on a real 2007 court case.

What happened? When the defendent was said to have been assessed as probably "dangerous" in future, people who were only told his diagnosis of schizophrenia usually sent him to the chair. But when they were given his psychological test scores - showing that he suffered from cognitive impairments - they were far more lenient. Seeing the neuroimages had no effect on top of that.

If the guy was described as posing a low risk of future violence, the verdicts were lenient, no matter what else they were told about him. In the real case, by the way, he got life.

This suggests that brain scans don't exert a seductive allure on jury decisions, at least not over-and-above psych test scores. But I'm not sure how representative the results are. The 'jurors' were all psychology undergrads. Most were Hispanic (63%) females (67%). Are psychology students especially resistant to the allure of brain scans - and/or especially vulnerable to the allure of psychological test scores? No-one knows, but it's surely plausible.

On some level, neuroimaging evidence clearly can influence people's decisions, like any other evidence; lawyers wouldn't bother presenting it otherwise. The question is how much of an impact it has, but that is surely going to depend on the details of the case as well as the juror's background; I'm not sure how much a study like this one, focussing on one example, will be able to tell us.

Greene E, and Cahill BS (2011). Effects of Neuroimaging Evidence on Mock Juror Decision Making. Behavioral Sciences and the Law PMID: 22213023

The Plight of Psychoanalysis?

2012-01-10T19:58:00.002Z

A New York psychoanalyst reveals her concerns about the profession in A Letter to Freud: On the Plight of Psychoanalysis

Dinah M. Mendes's letter covers several topics, but I was struck by the sections that deal with the contemporary challenges facing American analysts. She paints a rather sad picture of analysts who spend years in training, only to find a shortage of people out there who want their treatment:

At psychoanalytic training institutes it is often difficult for candidates to secure control or training cases—prospective analysands who sign on with analysts-in-training, usually at a low rate (sometimes as low as $10 a session). Here the issue is not the cost of the analysis but the low valuation of the opportunity offered—what might be regarded as the gift of self-knowledge.

The gratifications of instantaneous communication—texting, Facebook, and blogging—are immediate and obvious and erode the value of the slow and arduous route to communication and understanding offered by psychoanalysis. We seem to be transfixed in our culture by the allure of performance and public presentation, and a climate in which the exterior signifies the interior, where what you see and hear is what is true and real (no matter how often this fantasy is belied) is not receptive to the ideals of psychoanalysis.

She goes on to examine the increasing popularity of psychodynamic psychotherapy, approaches which draws on Freud's ideas but is much shorter (and hence cheaper) than classical psychoanalysis which involves hourly sessions, three times per week, over a period of years -

To judge from the mushrooming of new institutes of psychotherapy and shorter training programs within established psychoanalytic institutes, many people are interested in becoming psychotherapists, while there are fewer candidates for traditional psychoanalytic training and for psychoanalysis as a treatment choice.

For those who elect full-scale psychoanalytic training, the supply of certified psychoanalysts exceeds the demand in the population, and as psychotherapists they compete with psychotherapists of all stripes and denominations. The analytic institute can feel like a sequestered haven in which psychoanalysis is an “in house” specialty, tendered by training analysts (who have to earn their institutional stripes) to analytic candidates...

In my years of training, the contemporary challenges facing the would-be practitioner of psychoanalysis were rarely if ever openly addressed, although many recent graduates find themselves with few and sometimes no analytic cases...

All this, she says, can be seen in the context of

A zeitgeist in which the intrinsic and often intangible value of knowledge and education, and of self-knowledge and self-examination, has been supplanted by the appeal of material and pragmatic goals.

Of course this is all anecdotal. I wonder if any analysts amongst my readers have thoughts on this?

Mendes, D. (2011). Letter to Freud: On the Plight of Psychoanalysis The Psychoanalytic Review, 98 (6), 755-774 DOI: 10.1521/prev.2011.98.6.755

Men and Women - Alien Personalities?

2012-01-09T15:41:00.004Z

How different are men and women? Are they from two different planets?

In the cleverly-titled The Distance Between Mars and Venus, the authors argue that personality-wise, the differences between men and women have been underestimated by previous studies because they used simplistic statistics.

Traditional studies of gender and personality have given some men and some women a personality quiz, and calculated the average male and female scores on the different aspects of personality.

When you do this you find that there are differences, but that the standardized effect sizes are fairly small, which means that there is a lot of overlap. Even on measures where men score above women on average, lots of men score below the female average, and vice versa, like this:

Traditional studies of overall gender differences have looked to see the differences between the average man and woman on each personality aspect, and thenaveraged the differences on each scale to get an "overall difference" score. Which comes out as fairly small.

The authors of the new paper say that this approach fails to capture the true difference and they give a helpful analogy of why:

Consider two fictional towns, Lowtown and Hightown. The distance between the two towns can be measured on three (orthogonal) dimensions: longitude, latitude, and altitude. Hightown is 3,000 feet higher than Lowtown, and they are located 3 miles apart in the north-south direction and 3 miles apart east-west.

What is the overall distance between Hightown and Lowtown? The average of the three measures is 2.2 miles, but it is easy to see that this is the wrong answer. The actual distance is the Euclidean distance, i.e. 4.3 miles – almost twice the "average" value.

The main novel argument of this paper is that if you calculate the distance (technically the Mahalanobis distance) in 'personality space' between men and women then you get a larger value than if you just average the differences on each measure.

The paper also uses a couple of other methods that increase the effect sizes, namely using 15 different personality measures instead of the more common Big 5, and adjusting the differences upwards to take account of the fact that quizzes only imperfectly measure underlying 'latent' personality traits.

I don't want to get into the debate over how valid the underlying data are (a 1993 sample of over 10,000 American adults, used to standardize the 16PF questionnaire). There are lots of technical comments here. I'm going to focus on the distance method.

It's a very interesting approach and certainly raises questions about merits of the old approach, which when you think about it, does seem a bit crude. But I'm not sure that the average person is talking about distance in a hypothetical space when they talk about "personality differences".

As an analogy, consider the dog breeds Labrador and Golden Retriever. These are regarded as being pretty similar kinds of dog. On any given feature, the average differences are small, at least compared to the diversity of other breeds. They're roughly the same size, much the same build, coat type etc.

They are distinct breeds. This surely means that when you take all of the differences together, they define distinct regions of "dog space" (which has dozens or hundreds of dimensions), with little or no overlap.

Yet they are still regarded as similar. "Similar" and "distinct" are not mutually exclusive. In fact, isn't the definition of 'distinct yet similar' that two things separate in some kind of feature-space, but don't differ much on any one measure?

So I would say that these data show that, while men and women may be distinguishable in personality, they could still be similar. This is something of a semantic point but not "merely" semantic: it changes the interpretation of the numbers.

J. S. Hyde, who is most associated with the view that gender differences are small, makes a similar (or do I mean distinct?) point in her comment on the paper:

The gender difference found is along a dimension in multivariate space that is a linear combination of the original variables transformed into latent variables...[but] the resulting dimension here is uninterpretible. What does it mean to say that there are large gender differences on this undefined dimension in 15-dimensional space created from latent variables? The authors call it global personality, but what does that mean?

Her questioning of what the direction along which men and women differ means, is (I think) the same question I'm asking about whether it disproves the idea of "similarity", in the ordinary sense of the term.

Finally, take a step back and the whole debate seems a bit circular because, by definition, "personality" means "things that differ between individual people". Things we are have in common aren't even in the picture. Two groups could differ in personality space but still be very close in the much larger space of "possible creatures". There's no personality trait for 'being human'.

Del Giudice, M., Booth, T., and Irwing, P. (2012). The Distance Between Mars and Venus: Measuring Global Sex Differences in Personality PLoS ONE, 7 (1) DOI: 10.1371/journal.pone.0029265

The Real Story On That "Antidepressant Surge"

2012-01-07T09:39:00.005Z

Remember last week's story about how depression rates are soaring in Britain? It was all triggered by "new data" about an increase in antidepressant prescriptions.

At the time I was skeptical, not least because the data wasn't actually new, but I've done a bit more digging and it turns out the media coverage was even more misleading than I thought.

Here's some pretty graphs from the NHS Information Centre. I reiterate that all of these are freely available and have been for ages. Here's the one for antidepressants:

They've been rising strongly! In total prescription rates are about 60% higher now compared to in 2006. Oh dear.

What the papers didn't tell you is that pretty much every other class of drug has also increased over that period, by even more in some cases. Here's ADHD drugs, and dementia pills, which have increased by about 75% and 100% respectively:

There have also been steady increases in anticonvulsants and a 40% increase in meds for Parkinson's disease. All of the graphs are here.

So this suggests that there's been a general increase in prescriptions for brain drugs. But in fact it's even wider than that because if we look at the same data for cardiovascular system drugs, we find the same picture for most (although not all) kinds of these medications.

And for painkillers, we find over 50% increases in prescriptions of the stronger opioid drugs, a 20% increase in migraine drugs etc etc. I swear I'm not just copying and pasting the same graph.

Now clearly, all of these increased prescriptions don't mean that there are simultaneous explosions in rates of dementia, heart disease, pain, migraine, Parkinson's and ADHD, all in the past 5 years. We would have noticed if that were the case.

What's happened, clearly, is that doctors are just writing more prescriptions nowadays.

So it's misleading to say that there's been a spike in antidepressant prescriptions. Yes it's technically true but it ignores the context. The truth is that we seem to be experiencing a cultural shift in our relationship to medications - perhaps evidence of the creeping medicalization of life (although there are more prosaic explanations that need to be ruled out before we conclude that; this could be a bureaucratic change in the way prescriptions are counted.)

However, "Escalating Depression Crisis - Antidepressant Use Soars" is a better headline than "Possible Medicalization Gradually Continues For Sixth Year In Row".

The truth, sadly, has an inherent disadvantage in the battle for news coverage. If we find the truth boring, it's easy for someone to come along and make up something attention grabbing. But the only easy way to make the truth more interesting is to make it, well, less true.

Do You Have Free Will?

2012-01-06T10:27:00.000Z

I mean you, specifically.

I'm not asking whether people have free will. I think they do - except you. You're the one person on earth who doesn't have it.

If you disagree - how would you convince me that you do have it?

Alternatively, if you're one of the people who doesn't believe in free will - I agree with you, people don't have it... except me. I'm special.

This might seem like one of those thought experiments that only philosophers could care about, but it's of more everyday importance than the general question of 'whether we have free will'. That's an interesting debate, but really it doesn't change anything. If we have it, we always have, and if we don't, we never will. Either way, here we are, and we'd better get on with our lives.

On the other hand, the question of whether an individual has free will has real consequences. It can even be a matter of life or death. It comes up in court cases. Lawyers and psychiatrists don't use the words "free will", they'll talk about responsibility or capacity or sound minds, but what they mean, in essence, is what the rest of us mean by the term free will.

In some of these cases, free will is what you want - if, say, psychiatrists want to confine you to a hospital, and you say you don't want to be there. Other times it's the reverse - if you've committed a crime, and your defense is that some kind of mental or neurological illness made you do it, then you're arguing that you don't have it (or didn't, at the crucial moment.)

But while lots of people have opinions on the abstract "Free Will" question, I don't think many people pay attention to the issue of their own free will or lack of it - until they end up in court. We just assume that if everyone else has it, so do we, and vice versa.

Yet how can we be so sure? Everyone accepts that people differ in regards to how much free will they have. Wwhen people say "I believe people have free will", they don't really mean all people - they surely make an exception for babies, people in a coma, people having a seizure, and probably children, people with dementia, people with severe mental illness... Likewise, people who don't believe in free will recognize that there's a difference between a normal adult and one of those people.

But where do we draw the line, and how do you know which side you're on? This seems to me the most important questions to be asking about free will.

Hot Sex Prevents Breast Cancer

2012-01-04T20:04:00.000Z

Breast cancer is caused by sexual frustration. Women should ditch their unsexy husbands and find a real man to satisfy them if they want to reduce the risk of the disease.

That's according to An Essay on Sexual Frustration as the Cause of Breast Cancer in Women: How Correlations and Cultural Blind Spots Conceal Causal Effects, a piece that was published today in The Breast Journal.

Wtf. Really -

Endocrinological processes are important targets in breast cancer research. These processes are also important in human sexual behaviors. I hypothesize that these processes are capable of adjusting or distorting biological active forms of speciﬁc sex hormones depending on experienced sexual stimuli. These aberrantly metabolized sex hormones will ultimately lead to breast cancer.

...My thesis is that breast cancer is essentially caused by sexual frustration. The focus of this hypothesis is aimed at the (un)consciously experienced tension and sexual dissatisfaction between the chosen mate based on socio-economic, intellectual, ethnic or cultural motives and the nonchosen potential mate who has more appealing sexual incentive properties.

In most western societies the improved economic independence of women has not changed to such a degree that long-term partners are chosen entirely according to sexual incentive properties. If the selected partner has no or weak sexual incentive properties for the other member of the couple, it is likely that sexual frustration will follow in the long run (6), which ultimately will cause breast cancer in some women...

WHY HIGHER SOCIOECONOMIC GROUPS OF WOMEN ARE MORE AT RISK
...higher socio-economic group of women pay more than average attention to the assets or status of the potential partner(7)....The chances of some women from higher socio-economic classes to ﬁnd a sexually compatible mate are considerably reduced. This is due to an often self-imposed very limited range of potential partners. In this group of women, high status of the potential partner compensates for the acceptance of physically less attractive men (9)...

HEIGHT AS RISK FACTOR IN BREAST CANCER
...These women have a disadvantage because they have a smaller pool to choose from if they want a man they will not tower over. This increases the chances to settle for a sexually incompatible partner...

BREAST CANCER RISK IN NUNS...

There are 15 references, but they're all about sex, not cancer. Thus we get a citation to support the statement that "If the selected partner has no or weak sexual incentive properties for the other member of the couple, it is likely that sexual frustration will follow in the long run (6)", but not for the rather more controversial idea that disappointment in the bedroom somehow leads to malignant mutations in the DNA of cells of the mammary epithelium.

Well, except the line that "aberrantly metabolized sex hormones" are responsible, which is the scientific equivalent of waving your hands and saying "woo".

How did this happen?

The Breast Journal, so far as I can see, publishes lots of sensible research. It may not be a major journal but it's MEDLINE indexed and ranked 143/184 for impact in the field of oncology, which means there are 40 cancer journals in the world that have less impact than it.

If I had published there, I'd be a bit miffed that my work was appearing in the same pages. Thankfully I haven't but as a scientist I'm still insulted that this has been published in a scientific journal, and will be appearing on the shelves of libraries around the world under the heading "science".

Stuger, J. (2011). An Essay on Sexual Frustration as the Cause of Breast Cancer in Women: How Correlations and Cultural Blind Spots Conceal Causal Effects The Breast Journal DOI: 10.1111/j.1524-4741.2011.01206.x

Antidepressants: Bad Drugs... Or Bad Patients?

2012-01-03T21:40:00.002Z

Why is it that modern trials of antidepressant drugs increasingly show no benefit of the drugs over placebo? This is the question asked by Cornell psychiatrists Brody et al in an American Journal of Psychiatry opinion piece.

They suggest that maybe it's the patients fault:

Participation that is induced by cash payments may lead subjects to exaggerate their symptoms [i.e. in order to get included into the trial]... Another contributing factor to high placebo response rates may be the extent to which the volunteers in antidepressant trials are really generalizable to patients in clinical practice.

Since the initial antidepressant trials in the 1960s, participants have gone from being patients who were recruited primarily from inpatient psychiatric populations to outpatient volunteers who are often recruited by advertisements. At times, these symptomatic volunteers have participated in other trials. When we contact potential participants to schedule screening, they often ask to be reminded which trial we are screening for or mistake our research trial for a different protocol in which they recently participated.

They then recount the tale of two "professional subjects" who claimed to be depressed and enrolled in two antidepressant trials simultaneously, without telling the researchers; it only came to light when someone involved in both studies spotted the duplicate names.

I've been the victim of such nonsense myself, as have many of colleagues - it's a perennial watercooler topic. A few years ago I was running a study recruiting people who'd recovered from psychiatric illness. The main source of volunteers was online adverts.

That study was a learning experience. What I learned is that House was right. We recruited about 20 people. No fewer than 3 turned out to have enrolled in other studies and lied about it. After I realized this I Googled the offender's names and two of them turned up in the court pages of the local newspaper pleading guilty to various petty crimes.

Another volunteer was left handed and, upon realizing that I was only recruiting right-handed people, discretely switched his pen to his right hand and then took 5 minutes trying to fill out a form with his off hand. He didn't make it in, but if I hadn't been paying attention he would have.

So yes, it is a problem. However, it would have to be taking place on a massive scale for it to be having a significant effect on antidepressant trial results and this really seems pretty unlikely.

In my view, the authors miss out on the real problem with recruiting depressed people through adverts: depressed people don't tend to respond to adverts, because depressed people don't do anything. That's why they call it depression.

Getting recruited into a modern clinical trial is actually quite a challenge. There are many pieces of paper to fill in, calls to return, appointments to attend. Turn up late to the screening visit, or otherwise make life difficult for the study staff, and you'll be marked down as "unreliable" and they'll find someone who plays by the rules. Modern trials are very expensive. The last thing a study sponsor wants is a volunteer who will end up forgetting to take their pills on time.

Depression, unfortunately, makes you bad at doing things. You procrastinate, you forget, you put things off until too late, you have a change of heart and decide not to, you get cold feet, you can't be bothered... That goes for things as simple as cooking dinner in severe cases, let alone something as complicated as taking part in a trial.

So while you wouldn't go looking for aquaphobic people in a swimming pool, I'm not sure we should be looking for depressed people through adverts.

Brody B, Leon AC, and Kocsis JH (2011). Antidepressant clinical trials and subject recruitment: just who are symptomatic volunteers? The American journal of psychiatry, 168 (12), 1245-7 PMID: 22193668

What're You Lookin' At (When You Dream)?

2012-01-02T11:36:00.000Z

Why do our eyes move during sleep?

Here at Neuroskeptic we've already asked why do we sleep? and why do we dream? There are plenty of theories, but no clear answers to either of those questions.

We don't even know the function of one of the most famous sleep phenomena, rapid eye movements (REMs). It's been known for decades that during certain phases of sleep, the eyes show a pattern of rapid flickering movements, and that this REM sleep is when most (but not all) dreams occur.

But what are the eye movements?

In a new paper, French sleep researcher Isabelle Arnulf sets out the case for the "scanning hypothesis". The idea is that REMs represent the dreamer "looking at" things in the dream, just like waking eye movements - at least much of the time.

Some say that REMs are nothing to do with dreams, and it's just a coincidence that they tend to occur together. They may just be random, perhaps with the function of preventing the eyes from drying out during sleep, or maybe just a side-effect of sleeping brain activity with no function at all. A possible analogy: males usually get erections during REM sleep, even though most dreams have no sexual content.

There's lots of evidence that seems to support a deflationist view of dreams. In humans and other mammals, foetuses have lots of REMs, even though they've never seen anything. Lab animals with the visual areas of the brain removed also continue to display REMs, albeit not as many of them, and people who've been blind since birth have REMs.

Anaulf disagrees however, and discusses her work with the fascinating REM sleep behaviour disorder (RBD). RBD sufferers seemingly act out their dreams. Normally, we're paralyzed during REM by an inhibitory system which causes muscle relaxation during REM. The eyes are the exception, because they have a separate nerve pathway (which is also why some otherwise paralysed people can still communicate with their eyes). RBD can be a symptom of underlying neurological disease, such as Parkinson's, but it can also occur on its own.

Anaulf's team studied 56 patients with RBD over 1 or 2 nights (Leclair-Visonneau 2010). They found that the behaviours were correlated with the onset of rapid eye movements, although 80% of the eye movements were not accompanied by any actions. What's more, out of 19 distinct behaviours (ranging from running away from lions, to strangling someone), 60% were associated with REMs, and of these 90% were in the same direction as the actions.

This directional coherence between limb, head and eye movements during RBD suggests that, when present, REMs imitate the scanning of the dream scene. Because the REMs are similar in subjects with and without RBD, we suggest the extension of this concordance to normal REM sleep.

They suggest, however, that it may not be that the eye movements are the result of the dream content, but just correlated with it. It's not that something happens on the left in the dream, and then in response, the eyes move to the left; rather it's that whatever pattern of neuronal activity causes the dream, also causes the corresponding eye movements.

Either way it's an interesting idea, although it does rely on the assumption that RBD is a good model of normal sleep in this regard.

Arnulf I (2011). The 'scanning hypothesis' of rapid eye movements during REM sleep: a review of the evidence. Archives italiennes de biologie, 149 (4) PMID: 22205589

Britain - the Prozac Nation? Not So Fast...

2011-12-30T18:14:00.000Z

Oh no! The stress of the recession has turned us into a nation of antidepressant addicts, according to every single British newspaper this morning.

The media coverage has been predictable with lots of scary, context-free statistics, and boilerplate quotes from the usual suspects. No doubt tomorrow we'll see a selection of moralistic op-eds about this.

But not one of the many nigh-identical articles provided a link to the original data, or even a useful description of where one might find it. After contacting one of the NHS organizations named as the source, I managed to track the numbers down.

It turns out that the key figures have been publicly available since April 2011, so I'm not sure why this story appeared in British "news"papers at all. Also, it would have been easy for journalists to link to the source, if they respected the intelligence of their readers enough to do that. I just did it and it wasn't terribly hard to click "Add Link".

On that note, I actually read a bizarre article today criticizing British journalists for providing too many links to their source data... if only.

Anyway, the data. Ben Goldacre has already written an excellent piece on this (in fact, he wrote it back in April 2011, curiously enough...see above), but here's some more detail.

First off, the data are all about antidepressants, not depression. A crucial distinction, there, because nowadays, antidepressants are widely used for all kinds of other things. Everything from other psychiatric disorders like anxiety and OCD, to non-psychiatric stuff like back and joint pain, premature ejaculation, and menopausal hot flushes.

We can't tell how much of the antidepressant use was for depression. But there are clues suggesting that a lot of it wasn't. It turns out that the second most popular antidepressant (after citalopram) was the very old drug amitriptyline, with nearly 9 million prescriptions per year - or 20% of the total.

Nowadays amitriptyline is rarely used for depression, because newer, less toxic alternatives are available. However it is used, in low doses, to treat chronic pain. So I suspect that pain accounts for a large % of amitriptyline use. That would also explain why the cost to the NHS per prescription of amitryptiline was by far the lowest of all antidepressants: low doses are cheap.

How about the increase over time?

The newspapers are correct that antidepressant use rose from 33.9 million prescriptions in the year 2007/8, to 43 million in 2010/2011. That's a 28% rise over 3 years. However, if we go 3 years further back to the equivalent 2004/5 Prescription Cost Analysis, we find that antidepressant prescriptions were 28.9 million. So they rose 17% in the 3 years before 2007/8, long before the recession was on the horizon.

The recent 28% rise, in other words, is unlikely to be related to the recession, at least not entirely.

We also know(1,2) that the number of antidepressant prescriptions per person has been rising over the past several years in the UK. So the increase in prescriptions might not even mean more antidepressant users - it might just mean that the same number of users are using more each. (And that could mean anything, including that bureaucracies are saving money by prescribing for shorter periods).

One study found that there was no increase in the number of people taking antidepressants for depression from 1993 to 2005, with all of the rise in prescriptions over that period being a product of more prescriptions per person.

Another study did find a true rise in users from 1995 to 2007, albeit lower than the raw figures would suggest, but those figures were limited to a particular part of Scotland and it wasn't just about depression - it included all other uses of these drugs as well.

Overall, it's just impossible to know, from these data, whether there's been a true increase in antidepressant use for depression in recent years. The most we can say is that there might have been one, and if so it might have something to do with the economy.

How Realistic is fMRI?

2011-12-30T13:21:00.000Z

How representative are fMRI experiments? Is "the brain" that we investigate with fMRI the same brain that we use outside the MRI scanner?

A new paper from Bernhard Hommel and colleagues of Leiden in the Netherlands offers some important caveats. They looked to see what effect playing some recorded MRI scanner sounds had on people's ability to perform some simple cognitive tasks, while sitting outside the scanner.

MRI is notoriously noisy. When you have an MRI scan you have to wear earplugs to protect against the sound but they only block out some of it. Opinions differ on whether the sound is pleasant or not. Personally I find the repetitive tick-tock rather soothing now, but then I've heard it many times over the years. First-timers can find it quite overwhelming.

Anyway, Hommel et al found that while scanner noise had no overall effects on reaction time or accuracy, it actually improved performance on three measures of "cognitive control".

For instance in a task in which participants had to respond to the colour of a circle by pressing the left or the right arrow key, they were slower to react when the circle appeared on the "wrong" side of the screen, i.e. on the left when the correct answer was the right arrow. This slowing of responses caused by a stimulus-response clash is called the Simon effect.

The results showed that the Simon effect was reduced by noise. The same thing happened in two other studies: noise meant better performance.

All of the noise effects were modest and the sample sizes were also quite small (14-18 per task, with everyone studied twice, noisy vs silent) but this paper joins a number of others raising questions about the representativeness of fMRI, with evidence that fMRI activates the brain and maybe even improves mood (although I doubt that last one).

The authors' interpretation is that the noise made people pay more attention to the tasks, to compensate for the distraction, and that this means that fMRI studies may be biased in their measurements of cognitive control:

Generalizing from fMRI findings to behavioral observations and vice versa seems to be more problematic than commonly thought, at least as far as control processes are concerned. In a sense, then, investigating cognitive processes by means of fMRI... is inevitably facing Heisenberg’s (1927) uncertainty principle, according to which the act of measurement can change what is being measured.

To my mind the biggest weakness of this is that it only looked at noise. While scanners are noisy, that's not the only distracting thing about them: during an fMRI study you also have to lie down, in a small confined tube, and your only way to see the "screen" on which experimental stimuli are shown is indirectly via a small mirror which often doesn't give a good view.

So ironically, I'm not sure how realistic this study is...

Hommel, B., Fischer, R., Colzato, L., van den Wildenberg, W. and Cellini, C. (2011). The effect of fMRI (noise) on cognitive control. Journal of Experimental Psychology: Human Perception and Performance DOI: 10.1037/a0026353

Scanning The Brain While Looking At Scans

2011-12-27T15:55:00.000Z

A new study investigated what goes on in the brain when doctors make a diagnosis.

Radiologists use X-rays and other imaging techniques to diagnose diseases - but in this study, they went into the scanner themselves. Brazilian researchers Marcio Melo et al used fMRI to record neural activity while the radiologists were shown an array of chest X-rays.

Some of the scans showed evidence of disease, which the doctors were required to diagnose. There were also two control conditions, in which the stimuli were still X-rays but with little pictures of either animals or letters embedded in them, instead of diseases.

The image above shows how it worked. As well as pneumonia, one patient has a severe case of Alligator Lung, while the other looks like they've got the Influenza 'B' virus.

Now, the point of all this was to compare the mental process of making a diagnosis to that of seeing an object. The idea is that a trained radiologist sees particular diseases in the scans, in the same way that anyone can see an alligator.

Activity during diagnosis, object-recognition and letter naming was very similar (compared to doing nothing); this presumably represents the visual and language areas involved in looking at the image, recognizing what it is, and saying it out loud:

There were some slight differences, with the left inferior frontal cortex and the posterior cingulate cortex being more activated by diagnosis than animals. But this difference disappeared after controlling for the number of different possible descriptions the radiologists reported thinking about for each image.

The authors conclude that

These results support the hypothesis that medical diagnoses based on prompt visual recognition of clinical signs and naming in everyday life are supported by similar brain systems.

Which seems fair enough, although it's important to remember that the diagnoses in this study were quite easy ones. The mean response time was just 1.3 seconds and only 6% of those split-second diagnoses were wrong. Unfortunately diagnosis is not always that easy.

Anyway, this study is all very well, but why stop at chest X-rays? Last year I speculated on the fun neuroscientists could have with a real-time fMRI machine:

You could lie there in the scanner and watch your brain light up. Then you could watch your brain light up some more in response to seeing your brain light up...

We really need to scan people while they're looking at brain scans. Only then will we be able to understand the neurological basis of being a neurologist, and find the brain's looking-at-a-blob blob.

Melo M, Scarpin DJ, Amaro E Jr, Passos RB, Sato JR, Friston KJ, and Price CJ (2011). How doctors generate diagnostic hypotheses: a study of radiological diagnosis with functional magnetic resonance imaging. PloS ONE, 6 (12) PMID: 22194902

Neuroskeptic: The Video Game

2011-12-26T09:16:00.001Z

As a Christmas present, here's something I've been working on over the holidays - Neurubiks.

It's a free puzzle game. The brain is broken. Can you can restore neuro-harmony?

Download it here.

Features:

A bit like a Rubik's cube, but less annoying.
Millions of possible puzzles.
Easy to learn - just click on the blobs.
Neuroanatomically accurate.
Perfect for killing time while running fMRI analyses.

Notes:

If you like it, hate it, find bugs or have any suggestions, please let me know in the comments.

If I knew Flash, I would have programmed this in Flash. If any Flash developers like Neurubiks and are interesting in helping develop it please do get in touch.

Apologies to the color-blind. The game is all about colours I'm afraid. Let me know if you have any ideas for making it more color-blind-friendly.

An Objective Measure of Consciousness...?

2011-12-22T10:20:00.000Z

Could a puff of air in the eye offer a way to evaluate whether someone is conscious or not?

Yes it could, say Cambridge's Tristan Bekinschtein and colleagues in a new paper about Sea slugs, subliminal pictures, and vegetative state patients.

It's all about classical conditioning of the kind made famous by Pavlov. This is learning caused by the pairing of two stimuli, one of them somehow meaningful (usually unpleasant). So if I were to ring a little bell before, say, pepper spraying you, and I did that repeatedly, you would probably close your eyes whenever I rang that bell. Or just punch me, but you see the point.

Anyway, the key is that there are two kinds of classical conditioning. In the unhelpfully named "delay" conditioning, the warning stimulus overlaps with the painful one. Like if I started ringing my bell, then kept ringing it while I sprayed you with my other hand. In other words, there is no delay between the two stimuli... I said it was badly named.

By contrast in "trace", conditioning there is a delay - the warning stops shortly before the second stimulus. Bekinschtein et al argue that trace conditioning requires conciousness. While delay conditioning can occur without awareness of the link between the two stimuli, only conscious awareness can bridge the time gap in trace conditioning.

In trace experiments (in which rather than pepper spray, the unpleasant stimulus is just a puff of air in the eye), people who, when asked, can't explain the relationship ("sound means puff") don't learn to blink when they hear the sound. But with delay conditioning, this "unconscious" conditioning can occur. Likewise, under anaesthesia, trace conditioning is lost.

At first glance this looks like a piece of psychological trivia, but it could have literally life-or-death consequences. If trace conditioning is a measure of concious awareness then it could be used as a way of working out whether brain-injured people in a "coma" or "vegetative state" are aware or not.

This paper is in fact a follow-up to the author's own 2009 study showing that some people in a vegetative state do show trace conditioning - and the ones who did were more likely to subsequently wake up.

One snag is that the humble sea slug, Aplysia, can undergo trace conditioning, yet it is presumably not conscious, at least not in any recognizable sense.

But Bekinschtein et al say that trace conditioning is a product of convergent evolution. Alplysia can do it and we can do it, but we use different means to the same end. Their argument is that while in Alpysia trace conditioning is known to be dependent on just a handful of individual neurons in the creature's tiny "brain", in humans it requires an intact hippocampus (containing millions of cells). People with hippocampal damage, who suffer amnesia, also can't do trace conditioning.

That's a good point but does that mean such hippocampal patients aren't conscious? That would be weird because, apart from the amnesia, they seem perfectly normal. Presumably they're just not conscious of the relationship between things separated in time...

Also, primitive pathways for conditioning might still exist in humans, able to reactivate under special conditions. They do acknowledge this with a discussion of experiments showing that trace conditioning in the absence of conscious awareness of the relationship can occur but only when the warning stimuli are "scary", like pictures of snakes. They say that with generic, neutral stimuli there is no good evidence of unconscious trace conditioning, but this seems like a fairly fine distinction.

Ultimately, it's a very nice idea but only more studies on "unconscious" patients will tell us whether it's really able to measure consciousness in a useful way.

Bekinschtein TA, Peeters M, Shalom D, and Sigman M (2011). Sea slugs, subliminal pictures, and vegetative state patients: boundaries of consciousness in classical conditioning. Frontiers in psychology, 2 PMID: 22164148

Young, Canadian and on Antipsychotics

2011-12-17T10:27:00.000Z

Antipsychotic use in Canadian children and teens is rising dramatically - prescriptions more than doubled in just 4 years, from 2005 to 2009.

That's according to a paper just out from Pringsheim et al. It's been known for a while that broadly the same is true of the USA. The data reveal that the Canadian border is no barrier to the spread of antipsychotics.

What's surprising is that while in the USA, some of these drugs are officially licensed for use in certain children and adolescent psychiatric disorders, in Canada all such use is off-label. That didn't stop there being nearly 700,000 youth prescriptions for an antipsychotic in 2009, in a country with a total population of 35 million - although bear in mind that this includes multiple prescriptions for the same person.

The growth in antipsychotics is accounted for by the second-generation "atypical" antipsychotics. Risperidone (Risperdal) was the biggest success story accounting for well over half of the total.

What's disturbing about this, as I've said before, is not so much the fact that these drugs are being used but the speed of the growth. It represents a fundamental shift in the way children and adolescent mental health problems are treated, one which has happened so fast that it's hard to believe that there was time to properly think through the consequences...

Use of SSRI antidepressants and psychostimulants (mainly ADHD drug methylphenidate, Ritalin) also rose between 05 and 09, but only by about 40%. That means that there were more antipsychotic than SSRI prescriptions in children and teens by 09, which is pretty remarkable.

Only 13% of the youth antipsychotic recommendations were actually for psychosis, the original indication of the drugs. The leading diagnosis was ADHD, which is odd, because the main drugs for ADHD, such as Ritalin, boost dopamine release, while antipsychotics block dopamine's effects via D2 receptors.

Other popular indications were mood disorders and conduct disorders. Overall, the fact that the vast majority of the antipsychotic prescriptions were not for psychosis confirms the view that the term "antipsychotic" for these drugs is misleading.

Pringsheim T, Lam D, and Patten SB (2011). The Pharmacoepidemiology of Antipsychotic Medications for Canadian Children and Adolescents: 2005-2009. Journal of child and adolescent psychopharmacology PMID: 22136092

"Mad Honey" Sex Is A Bad Idea

2011-12-15T07:54:00.000Z

A cautionary tale from Turkey - do not eat poison honey to try to spice up your sex life.

"Mad honey" is honey made by bees from the nectar of toxic Rhododendron flowers. In places where wild Rhododendrons grow, including Turkey, it's a health hazard. The dangers of mad honey were known to the ancient Greeks and Romans, and it's reported that leaving tainted honeycombs in the path of invading armies was a popular military tactic.

2000 years later, some people still haven't quite got the message. According to a case report from cardiologists Yarlioglues et al, a married couple deliberately ate some mad honey "for reasons of sexual performance".

After eating one teaspoon per day for a week, they decided to crank it up a notch and ate a full tablespoon of the stuff. But their attempt to heighten their Turkish delight quickly turned sour, as they both suffered symptoms of confusion, chest pain, low blood pressure and slowed heartbeat. After presenting themselves to hospital, doctors discovered that they had both suffered an acute inferior myocardial infarction - a mild heart attack.

It's not clear whether the sex was a contributing factor.

The randy Rhododendron fans were lucky - following treatment, they both recovered. In fact, the authors say "To our knowledge, no fatal cases of mad-honey poisoning have been reported since ancient Roman times." However, it seems that some people are still willing to try their luck.

The toxin in mad honey is gryanotoxin. It acts by potentiating the opening of sodium channels, which are found both in the heart and the brain. This may be why it produces a combination of cardiovascular and psychoactive effects.

Mikail Yarlioglues et al (2011). Mad-Honey Sexual Activity and Acute Inferior Myocardial Infarctions in a Married Couple Texas Heart Institute Journal

Genes for Intelligence - Back to Square One

2011-12-13T08:10:00.000Z

Here's a paper - soon to appear in Psychological Science - which says that Most Reported Genetic Associations with General Intelligence Are Probably False Positives

The authors tried to replicate published associations between particular genetic variants (SNPs) and IQ (specifically the g factor). They looked at three datasets, a total of about 10,000 people, and didn't confirm any of the 12 associations.

As Razib Khan says in his post on this, "My hunch is that these results will be unsatisfying to many people." I'd go further and say that no-one will be happy with these.

For those who believe that IQ is purely environmental and not genetic, any satisfaction they might feel will be short lived because these authors did replicate the recent finding that genetic variants explain about 50% of the variance in IQ. Looking at all SNPs together, there was a strong correlation between "genetic similarity" and similarity in IQ. That independently confirms what the much-criticized twin studies of IQ said - IQ is about 50% heritable.

But for people who do believe in the genetics of intelligence, this shows us that we have no idea what the genes are, and that everything published so far has been pretty much for naught.

There's another implication. We actually do know of many "IQ genes" in that we know genes that, when mutated, cause mental retardation (very low IQ).

Now many researchers have hoped that if a certain gene causes you to have an IQ of, say, 50 when it's completely deleted by a mutation, then more subtle variants in that gene would have minor effects on IQ. Maybe a variant that reduces expression of the gene by 10% would knock off 5 IQ points.

In other words, if big mutations cause big phenotypes, then small mutations in the same place ought to cause small phenotypes. It seems to make sense - but today's IQ literature shows that it's just not true.

That's not just a problem for IQ though. Take autism or ADHD, we know that there are rare, severe mutations that cause these conditions. Many people are hoping that common variation in the same genes might also be interesting - but if IQ is anything to go by, it won't be.

Perhaps this is not so surprising. Breaking your neck and becoming paraplegic is going to seriously impair your ability to play baseball. That doesn't mean that normal variation in baseballing skill has much to do with minor neck injuries.

Chabris, C. F. et al (2011). Most Reported Genetic Associations with General Intelligence Are Probably False Positives Psychological Science

Do Antidepressants Make Some People Worse?

2011-12-11T12:58:00.000Z

Antidepressants may help depression in some people but make it worse for others, according to a new paper.

This is a tough one so bear with me.

Gueorguieva, Mallinckrodt and Krystal re-analysed the data from a number of trials of duloxetine (Cymbalta) vs placebo. Most of the trials also had another antidepressant (an SSRI) as well. And the SSRIs and duloxetine seemed to be indistinguishable so from now on I'll just call it antidepressants vs. placebo as the authors did.

People on placebo got, on average, moderately better over 8 weeks.

People on antidepressants fell into two classes. The largest class got, on average, a lot better. But about 25% did poorly, staying just as depressed as before. This "nonresponder" group did much worse than the placebo group - again on average. Here you can see the mean "trajectories" of depression symptoms (HAMD scores) in the three groups:

This raises the scary possibility that while antidepressants are helping some people, they're harming others. But hang on. It's complicated.

First off, maybe this is all a statistical illusion. When the authors say that the people on drug fell into two classes, what they mean is that when you try to model the data according to a certain mathematical model, assuming either 1, 2, 3 or 4 underlying classes, the 2 class solution was the best fit. While for placebo a 1 class solution was best.

We considered linear, quadratic, and cubic trends over time, with between 1 and 4 trajectory classes. We also considered piecewise models with a change point at 2 weeks, linear change before week 2, and quadratic change after week 2. The selection of the best model was based on the Schwartz-Bayesian information criterion and on the Lo-Mendell-Rubin (LMR) likelihood ratio test...

That's nice... but they don't present the raw data. They don't tell us whether, looking at the individual trajectories of people on antidepressants, you'd actually see two classes. What I want is a graph of how likely people are to get better by a certain amount. If Gueorguieva et al are right, I want it to look like this i.e. bimodal -

We're not shown this graph. I'll eat my hat if it does look like that, frankly, because if it did people would have noticed the bimodality in antidepressant trials ages ago.

True, statistical models can tell us things that aren't obvious by inspection, so even if this isn't what the data look like, they might still be right. It could be that the two "peaks" are so broad, and there's so much random noise, that they blur into one.

However, it's also true that you can fit an infinite number of models to any set of data and at some point you have to step back and say - am I making this more complicated than it needs to be?

It could be that a 2-class model is better than a 1-class model for the people on antidepressants, but only because they're both crap, and really, every patient has a different, unpredictable trajectory which is poorly captured by such models.

Let's assume however that this is true. What would it mean?

Firstly, the fact that one class of people on antidepressants does worse than people on placebo doesn't mean that antidepressants are harming them. The authors miss this point, when they say

there are 2 trajectories for patients treated with antidepressants and 1 trajectory for patients treated with placebo [so] some patients would seem to be more effectively treated with placebo than with a serotonergic antidepressant.

But that's fallacious. It treats a purely statistical entity as representing individual people. Suppose that what antidepressants do is to take people who, on placebo, would have improved a bit, and make them improve a bit more than they otherwise would have. You'd then end up with more people doing well, but also fewer people doing moderately because they'd have been "moved up" out of the middle ground.

That "nudging people off the fence" could lead to a bimodal distribution and two distinct classes. But in this case the people doing badly would have done badly either way. The drug didn't make them do badly, it just made doing-badly into a class. On the other hand it's consistent with antidepressants doing real harm. We can't tell.

We do know that other randomized controlled trials show very convincingly that in a small minority of people, mostly but not exclusively young people, antidepressants do worsen suicidal thoughts and behaviours. So it's plausible. But we just don't know yet.

What worries me is that this paper is the latest in a series of attempts to use, well, creative statistical approaches to antidepressant trial data. This one is nowhere near as dodgy as the Cherrypicker's Manifesto I discussed last year, but it cites that paper and others by the same group. The first sentence of the Abstract of this paper makes the intention clear:

The high percentage of failed clinical trials in depression may be due to high placebo response rates and the failure of standard statistical approaches to capture heterogeneity in treatment response.

In other words, the reason clinical trials of new antidepressants often fail to show a benefit over placebo is not because the drugs are crap but because the statistics aren't subtle enough. And you can see where this is going: if only we could use statistical models to find the people who do benefit from antidepressants, and compare them to placebo, there'd be no problem...

Gueorguieva R, Mallinckrodt C, and Krystal JH (2011). Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Archives of General Psychiatry, 68 (12), 1227-37 PMID: 22147842

The Brain's High School Spot

2011-12-09T13:21:00.001Z

It's been known for a long time that electrical stimulation of the brain's temporal lobe can sometimes evoke vivid memories.

The famous neurosurgeon Wilder Penfield first noticed this effect as part of his pioneering stimulation experiments, but he believed that it was both uncommon and haphazard with any given stimulation able to evoke any memory, more or less at random.

A new paper, however, says different. Philadelphia's Joshua Jacobs et al report that they found a spot in the left temporal lobe of a male patient, stimulation of which evoked memories of the man's time at high school. The guy was in his 30s at the time, so these are quite distant memories.

When it first happened, he is reported to have said:

Iʼm, like, remembering stuff from, like, high school…. Why is this suddenly popping in my head?

Repeated stimulation of the same electrode - but not nearby electrodes - caused other high school memories to emerge.

Even more interestingly, when the same stimulating electrode was used to record activity during memory retrieval, the "high school spot" was found to be significantly less active when high school was being remembered, compared to when various other kinds of memories were being accessed.

This graph shows that all kinds of memories evoked high-frequency activity in the high-school zone, but high-school memories did so less:

No other electrode location caused the same effects (or indeed, any detectable memory effects), although as you can see on the image at the top, the electrode coverage was not huge.

A little background: the guy had these electrodes in place because he suffered from epilepsy, resistant to medication, which was believed to originate in the temporal lobe. Temporal lobe epilepsy can cause memory phenomena rather like this, but this patient had never experienced that, and the electrically-evoked memories were experienced as entirely novel.

It's a nice case report and it raises many questions. Why is the high-school spot less active during memory retrieval? That seems the wrong way around (I did a double-take to make sure I was reading it properly).

And what would happen if you somehow disabled (or overactivated) this area, and asked him to remember a particular school memory? Would he draw a blank, or would he remember it but without the "high-school-ness"? What would that feel like?

Either way, this case suggests that memories are stored in the brain "by topic", in the sense that "similar" memories are associated with nearby areas of the brain. At least sometimes. But then, why didn't nearby electrodes evoke other memories? If there's a high-school spot, why not a kindergarten spot, a my-first-job spot?

Maybe those spots lay in areas with no electrode coverage... but the fact that many temporal electrodes didn't bring back any memories suggests that there's lots of cortex which isn't part of a "spot". Perhaps those areas are "spare", waiting to be used up? Clearly, he wasn't born with a high school spot. It must have emerged during high school. But in that case there had to be a "blank" area first.

Jacobs J, Lega B, and Anderson C (2011). Explaining How Brain Stimulation Can Evoke Memories. Journal of cognitive neuroscience PMID: 22098266

Scientific Databases - or Filters?

2011-12-07T08:11:00.002Z

A new online database called AutismKB offers a quick way to find the evidence linking genes to autism.

You can read up on it in a paper describing the project.

You can browse by chromosome or gene name, it includes data on all kinds of genetic variants from SNPs to CNVs and it gives each variant a score according to the strength of the evidence. I haven't had a chance to really tell how useful these scores are, but there's an option to create your own score based on how much weight you give different kinds of evidence. The dataset is huge although it doesn't seem to have been updated for a few months.

Overall, it's a new tool and there's sure to be bugs to iron out, but it seems like it could be very useful. I do worry though that this kind of database encourages misleading ways of thinking about autism genetics.

There are numerous genetic variants which have been strongly linked to autism, although none of them account for more a small proportion of cases because these variants are rare. But many (most, actually, is my impression) of them have also been observed in people with other symptoms ranging from ADHD to epilepsy to schizophrenia.

So searching a database of "autism genes" could encourage you to think that these were only autism genes, which is far from true. Genetics, it is becoming increasingly clear, doesn't respect our current concepts of psychiatric illness or our academic specialities. There are few (if any) parts of the genome that can be neatly fenced off and declared exclusive to ADHD experts, schizophrenia researchers or whatever.

But disease-specific databases encourage the illusion that they do exist. It's the same old problem of the filter bubble which many people have warned about in the context of general purpose search engines. Scientists have filter bubbles too.

This is not of course a criticism of AutismKB in particular - the same goes for any similar "disease-gene" database. And to be fair AutismKB does provide links to a schizophrenia database, and a couple of others but you have to dig quite deep to get there. The "main page" of results for any given variant is pure autism.

That's the whole problem with filter bubbles - they make it too easy to hear what you want to hear, compared to getting a new perspective, so you don't even think to look outside the filter.

Xu LM, Li JR, Huang Y, Zhao M, Tang X, and Wei L (2011). AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic acids research PMID: 22139918

The Network of Mental Illness

2011-12-06T17:43:00.000Z

A provocative but problematic paper just out offers a new perspective on psychiatric symptoms.

The basic idea is that rather than psychiatric disorders being entities, they are just bundles of symptoms which cause each other:

...symptoms are unlikely to be merely passive psychometric indicators of latent conditions; rather, they indicate properties with autonomous causal relevance. That is, when symptoms arise, they can cause other symptoms on their own. For instance, among the symptoms of MDE we find sleep deprivation and concentration problems, while GAD (generalized anxiety disorder) comprises irritability and fatigue. It is feasible that comorbidity between MDE and GAD arises from causal chains of directly related symptoms; e.g., sleep deprivation (MDE)→fatigue (MDE)→concentration problems (GAD)→irritability (GAD).

The authors seem to have mixed up their labels in the middle there, but you see the drift.

This symptom-based approach stands in contrast to the idea that psychiatric illnesses are underlying things which lead to some symptoms. So it's a challenge to the notion of underlying biological dysfunction (except maybe for specific symptoms) but it's equally incompatible with any theory of underlying psychological causes - there's no room for Freudian unconscious "complexes" here.

So there's something very straightforward and un-mysterious about this model, which will either make it attractive or suspect, depending on whether you think human life is mysterious or not.

What's the evidence? First, the authors do an analysis of the DSM-IV diagnostic manual in terms of symptoms. They take every symptom which is mentioned in at least one diagnosis. They found 439 symptoms in total, over 201 disorders, with many symptoms, such as insomnia, shared between lots of different "disorders".

They then used network analysis to create a kind of graph where the "distance" between the nodes (symptoms) is based on the number of shared diagnoses. They found that while some symptoms are unique to just one disorder, there's a core of highly shared symptoms which form a "giant component"

It's a very clever approach but I wonder what it really tells us. The DSM-IV is not data about mental illness. It's data about what we think about mental illness. Actually, it's not even that: it's data about what a particular set of people, at a particular time, were able to agree upon.

DSM-V is coming soon, and before that we had DSM's I, II and III. What about them? Do they have a different network structure? I'd have thought they would, but we don't know.

We've already seen the kinds of politics that lie behind the decision to include or exclude a diagnosis in the DSM. In the upcoming DSM-V they're seriously proposing to add a new diagnosis ("TDDD"), purely in order to stop people getting another diagnosis (childhood "bipolar").

There is a lot of symptom overlap between TDDD and bipolar disorder. Because one was designed for the purpose of diverting patients from the other. But that doesn't tell us anything about real people with real symptoms. This is an extreme example and to be fair to the authors they do acknowledge some of these problems with the DSM, but still.

The authors then show that the symptomatic closeness between DSM-IV disorders predicts the rates of comorbidity between those disorders, as measured in the American population survey the NCS-R. This is true even of disorders which don't share a common symptom but which are connected indirectly by a mutual friendship, as it were.

Finally they show that a statistical model based on interacting symptoms can predict the prevalence of depression (10% per year according to the NCS-R survey) and GAD (3% per year). It does so much better than a random model in which symptoms randomly interact.

However, I'm not convinced that all these show us that the symptom-network approach is the best model to explain the occurence of these disorders. It only shows us that it's a model that works better than a crazy random model. I'm also not sure that being able to model the NCS-R data is even a good thing, since these data are themselves of questionable validity.

But it's a genuinely interesting approach and well worth following up.

Borsboom D, Cramer AO, Schmittmann VD, Epskamp S, and Waldorp LJ (2011). The small world of psychopathology. PloS one, 6 (11) PMID: 22114671

A Psychedelic Tale of Two Neurotransmitters

2011-12-03T13:33:00.000Z

An unexpected interaction between neurotransmitter systems may explain psychosis and hallucinations, according to a fascinating new paper.

Serotonin (5HT) and glutamate are two neurotransmitters. Up until now, it was thought that they acted independently. A given neuron might have receptors for both serotonin and glutamate, but they didn't interact: serotonin would never affect the glutamate receptors, and vice versa.

The new research overturns that view. Authors Miguel Fribourg and colleagues of Mount Sinai School of Medicine show, in a series of elegant experiments in mice, that different receptors can cluster together, forming a complex. The two receptors, serotonin's 5HT2A and glutamate's mGluR2, can talk to each other.

However, this doesn't seem to happen under normal conditions. Serotonin and glutamate don't seem to trigger the receptor interaction, or at least not very much. Only certain drugs can do it. And this is where it gets really interesting.

Psychedelic drugs, like LSD, have long been thought of as 5HT2A agonists, binding to the receptor and activating it. It turns out that this was only half right. They also inhibit mGluR2 transmission via the receptor complex. Serotonin itself is a 5HT2A agonist, but it doesn't do that. So psychedelics seem to be a kind of (for want of a better word) "superagonist".

It also works in reverse. The antipsychotic drugs clozapine and risperidone are known as 5HT2A antagonists. But Fribourg et al show that they also activate the mGluR2 receptor.

And the cross-talk can go in the other direction. Certain molecules that act on mGluR2 can either inhibit or promote 5HT2A. Unlike psychedelics and antipsychotics, these mGluR2 drugs have not been tested in humans yet. But these data predict that they will have psychedelic-like or antipsychotic-like effects, depending which way they work.

The interaction turns out to be all about G proteins, which are part of the chain of transmitter substances that convey signals within the cell, in response to neurotransmitters outside it. Here's a chart showing the effects of various drugs on the balance between different G proteins: the LSD-like psychedelic DOI has the opposite effect from the antipsychotics clozapine and risperidone.

This paper builds on a previous one from the same team showing that psychedelic 5HT2A "agonists" (like LSD and DOI) have different effects on G proteins from other, non-psychedelic agonists. That was interesting in itself but by adding glutamate to the picture, this new paper is really ground-breaking.

This goes a long way to explaining one of the mysteries of serotonin which is this: if 5HT2A agonists like LSD are psychedelic, why aren't antidepressants the same? Almost all antidepressants work by increasing extracellular 5HT levels. That ought to mean that they activate 5HT2A receptors (indirectly). This explains why not - 5HT alone doesn't promote the crucial 5HT2A-mGluR2 interaction.

Taken together, these interesting results show clearly that 5HT2A and mGluR2 are hooking up and doing something exciting. Certainly in terms of how hallucinogens work.

I'm less convinced that this can directly explain antipsychotic effects though. The problem is that while newer "atypical" antipsychotics act on 5HT2A, the older antipsychotics don't, and atypicals are at best only slightly more effective on average.

What we don't yet know is whether this kind of complex receptor interactions can happen with other receptors. I'd have thought it unlikely that these two receptors were the only ones that could ever do it. The synapse looks like it's more complex than we could have imagined.

Fribourg M, et al. (2011). Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs. Cell, 147 (5), 1011-23 PMID: 22118459

Beware Good Theories

2011-12-01T07:22:00.000Z

The ancient Greeks had a lovely theory. Certain places on the earth (caves, mostly) were, they thought, gateways to the underworld. Plants growing near these places could absorb the deadly essence of Hades and became poisonous.

Snakes and other venemous creatures got their poison by consuming these plants. And stinging insects got their little doses of poison by feeding off dead snakes.

Isn't that a great narrative? It explains everything, in a nice logical progression. OK, it presupposes what we would call a "supernatural" force as the ultimate origin of poison, but other than that, it's an entirely "scientific" account. In accordance with Occam's Razor, it proposes a single unified process underlying diverse phenomena.

It is, in other words, a perfect scientific theory. It's completely wrong, on every point, but we only know that because we now understand atoms, molecules, chemistry and biochemistry, which the Greeks had no way of knowing. At the time, the Hades theory was surely the best possible theory about where poison came from.

The moral of this story is, beware nice theories based on incomplete data.

Reference: Greek Fire, Poison Arrows and Scorpion Bombs, which I'm currently reading, all about chemical and biological weapons.

Cognitive Behavioural Therapy vs. Psychoanalysis

2011-11-29T10:15:00.000Z

Clinical trials of cognitive behavioural psychotherapy (CBT) for depression are often of poor quality - and are no better than trials of the rival psychodynamic school.

So says a new American Journal of Psychiatry paper that could prove controversial.

CBT is widely perceived as having a better evidence base than other therapies. The "creation myth" of CBT (at least as I was taught it) is that it was invented by a psychoanalyst who got annoyed at the unscientific nature of psychodynamic i.e. Freudian-influenced therapy. CBT has always looked on clinical trials more favorably than the dynamic school.

However, the authors of this meta-analysis found that while there are certainly lots of published CBT trials for depression, they're actually no better quality than the psychodynamic trials.

"Surprisingly" (their word), they found no difference between the CBT for depression trials, and the psychodynamic trials, on a rating score of trial methodology.

Trials got better over time, but the two groups improved equally (see above). The mean score was 25.5 for CBT and 25.1 for dynamic, on a scale that goes from 0 to 48. Anything over 24 points is deemed acceptable but this is clearly an arbitrary cut-off.

The RCTP-QRS scale is relatively new and it was developed by the people who wrote this paper (albeit with the input of other experts.) There's 24 items and each gets a score from 0 (bad) to 2 (good). Items are things like "Adaquate sample size", "Patients randomly assigned to group", etc.

Worryingly, better CBT trials tended to find smaller benefits of CBT over the comparison treatment. The overall results showed that while CBT was clearly better than doing nothing, it was pretty much the same as antidepressants, and other psychotherapies, in adults with depression:

The article follows one from the same group, Gerber et al, who reviewed the evidence for psychodynamic therapy in more detail. And last year, another team reported evidence of publication bias in psychotherapy trials. In this study, the authors report possible publication bias, but they don't go into detail.

Overall this is interesting stuff, and a reminder that while CBT has the most evidence of any psychotherapy, this is not the same thing as saying that it has the best evidence...

Nathan C. Thoma et al (2011). A Quality-Based Review of Randomized Controlled Trials of Cognitive-Behavioral Therapy for Depression: An Assessment and Metaregression American Journal of Psychiatry

Beware Dead Fish Statistics

2011-11-26T14:32:00.000Z

An editorial in the Journal of Physiology offers some important notes on statistics.

But even more importantly, it refers to a certain blog in the process:

The Student’s t-test merely quantifies the ‘Lack of support’ for no effect. It is left to the user of the test to decide how convincing this lack might be. A further difficulty is evident in the repeated samples we show in Figure 2: one of those samples was quite improbable because the P-value was 0.03, which suggests a substantial lack of support, but that’s chance for you! A parody of this effect of multiple sampling, taken to extremes, can be found at http://neuroskeptic.blogspot.com/2009/09/fmri-gets-slap-in-face-with-dead-fish.html

This makes it the second academic paper to refer to this blog as far. Although I feel rather bad about this one, since the citation ought to have been to the original dead salmon brain scanning study by Craig Bennett. I just wrote about it.

Actually, though, this editorial was published in five separate journals: The Journal of Physiology, Experimental Physiology, the British Journal of Pharmacology, Advances in Physiology Education, Microcirculation, and Clinical and Experimental Pharmacology and Physiology. Phew.

In fact, you could say that this makes not two but six citations for Neuroskeptic now. Yes. Let's go with that.

Anyway, after discussing the history of the ubiquitous Student's t-test - which was invented in a brewery - it reminds us that the p value you get from such a t-test doesn't tell you how likely it is that your results are "real".

Rather, it tells you how often you'd get the result you did, if there was no effect and it was just random chance. That's a big difference. A p value of 0.01 doesn't mean your results are 99% likely to be real. It means that there's a 1% chance that you'd get them, by chance. But if you did say 100 experiments, or more likely, 100 statistical tests on the same data, then you'd expect to get at least one result with a p value of 0.01 purely by chance.

In that case it would be silly to think that the finding was only 1% likely to be a fluke. Of course it could be true. But we'd have no particular reason to think so until we get some more data.

This is what the dead salmon study was all about. This multiple comparisons issue is very old, but very important. Arguably the biggest problem in science today is that we're doing too many comparisons and only reporting the significant ones.

Drummond GB, & Tom BD (2011). Statistics, probability, significance, likelihood: words mean what we define them to mean. British journal of pharmacology, 164 (6), 1573-6 PMID: 22022804

A Dangerous Truth about Antidepressants

2011-11-25T09:25:00.000Z

An opinion piece by veteran psychiatrist and antidepressant drug researcher Sheldon Preskorn contains a remarkable historical note -

“A dangerous idea!” That was the response after a presentation I gave to a small group of academic leaders with an interest in psychopharmacology [over 15 years ago].

What evoked such a response? The acknowledgment that most currently available antidepressants specifically treat only one out of four patients with major depression based on the bulk of clinical trials data.

There was no argument about the accuracy of this statement, but...some claim it is “dangerous” to admit that the specific response rate to most antidepressants is 20%–30% because such an acknowledgment might undermine the value of antidepressant treatment.

By the "specific" response rate Preskorn means the number of depressed people who'll get better on antidepressants and who wouldn't have done so well on placebo. This rate is fairly low because, while most people get better on antidepressants, most of those improve on placebo as well.

Preskorn rejects the view that it's dangerous to acknowledge this:

...there are several problems with this reaction. First, it is hard to deny reality. The “placebo” response rate in antidepressant trials is arguably the most reproducible finding in psychiatry. Moreover, if available antidepressants were magic bullets, then polypharmacy would not be so common. Second, this reaction ignores the fact that antidepressants are tremendously valuable to the patients who specifically benefit from them...

Every treatment in every area of medicine has limitations. Acknowledging that fact should galvanize us to action. Denial on the other hand perpetuates the status quo.

Unfortunately, we're not told who these academic leaders were. I wonder if they included amongst their ranks some of the "key opinion leaders" in the field whose leadership proved rather less than ideal. The column is actually adapted from a 1996 article by Preskorn.

Preskorn is right, of course, that denying the fact that antidepressants are only substantially better than placebo in a fraction of people who get diagnosed with "depression" is wrong, and also misses the point: because hundreds of millions of Americans have diagnosable depression (due to the loose definition of "depression"), even if they only helped 1% of them, they'd still help over a million people.

But he doesn't mention that this approach was ultimately self-defeating. As a result of the failure to acknowledge that antidepressants are only helpful in some cases of depression (namely "severe" depression), these drugs became very widely used and - oh dear - people started saying that the drugs are being overused, and don't work in most people who take them.

Whoever could have seen that coming.

This has "devalued" antidepressants - and psychiatry itself - more than anything else has.

Preskorn SH (2011). What Do the Terms "Drug-Specific Response/Remission Rate" and "Placebo" Really Mean? Journal of psychiatric practice, 17 (6), 420-424 PMID: 22108399

The Gene That's "For" Nothing

2011-11-23T18:23:00.001Z

Scientists like to warn you not to talk about "the gene for" a particular disease or trait.

I've done so in previous posts e.g. this one or this one.

But such scalding is not always very effective. We like simple explanations, so we like to find simple connections between genes and phenotypes.

Which is why a new paper is important. The authors, a large Turkish-American collaboration, found that mutations in a gene, WDR62, are associated with severe brain malformations in 9 patients. But what's interesting is that it doesn't cause any particular malformation.

If you have two faulty copies of this gene, your brain won't be normal, but what goes wrong varies widely amongst different people. Although the 9 cases had some features in common, such as microcephaly (small head and brain), in other respects they differed greatly.

As the authors put it, mutations in WDR62 cause

a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients... had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities.

These are distinct entities, in the sense that you can have any one of them, without having the others. And they are different brain changes. What the authors mean is that everyone assumed that, because they're different, they must have different genetic causes. They've just shown that this is wrong.

So what is WDR62 "for"? Experiments in mice showed it to be involved in the migration of new neurons from their origin to their final location in the brain. So it's "for" correct neuronal placement, although how it works remains unclear.

WDR62 ought to remind us that there's a long and winding road from gene to phenotype, and that the same gene can, when mutated, cause very different symptoms. This is especially interesting in the light of recent evidence showing that the same mutations can cause a range of behavioural disorders from autism to ADHD to schizophrenia.

Bilgüvar K, et al (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467 (7312), 207-10 PMID: 20729831

Was Evita Lobotomized?

2011-11-22T07:36:00.001Z

Eva Peron, or Evita, is perhaps the most famous woman in Latin American history. As the wife of Argentinian leader Juan Peron she was immensely popular. But she died at the age of just 33 from cervical cancer, after a two year struggle with the disease.

A new paper makes the startling claim that Eva Peron may have received a prefrontal lobotomy in the months before her death. The lobotomy is best known as a treatment for mental disorders such as schizophrenia, but according to Nijensohn et al, Peron was given the operation as a kind of pain relief.

The claim was first made in 2005 by Dr George Udvarhelyi, who worked as a neurosurgeon in Argentina before moving to John Hopkins in Baltimore. After his retirement, Udvarhelyi told the Baltimore Sun that he'd performed the operation.

The authors of this paper checked out the claims against his unpublished memoirs. It turns out that they've just written Udvarhelyi's biography, and managed to slip in a plug for their book. Indeed, this paper could be seen as a plug. But anyway.

The early 1950s were the golden age of lobotomy and it does seem plausible that if she had one, it would have been kept secret. But it seems that the only direct evidence is Udvarhelyi's testimony. The authors point to various facts that could be seen as consistent with it, like this memoir by a close friend:

“The illness continued to advance. I visited her one afternoon andwas shown a notebook belonging to her brother Juancito. There was a drawing of Evita with her head criss-crossed by scissors. The sinister image suggested that she was either crazy or brain damaged. I found her very thin, quiet, and deeply introverted”

But to be honest this is pretty weak. The authors also admit that in interviews with scholarly experts on Peron's illness, they were all surprised by the idea.

They then point to postmortem X-rays of Peron's skull which were made public in 1955 to prove that her corpse hadn't been burned (long story). These, they suggest, show evidence of the kind of burr holes that were used to insert the lobotomy tools -

And they say that a photo of her shortly before her death shows an "indentation at the coronal level" -

Hmm. Not sure what to make of those. Ultimately though, the authors admit that the only way to know for sure would be to exhume Evita and study her skull, but this is unlikely to happen any time soon.

Nijensohn DE, Savastano LE, Kaplan AD, & Laws ER Jr (2011). New Evidence of Prefrontal Lobotomy in the Last Months of the Illness of Eva Perón. World neurosurgery PMID: 22079825

Potential Personal Genomics

2011-11-19T10:35:00.001Z

A while ago I wrote about how new findings in genetics could herald a new kind of "eugenics", based not around selective breeding to ensure that "bad" genes aren't passed on, but rather based on using fetal genetic testing to choose which variants enter the gene pool in the first place.

I said-

In the near future, we might be able to routinely sequence the genome of any unborn child shortly after conception

But I didn't realize that this may be really very near indeed. Two recent reports have shown that it's possible to sequence fetal DNA from a maternal blood sample. In one case it was used to diagnose a 35 week fetus with a genetic deletion on chromosome 12 seemingly associated with autism, developmental delay and shortness.

In this case it was inherited from the father (which is why they decided to test for it), but this approach could equally be used to screen for the de novo mutations that account for much disease, as I discussed in the last post.

This is big. Currently, the main way to get fetal DNA is through amniocentesis, i.e. inserting a needle into the womb. It's a substantial and not entirely safe medical procedure. A blood sample would be an order of magnitude cheaper and safer, but most of all it would be something you could do at home.

No longer would you need to go to a hospital and discuss everything with a doctor. You could take some blood, send it off anonymously to a sequencing company, and get the results in an email. It would take it out of the hands of professionals and open up a space for individual choice.

The cost of whole-genome sequencing has been falling exponentially and many think it will fall below the $1000 mark within a few years. Combine that with fetal DNA testing and we might see moderately well-off parents able to sequence fetal DNA within the next decade.

When this happens I think the personal genomics industry will suddenly become extremely "hot". At the moment you can sequence your own DNA for a few thousand $ if you want. The results may be interesting but they're of little obvious use. Whatever your genes are, you're stuck with them.

But as soon as we're talking about potential human genomes, it'll kick things up a notch. Media interest and political controversy is sure to follow. Personally I think it'll the debate will begin in earnest when we start seeing selective abortions on the basis of genes for "normal" variants rather than "disease" genes.

It's one thing to not want a child with blindness, or a high risk of leukaemia. But as a society I don't think we're ready for not wanting a child because they're predicted to be a B student rather than an A student, or brunette rather than blonde. At some point soon, though, we'll have to decide what we think about that.

Peters D, Chu T, Yatsenko SA, Hendrix N, Hogge WA, Surti U, Bunce K, Dunkel M, Shaw P & Rajkovic A (2011). Noninvasive prenatal diagnosis of a fetal microdeletion syndrome. The New England journal of medicine, 365 (19), 1847-8 PMID: 22070496

Srebniak M, Boter M, Oudesluijs G, Joosten M, Govaerts L, Van Opstal D, & Galjaard RJ (2011). Application of SNP array for rapid prenatal diagnosis: implementation, genetic counselling and diagnostic flow. European journal of human genetics : EJHG, 19 (12), 1230-7 PMID: 21694736

Does MRI Make You Happy?

2011-11-18T08:49:00.000Z

A startling new paper from Tehran claims Antidepressant effects of magnetic resonance imaging-based stimulation on major depressive disorder.

Yes, this study says that having an MRI scan has a powerful antidepressant effect.

They took 51 depressed patients, and gave them all either an MRI scan or a placebo sham scan. The sham was a "scan" in a decommissioned scanner. The magnet was off but they played recorded scannerish sounds to make it believable. Patients were blinded to group.

They found that people in the scanner group improved much more than those in the sham group over two weeks. Actually there were two different kinds of scans, T1 structural MRI and EPI functional MRI, but they were the same:

Now, if this is true, it's huge. Obviously. For one thing, it would undermine the whole premise of functional MRI, which is that it's a method of recording brain activity. If it's also stimulating the brain in some way at the same time, then it would make it hard to interpret those activations. In particular it would cast all the studies using fMRI in depression into doubt.

So is it true? I can't see any obvious flaws in the design. Assuming that the authors are right when they say that "patients could not distinguish the difference between the actual and sham MRI scan", i.e. assuming that the blind was truly blind, then the methodology was sound.

But let's look at the statistics. The paper is full of very impressive p values less than 0.001 but those turn out to all be referring to the changes within each group, and those changes are fairly meaningless. What matters is the differences in the groups and

Changes in BDI scores (between baseline and day 14) were significantly different among the three studied groups (F=5.48, p=0.007 overall) using ANOVA, and between the DWI group vs. Sham and T1 vs. Sham (p<0.05) using post hoc tests. Changes in HAMD24 scores (between baseline and day 14) were also compared among the 3 groups using ANOVA but the level of significance was slightly above the significance threshold (F=2.89, p=0.06).

Which is rather less convincing. There was a close-to-significant group difference in the HAMD24, and a significant but only just effect on the BDI. Remember that there were only 17 people in each group.

I'm inclined to think that this is one of the 5% of experiments which will produce a nominally significant result even assuming everything goes to plan and there are no confounds. My suspicion is that everyone in the trial got better (they were all on antidepressants, plus there's the placebo effect and the effect of time) - except a small number of people who didn't improve. And by chance they were all in the sham group.

The reason I'm skeptical is that I just can't see a plausible mechanism. The authors suggest that MRI scans might stimulate the brain in a similar way to TMS and that this could have antidepressant effects.

But there's a lot of problems with this: 1) the evidence is questionable whether TMS even works for depression 2) the magnetic stimulation of the brain generated during MRI is much weaker than in the case of TMS and 3) if MRI really stimulated the brain like TMS, then, like TMS, it would have a risk of triggering seizures in people with epilepsy. But it doesn't.

Vaziri-Bozorg SM, et al (2011). Antidepressant effects of magnetic resonance imaging-based stimulation on major depressive disorder: a double-blind randomized clinical trial. Brain imaging and behavior PMID: 22069111

One in Four Revisited

2011-11-16T07:46:00.000Z

In a recent Telegraph article, professional contrarian Brendan O'Neill argues against the idea that one in four people experience mental illness - and indeed against the idea that one in four people are bullied, abused or whatever else:

Can it really be true that a quarter of Brits are bullied or beaten up at home or are mentally ill, or is this simply a case of social campaigners exaggerating how bad life is in order that they can continue to make headlines, make an impact, and get funding? I reckon it's the latter. Next time you see the "one in four" figure, be very sceptical – it's probably Dickensian-style doom-mongering disguised as social research, where the aim is to convince us, against the evidence of our own eyes and ears, that loads of the people we encounter everyday are basket cases in need of rescue.

I say "argues against", but he doesn't actually provide any arguments. He just links to the claims and says they're silly.

As Neuroskeptic readers know, I am myself skeptical of the idea that one in four people are mentally ill, but I'm skeptical of it because I've looked at the evidence and it doesn't support that figure. Actually, if you take the available evidence at face value, it says that the true figure for the lifetime prevalence is much higher than one in four. I don't think those figures are very useful however because of various methodological issues.

So in my view we just don't know how many people are mentally ill, largely because we don't have any clear definition of what "mentally ill" means. But that doesn't mean we can just assume that it can't possibly be one in four just because "our own eyes and ears" tell us that most people are not "basket cases".

Much mental illness goes undiagnosed and unnoticed, and I'd imagine also that Brendan O'Neill and the kind of people who read him don't tend to "encounter everyday" people from groups such as the unemployed, the elderly and so forth, in whom the rates are higher.

But even beyond that, it's a silly argument because of selection bias. If you as a healthy person encounter someone everyday, chances are they're not severely ill - mentally or physically - because if they were, they'd be less likely to be around in places for you to encounter. Unless you're a doctor or whatever, you live your life in the world of healthy people.

It's like saying that you don't believe children or the elderly exist, because in your life as a working age adult, you never meet any of them.

Modern War-fMRI : Graphics Cards for Science

2011-11-14T21:07:00.000Z

Videogames and neuroscience have a rocky relationship.

On the one hand you have Susan Greenfield and her games-hurt-the-brain theory. But she's not representative of neuroscientists as a whole: games have also helped neuroscience, for example, in this study of the neural correlates of "flow" experiences.

Now neuroscientists have another reason to be thankful for games, according to a new paper. It turns out that modern 3D graphics cards - which mostly exist in order to render videogame visuals - can be used to do fMRI data analysis.

According to Sweden's Eklund et al, a graphics card can perform intensive fMRI analysis hundreds of times faster than a regular processor of the equivalent speed, because graphics processors make use of parallel computing optimized for 3D images and that's ultimately what all brain scans are.

They developed a way to run non-parametric statistical analyses of brain imaging data. Proponents say that non-parametric stats have many advantages over conventional parametric ones - and they're certainly becoming increasingly popular. But they involve doing far more calculations. Thousands of times more, in some cases.

It turns out though that armed with 2.5 GHz CPU and three NVidia GTX 480s, and making use of NVidia's graphics programming language, they were able to cut the time to analyse one person's brain with 100,000 permutations, from 24 hrs to just 9 minutes. The whole setup cost $4000, so it's not cheap, but they say it's "a fraction of the price for a PC cluster with equivalent computational performance" i.e. one relying on lots of general purpose processors, rather than graphics cards. Even on GTX480 did the job very well.

Best of all, this gives neuroscientists an excuse to spend their grant money on awesome gaming rigs. Why do I want the latest GForce on my work computer? To do non-parametric data analysis, obviously. Sure, it would also allow me to run Modern Warfare 3 at the highest settings... but that's not why I want it.

Eklund A, Andersson M, Knutsson H (2011). Fast random permutation tests enable objective evaluation of methods for single-subject FMRI analysis. International journal of biomedical imaging, 2011 PMID: 22046176

Autism: What A Big Prefrontal Cortex You Have

2011-11-12T12:27:00.000Z

A new paper has caused a lot of excitement: it reports large increases in the number of neurons in children with autism. It comes to you from veteran autism researcher Eric Courchesne.

Courchesne et al counted the number of cells in the prefrontal cortex of 7 boys with autism and 6 non-autistic control boys, aged 2-16 years old. The analysis was performed by a neuropathologist who was blind to the theory behind the study and to which brains were from which group. That's good.

They found that the total brain weight of the brain was increased in autistic boys, by about 17% on average. But the number of neurons in the prefrontal cortex was increased by an even higher margin - about 60%. The difference was specific to neurons - glial cell counts were normal. Of the 7 autistic boys, 4 also had intellectual disability - an IQ less than 70. However, the 3 without showed broadly similar results.

As well as having more prefrontal neurons, there were also some other issues in some but not all of the autism brains. Two had prefrontal cortical abnormalities - dysplasia in one case and abnormal cell orientation in another. And no fewer than 4 had flocculonodular lobe dysplasia in the cerebellum.

None of the nonautistic brains had any abnormalities reported but they don't seem to have looked very closely in the controls because that was based on "coroner's report only", rather than a detailed neuropathological exam...

It's a nice piece of work, but very small. These postmortem neuropathology studies always are because postmortem brain samples are in short supply, especially for disorders like autism.

In fact, it's so small, that doing statistics on these data is not really meaningful. The authors do some stats and get some impressive p values but we should take those with a pinch of salt and just look at the individual data (see the scatterplots above).

Now, prefrontal cortical neurons are generated while you're still in the womb. New ones can't be created after you're born - numbers can only decrease. So the increased neuron count in autism must have a very early origin, either genetic or caused by pre-natal environmental factors. Unless the timeline for cell genesis is totally different in autism.

Still, it casts doubt on the idea that, in the brain, bigger is always "better". Assuming that we consider autism to be "bad" - which I'm not saying is necessarily right, but it's fair to say most people do assume that - then the common practice of equating volume increases with all kinds of good things seems rather silly.

Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, & Pierce K (2011). Neuron number and size in prefrontal cortex of children with autism. JAMA : the journal of the American Medical Association, 306 (18), 2001-10 PMID: 22068992

Another Antidepressant Bites The Dust

2011-11-11T07:30:00.000Z

Yet another up-and-coming antidepressant has flopped.

A paper just out reveals that the snappily-named GSK372475 doesn't work and has lots of side effects. It's a report of two clinicals trials in which Glaxo's contender was pitched against placebo and against older antidepressants in the treatment of depression.

GSK372475 failed to improve depression any better than placebo, even though the trials were large (393 and 504 patients respectively) and twice as long as most antidepressant trials (10 weeks whereas 4 or 6 is more usual)which ought to have given it plenty of room to shine.

The comparison drugs, the widely used venlafaxine and paroxetine, did work. A bit.

One of the trials even used the Bech "Melancholia Subscale" as an outcome measure, which Neuroskeptic readers may remember as I've praised it before. Venlafaxine worked on that, GSK's new pill didn't. If anything, the new drug was worse than placebo, in that patients improved slower.

In terms of side effects it caused dry mouth, insomnia, and nausea serious enough to make many people quit the study early. But even worse, it raised heart rate by almost 10 beats per minute on average, which is really never a good sign.

So, overall, it was an utter flop. In one sense this is not surprising. New "antidepressants" that don't work in trials have been all too common recently. Just last week we learned about the failure of "Serdaxin" in a Phase II trial. Actually Serdaxin isn't a new drug but an old antibiotic called clavulanic acid that a company was trying to rebrand as a mood lifter.

However the failure of GSK372475 is a bit of a mystery. The drug is a potent triple reuptake inhibitor (TRI) which acts on the neurotransmitters serotonin, noradrenaline and dopamine. By contrast, venlafaxine is a double reuptake inhibitor which doesn't hit dopamine, and paroxetine only targets serotonin. I've written about other TRIs before.

Now it seems surprising that venlafaxine worked, but a TRI didn't, in the same trial. That would imply that blocking the reuptake of dopamine makes you more depressed, enough to cancel out the other actions which are shared with venlafaxine. Which is not what I'd have predicted.

There are other differences between the drugs though. Venlafaxine has a very short half-life - it's broken down in the body in a matter of hours. But GSK372475 has a halflife of 8-10 days. Could this be the problem?

Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, Zamuner S, Evoniuk G, & Ratti E (2011). Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials. Journal of psychopharmacology (Oxford, England) PMID: 22048884

The Transexual Brain

2011-11-09T08:07:00.001Z

According to a new paper, the brains of male-to-female transexuals are no more "female" than those of men.

The authors write that "The present data do not support the notion that brains of male-to-female transexuals are feminized" and conclude "The present study does not support the dogma that male-to-female transexuals have atypical sex dimorphism in the brain".

That last sentence has gained quite a bit of coverage, including a quote on the Wikipedia page for "transgender".

But is it so simple?

Structural MRI scans were used to compare the size of various brain structures between three groups of volunteers: heterosexual men, heterosexual women and the transexuals (or "MtF"s as I will call them for short) who were diagnosed with gender dysphoria and were "genetically and phenotypically males".

There were 24 in each group, which makes it a decent sized study. None of the MtFs had started hormone treatment yet, so that wasn't a factor, and none of the women were on hormonal contraception.

The scans showed that the non-transsexual male and female brains differed in various ways. Male brains were larger overall but women had increases in the relative volumes of various areas. Male brains were also more asymmetrical.

The key finding was that on average, the MtF brains were not like the female ones. There were some significant differences from the male brains, but they weren't the same differences that distinguished the females from the males.

This is a fairly crude approach. It looks at the groups on average. It's a finding, but there's more you could with this data. It would be better perhaps to look at the male and female groups, and then try to work out which group each individual MtF is most similar to. You could do that using a Support Vector Machine such as was previously used to detect autism.

This would also have the advantage that it would integrate the results across different brain areas: maybe the important thing is not just the size of individual areas but the relative size of one area to another area.

My real problem though is with the language used to discuss the data. The authors say that the study doesn't support "atypical sex dimorphism in the brain" yet this wasn't a study of "the brain". It was a study of one specific aspect of the brain, namely the volume of different regions. There could be all kinds of chemical and microstructural differences that don't show up on these scans.

There are lots of people with severe epilepsy, for example, whose brains clearly differ in some major way from people without epilepsy, yet they look completely normal on MRI. Only using other methods, like EEG, reveals the difference. Because the difference is chemical, not structural.

I have no idea how, or if, the brains of MtF transsexuals are "feminized" but this study doesn't rule it out. Now I'm sure the authors know all this. And in fact they themselves recently published a paper showing atypical neural responses to smelling "oderous steroids" in transsexual people. But while neuroscientists will know what they meant, I worry that studies like this could be miscontrued by other people (like Wikipedia readers) as a result of overenthusiastic language in papers.

Link: Also blogged at BPS Research Digest.

Savic I, & Arver S (2011). Sex dimorphism of the brain in male-to-female transsexuals. Cerebral cortex (New York, N.Y. : 1991), 21 (11), 2525-33 PMID: 21467211

Susan Greenfield's Dopamine Disaster

2011-11-06T11:09:00.001Z

It's Susan Greenfield again.

Continuing her campaign warning of the dangers of modern technology in terms of their effects on the vulnerable brains of the young, the British neuroscientist and Baroness has written another article. This is the latest of many. None of them have been in peer reviewed academic journals.

This one's behind the Great Times Paywall so I can't link to it, but it's called Are video games taking away our identities?

The first part of the article is hard to argue against. Either you'll agree with it or you won't. Personally, videogames as Greenfield describes them bear little resemblance to any games that I've played recently. Similarly for her account of the Internet. But maybe this rings true for some:

Screen images do not depend for their impact on seeing one thing in terms of anything else. Their premium lies invariably in their raw sensory content... we are perhaps heading towards a much weaker sense of identity by engaging in a world where we are the passive recipient of senses and where there is no fixed narrative of past and future but an atomised thrill of the moment. One could even suggest that the constant self-centred readout on Twitter belies a more childlike insecurity, an existential crisis.

Greenfield then moves into discussing the brain, and this is where the science comes in. This is her "home turf" - she's Professor of physiology at Oxford. Yet it's a shambles.

There is one alarm bell ringing, which suggests that increasing 2D screen existence may be having undesirable effects: it is the threefold increase over the past decade in prescriptions for drugs for attention deficit hyperactivity disorder.

While this could be due to changes in doctors’ prescribing procedures, or indeed to a greater recognition and medicalisation of attentional problems, a third possibility could indeed be that if the young brain is exposed from the outset to a world of fast action-reaction, of instant new screen images flashing up with each press of a key, then such rapid interchange might lead to a shorter attention span.

The human condition can be basically divided into two alternating modes, first described by Euripedes... the rational “bread force”, characterised by a strong cognitive take on the world — a personalised past, present and future, in turn related to an active prefrontal cortex and lower levels of the brain chemical dopamine; and the “wine force”, more the state of young children or those adults indulging in “letting themselves go”, in situations perhaps involving wine, women and song, where a strong sensory environment demands less reflection, more passive reaction.

...An increase in physiological arousal can be linked to excessive release of dopamine. Could the screen experience be tilting this ancient balance in favour of the more infantile, senses-driven brain state?

Greenfield says that high dopamine and low prefrontal cortex activity is associated with irrationality and a deficit in attention. Video games are causing a flood of dopamine and causing ADHD. That would make sense, if ADHD was caused by too much dopamine, and if drugs for ADHD reduced dopamine release.

The problem is that it's the exact opposite. Drugs for ADHD increase dopamine release and ADHD is widely believed (although it's controversial) to be caused by a dopamine deficit.

Greenfield then says "We know too that dopamine suppresses the activity of neurons in the prefrontal cortex", but this is a serious oversimplification. Dopamine has complex effects on target neurons. It can inhibit firing, but it can also excite it. It all depends on the conditions. Here's what the authors of an influential scientific review said in 2004: "It is agreed by most researchers is that dopamine is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter"

Some say that dopamine helps to "tune" the prefrontal by increasing the signal to noise ratio - more signal, less noise. Here's one of the most cited papers about dopamine and the PFC: Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey.

Remember that drugs for ADHD like Ritalin, which are sometimes used illicitly by students without that disorder to help them focus and concentrate, cause dopamine release. If Greenfield were right, it would be the exact opposite.

...[other] people characterised by an underactive prefrontal cortex are those with schizophrenia, this time not due to physical damage but rather a chemical imbalance, in particular an excessive amount of the transmitter dopamine. In schizophrenia, like children, the patient is easily distracted, cannot interpret proverbs, is not strong on metaphor but takes the world literally; it is a vibrant world that can implode on, and overwhelm, the fragile firewall of the schizophrenic mindset.

This again is a serious simplification. Actually, you don't need to be a neuroscientist to work that out. Just recall the earlier bit: Greenfield has said that ADHD is caused by too much dopamine leading to an underactive prefrontal cortex. Now she says that schizophrenia is the same. So why are the symptoms of ADHD completely different from schizophrenia?

Why is it, in fact, that Ritalin and similar dopamine releasing drugs help with ADHD, but can make schizophrenia worse?

As a neuroscientist, I can tell you that we don't really know what's going on with dopamine in ADHD or schizophrenia. There's decent evidence that dopamine is involved in schizophrenia, but not in any straightforward sense. Schizophrenia is now believed to be linked to reduced dopamine in the prefrontal cortex, and too much in other areas.

As for ADHD, remember: the leading theory is that it's about too little dopamine. Not too much.

The only disease that we know certainly is associated with too little dopamine is Parkinson's. Contrary to Greenfield's theory, people with Parkinson's often have cognitive and mood problems as well as the better known difficulties with movements. They're not super intelligent, prefrontal-cortex-wielding geniuses.

I appreciate that an opinion piece in the Times is never going to be a rigorously argued scientific paper, but the fact that Greenfield's article contains several claims which are the exact opposite of the truth (or at least of current scientific thinking) calls her credibility into serious question.

Dream Action, Real Brain Activation

2011-11-04T09:18:00.004Z

A neat little study has brought Inception one step closer to reality. The authors used fMRI to show that dreaming about doing something causes similar brain activation to actually doing it.

The authors took four guys who were all experienced lucid dreamers - able to become aware that they're dreaming, in the middle of a dream. They got them to go to sleep in an fMRI scanner. Their mission was to enter a lucid dream and move their hands in it - first their left, then their right, and so on. They also moved their eyes to signal when they were about to move their hands.

Unfortunately, only one of the intrepid dream-o-nauts succeeded, even though each was scanned more than once. Lucid dreaming isn't easy you know. Two didn't manage to enter a lucid dream. One thought he'd managed it, but the data suggested he might have actually been awake.

But one guy made it and the headline result was that his sensorimotor cortex was activated in a similar way to when he made the same movements in real life, during the lucid dream - although less strongly. Depending on which hand he was moving in the dream, the corresponding side of the brain lit up:

EEG confirmed that he was in REM sleep and electromyography confirmed that his muscles were not in fact being activated. (During REM sleep, an inhibitory mechanism in the brain prevents muscle movement. If the EMG shows activity this is a sign that you're actually partially awake).

They also repeated the experiment with another way of measuring brain activation, NIRS. Out of five dudes, one made it. Interesting this showed the same pattern of results - weak sensorimotor cortex activation during movement - but it also showed stronger than normal supplementary motor area activation, which is responsible for planning movements.

This is rather cool but in many ways not surprising. After all, if you think about it, dreaming presumably involves all of the neural structures that are involved in really perceiving or doing whatever it is you're dreaming about. Otherwise, why would we experience it so clearly as being a dream about that thing?

It may be, however, that lucid dreaming is different, and that the motor cortex isn't activated in this way in normal dreams. I suppose it depends what the dream was about.

That raises the interesting question of what someone with brain damage would dream about. On the theory that dream experiences come from the same structures as normal experiences, you shouldn't be able to dream about something that you couldn't do in real life... I wonder if there's any data on that?

Dresler M, Koch SP, Wehrle R, Spoormaker VI, Holsboer F, Steiger A, Sämann PG, Obrig H, & Czisch M (2011). Dreamed Movement Elicits Activation in the Sensorimotor Cortex. Current biology : CB PMID: 22036177

Who Should Catch Fraud?

2011-11-02T09:24:00.004Z

Whose job is it to detect scientific fraud?

You've probably heard of Diederik Stapel, a Dutch psychologist who's just admitted to scientific fraud on a grand scale, with dozens and maybe over 100 papers published based on made-up data. This comes just months after Harvard's Marc Hauser resigned over unspecified data-meddling activities.

What disturbs me is not just that this fraud happened, but the way it was detected. Both Stapel and Hauser were busted by their own junior lab members. Browsing Retraction Watch and reading over other fraud cases reveals that fraud is almost always detected either by 1) By readers of published papers who notice oddities in the data, or 2) by internal whistleblowers, almost always junior lab members

But these are both ad hoc methods. They rely heavily on individual vigilance and courage in speaking out (especially in the latter case). It seems to me that there's no working mechanism for catching fraud. If there were, such acts of individual heroism wouldn't be needed.

So whose job is it to catch fraud? At the moment, it's all the work of private investigators. Where are the police?

First off, is it the job of journals? That seems plausible. Journals publish scientific papers and by doing so they are saying, implicitly, that the papers are good quality. The way this works is meant to be through peer review.
But peer review is failing to catch many cases of fraud. I guess we don't know how many fraudlent papers are caught at the peer review stage and never published. But one would hope that such cases would come to light anyway because reviewers who suspect fraud ought to alert the relevant authorities. I can't think of any recent cases in which fraud investigations were started by peer reviewers, or at least not that we know about.

Maybe it's up to the institution that employs the fraudster? It's the institution that carries out investigations, "convicts" the fraudster and enacts the punishment. Clearly it's in their interests to do this because they don't want to be seen as soft on misconduct. But rarely do they go out and proactively try and catch or prevent fraud. It's not in their interests to do that.

Undetected fraud does no harm to anyone's reputation. On the contrary fraudsters are often the "stars" of their faculty until they get caught. Hauser and Stapel were. Plus, a department that got a reputation for hard-hitting anti-fraud measures might struggle to recruit people, even perfectly innocent ones who just found it annoying.

So what we see is departments who perform (fairly) good investigations into fraud, but only when someone else tells them to.

Maybe it's the funding bodies? They're paying for the research, so they clearly have an interest in making sure their money is well spent. At present, though, they lack the mechanisms to investigate it.

So those are the three possibilites as I see them - journals, institutions and grant awarders. While all of these organizations have policies for investigating and punishing fraud when it comes to light, they rarely (if ever) actually catch it, leaving this hazardous and stressful job to individuals.

Is there a better way?

The Google of Negative Results

2011-10-31T20:12:00.000Z

A new online resource has been launched which offers us the chance to find out what isn't happening in science.

BioNOT is a free searchable database of negative findings in biology and medicine.

Text mining approaches to the scientific literature have become increasingly popular as a way of helping researchers to make sense of a growing number of papers. But they've tended to focus on positive findings and skim over negative ones. In this sense they're following in the tradition of scientists themselves, unfortunately.

It's also hard to search for negative findings on PubMed, because if you type in, say, vaccines NOT associated with autism in the hopes of finding papers showing that vaccines don't cause autism, it will think you are trying to search for "vaccines" and don't want to see any papers mentioning the words "associated with autism". So you end up with 160,000 hits about vaccines with no reference to autism at all. There are ways around this but it's surprisingly tricky.

BioNOT uses text mining to mine null findings from a large database which includes everything you can find on PubMed and also a large number of full text articles (some behind paywalls).

Authors Agarwal et al of Wisconsin say that this will help to map out the "incidentalome" (a brilliant word I'd never heard before) for a given disease or trait i.e. the regions of the genome that turned out not to be associated with it. It should work for anything, though, not just genes.

However the BioNOT system isn't perfect. The authors note that it is rather over-enthusiastic in finding negative sentences.

A quick try on the system bears this out. I searched for 5 HTTLPR, the claimed "happiness gene". This revealed many papers finding no link between the gene and various things. But it also threw up false positives (how ironic), such as:

young rhesus monkeys were split into two groups... those having, or not, the short variant of the 5 -HTTLPR polymorphism

This is just telling us about the methods of a study. It's not a null finding, but it set the BioNOT alarm bells ringing, presumably because it contained the word "not".

So BioNOT is only a first step, but it's an important one.

Agarwal S, Yu H, & Kohane I (2011). BioNOT: A searchable database of biomedical negated sentences. BMC bioinformatics, 12 (1) PMID: 22032181

The Teen Happiness Gene?

2011-10-27T09:26:00.001+01:00

Whether you were happy with life as a teenager could be down to a certain gene, says a new study.

In a large study of American adolescents, the AddHealth project, teens who carried the long form of the 5HTTLPR locus were more likely to say they were satisfied or very satisified with their lives (at age 18 to 26). People with two long variants were the most cheerful, with short/long carriers in the middle and short/short being the least so.

The effect was significant controlling for ethnicity (p=0.013), however looking at the data shows that this effect was largely driven by the unhappy teens who reported being "Dissatisfied" or "Neither" on the 5 point scale of life satisfaction - but there were only a small number of these, because the great majority said they were "Satisfied" or "Very Satisfied". Still, there you go.

Incidentally, Neuroskeptic readers may remember AddHealth because of its role in the "black women are ugly" race row from earlier this year.

This study is the latest in a long, long line of attempts to correlate 5HTTLPR with happiness, depression, stress and so on. A few months ago I discussed the history of this busy little gene and covered a meta-analysis of no fewer than 54 papers which claimed that there was indeed a link, with the short allele increasing the risk of depression in response to stressful events.

However many studies failed to find one, and worryingly the three largest studies were all negative which is a classic tell-tale sign of publication bias - maybe people were only bothering to publish smaller studies if they did find a link and hence were "exciting findings". This is quite possible because so many researchers collect DNA as part of psychology studies these days. When the 5HTTLPR story got big (about 5 years ago) I know a lot of people decided to jump on the bandwagon by looking at it in the context of their old data.

Personally I have no idea whether 5HTTLPR is associated with anything. I used to think it probably did, but now I'm just confusion. There have been so many studies and so much inconsistency that it's very hard to know. What worries me is that I'm not sure whether we'll ever get a consensus. We've already had a gigantic study (over 80,000 people) showing no link and many meta-analyses coming to different conclusions.

What will it take to settle the issue? An even bigger study? Would 200,000 people do it? A million? I don't know.

De Neve JE (2011). Functional polymorphism (5-HTTLPR) in the serotonin transporter gene is associated with subjective well-being: evidence from a US nationally representative sample. Journal of human genetics, 56 (6), 456-9 PMID: 21562513

The Limits of (Neuro)science

2011-10-25T20:10:00.004+01:00

Will science ever understand the brain?

To start off with, it must be admitted that science has done a pretty good job of explaining pretty much everything else in the universe, so just going on past experience, it probably will.

But some say that, sure, the scientific method is fine for things like chemistry, but not for others. The human brain (or some aspect of it: consciousness, the mind, love, belief, or whatever) is the most popular exception. Science just won't work on it, we're told. It's too complex.

Maybe, but I find this view rather blinkered. It relies on taking our current state of knowledge as an eternal truth.

To see humanity as a mystery surrounded by a world of unmysterious things is a very new idea. It would have seemed bizarre just 300 years ago. Back then, nature was pretty much inscrutable. At best human life was no more mysterious. In many ways, less so. There were no end of philosophical, psychological and religious theories, many of them so plausible that they're still around today.

The notion that humans are complex and hard, while nature is easy, is an illusion created (ironically) by the successes of reductionist science. Some of the biggest questions facing mankind for eons have answered so well, that we don't even see them as questions. Why do people get sick? Bacteria and viruses. Why does the sun shine? Nuclear fusion. Easy.

But only easy now. Think of the billions of people who lived and died before say 1800 - they saw the sun every day and they had no idea why it shone, and they knew no-one else did. You may not understand nuclear fusion, but you know that physicists do, you know it's no mystery. 300 years ago, it would have been very tempting to think that no-one would ever know, that the answers were known only by God.

So, to confidently claim that explaining the human mind will just be too hard is presumptuous. It may or may not be, I don't know. Historically, though, the theory that things are inexplicable has a bad track record.

Then there's the idea that humanity is not so much hard, as different. Philosophers have spent many pages coming up with new ways of phrasing that point. Nature is material, but we're spiritual. Nature is in-itself, but we're for-itself. And so on. If we can understand the mind at all, it certainly won't be through reductionistic, mechanistic, rationalist, objectivist (phew) science, they say.

Again, this seems perfectly plausible... to us, now. But people used to say the same thing about living things in general. That was vitalism, the idea that physics and chemistry were fine for inert matter, but anything alive was radically different.

At a certain point in history, when biology was almost completely seperate from (and primitive compared to) the other sciences, that seemed fine. But it turned out to be wrong. With the benefit of hindsight. Nowadays, no-one sees a radically difference between nature and bacteria, plants or animals... well, except humans.

Maybe the mind will never be understood within the framework of the rest of science. I don't know, but I don't think anyone else does right now, either.

Life With Low Serotonin, Revisited

2011-10-22T11:40:00.001+01:00

Last year I covered the case of a young man born with a genetic disorder which caused him to suffer low levels of the monoamine neurotransmitters - serotonin, dopamine, and noradrenaline.

These are the chemicals that are widely thought to be deficient in depression, and they're the target of antidepressant drugs (especially serotonin).

If low monoamines cause depression, you'd expect someone with low monoamines to be depressed, at least on the simplest view. But the case from last year had no reported mood problems, although he did show appetite, sleep and concentration problems that were cured by serotonin replacement therapy.

Now a new case report has just appeared that tells a different story. Gabriella Horvath and colleagues from British Columbia describe two sisters. Both had a normal birth and childhood, but at the ages of 11 and 15 respectively, began to suffer severe migraines and other symptoms. Sister 1:

started having hemiplegic migraine at age 11 years, initially occurring every 3–8 weeks, lasting 4–48 hours, presenting with right or left-sided numbness and paralysis, no visual disturbances, but slurred speech, associated with vomiting, headache, and confusion, followed by weakness lasting up to 7 days, and then complete recovery. The frequency of her migraine increased slowly with age up to twice a month...

Between 12 and 20 years she had developed progressive spastic paraparesis; sensory loss in stocking distribution... urinary and bowel incontinence; bladder instability... irritable bowel syndrome; sleep problems; depressed mood; and anxiety. She needed to use a wheelchair for most of the time by the age of 17.

Sister 2 had a rather different course:

The older sister originally presented at the age of 15 years with a history of hemiplegic migraine and seizures and myoclonic jerks. EEG showed generalized spike-and-wave activity, and polyspikes with photoconvulsive [light-induced seizures] response, in keeping with juvenile myoclonic epilepsy. Her seizures were brief and infrequent and not associated with the migraine episodes...

She subsequently developed progressive weakness, frequent falls, depression, and mild bladder instability...

Various blood and genetic tests failed to get to the bottom of it. MRI scans showed abnormalities in the spinal cord and parts of the brainstem in both cases, but why?

Spinal tap studies in Sister 1 revealed very low levels of 5HIAA, which is a by-product of brain serotonin (5HT). This suggested low 5HT levels. So doctors started her on 5HTP to try to boost it.

They report that 5HTP treatment caused "improvement" in all symptoms, including the migraines, slurred speech, depression, and movement, but not immediately. She gradually went from being in a wheelchair to being able to walk around the house on crutches, although she used a wheelchair outside. However, after 3 years of treatment, at age 20, she suddenly fell into a coma lasting 2 months. She is now recovering.

Sister 2 also had low 5HIAA, and was given 5HTP. She also reported symptomatic improvement.

Blood tests reported very low platelet serotonin levels. 5HTP treatment increased this but they were still below normal. Platelet 5HT reuptake rate was also low, suggesting a problem with the 5HT reuptake transporter protein 5HTT.

But the 5HTT gene (famously known as "The Happiness Gene" although that's questionable) seemed entirely normal in these patients. The authors say however that the symptoms are, in some ways, reminiscent of mice who lack the 5HT reuptake protein (5HTT knockout mice), who also show low serotonin. Also, if it were genetic, that wouldn't explain why there were no problems at all during childhood.

So this case is a mystery. The low serotonin has no known cause, and it might just be a side effect of a deeper underlying problem, but serotonin has long been linked to migraines so it might account for some of the symptoms. The fact that 5HTP helped supports this, though it wasn't a controlled trial so we can't know for sure.

As for the depression and anxiety, improved by 5HTP, this could have been a result of low serotonin, but it could also have been a psychological reaction to the severe medical problems. It's impossible to know.

Horvath GA, Selby K, Poskitt K, Hyland K, Waters PJ, Coulter-Mackie M, & Stockler-Ipsiroglu SG (2011). Hemiplegic migraine, seizures, progressive spastic paraparesis, mood disorder, and coma in siblings with low systemic serotonin. Cephalalgia : an international journal of headache PMID: 22013141

The Facebook Brain

2011-10-20T07:53:00.005+01:00

Facebook friend tally is associated with differences in brain structure

People with lots of Facebook friends have denser grey matter in three regions of the brain, a study suggests

When I heard about this, my heart sank. The Facebook area of the brain? It had all the hallmarks of a piece of media neuro-nonsense: a hook (Facebook!), a simplistic neo-phrenological story (bigger brains are better!)... so I was expecting to discover that the fuss was all about some tiny, statistically questionable study, which wasn't really about what the newspapers said it was, as is so often the case.

So I was very surprised to find that it's actually an extremely good paper.

Kanai et al from London took 125 young Facebookers (mostly students) and correlated their friend count with grey matter density across the brain. They found some correlations:

The numbers seem solid. It was a large study. They used whole-brain correction for multiple comparisons (a=0.05 FWE corrected), controlling for age, gender and overall brain grey matter.

Most importantly, they included a replication sample, something that very few neuroscience papers do. After having done the first 125 people, they got another 40, and looked in the areas where they'd previously found results. They found the same correlation in all three cases - in fact, it was even stronger.

They even made sure to only display the scatterplots from the replication sample, thus avoiding the dreaded voodoo correlations problem that so often plagues such graphs. Note that the correlations are actually with the square root of the number of friends.

As if this wasn't enough, they confirmed a previously reported correlation between amygdala size and social network size, in both of their samples. And to cap it all, they show that Facebook friends are correlated (albeit not hugely) with other measures of number of friends.

So, as unlikely as it sounds, this Facebook finding is stronger than a good 90% of similar papers.

What does it mean that the size of the amygdala, left MTG, right STS and right entorhinal cortex are correlated with your Friend count? Good question. The authors discuss the result in terms of the known functions of these areas, e.g. the entorhinal cortex is involved in learning to associate pairs of stimuli, such as matching names to faces, which might be related to keeping track of your friends... but frankly this is just a post-hoc story.

You could tell an equally convincing tale about almost any part of the brain, if you found a correlation there. And as the authors point out, they didn't find correlations with other "social" areas you might expect like the mirror neuron system.

But that doesn't change the fact that the results of the study seem rock solid. So what's going on? It could be that having lots of friends makes your brain bigger. Or it could be the reverse, that having a certain kind of brain wins you friends, or at least Facebook ones. Or it could be that there's some third factor underlying the correlation, although who knows what that is.

Kanai, R., Bahrami, B., Roylance, R., & Rees, G. (2011). Online social network size is reflected in human brain structure Proceedings of the Royal Society B: Biological Sciences DOI: 10.1098/rspb.2011.1959

What Is Brain "Activation" on fMRI?

2011-10-18T20:41:00.004+01:00

Functional MRI is one of the most popular ways of measuring human brain activity. But what is "activity"?

Fundamentally, neural activity is electical potentials and chemical signals. fMRI doesn't measure these directly. Rather, it measures changes in the oxygen content of blood in different parts of the brain.

The more the brain cells are firing, the more oxygen they use up, although oxygenation actually increases as a kind of compensation for the activity and this increase is what gets measured. The oxygenation changes associated with neural firing is called the BOLD response.

Using fMRI you can measure BOLD and end up with some pretty blobs of activation. But what does it mean for a region of the brain to be activated? Just as no man is an island, no brain region can do anything on its own. Every area gets inputs from other areas, and sends outputs as well.

So if an area gets more active, that could mean one or more of three things:

It's sending more outputs
It's getting more inputs
It's doing more "internal" processing within that area - "talking to itself".

Which of these contributes to BOLD? It's known that number 1 - output from the area in question - is not a major contributor to the fMRI signal, but what about 2 and 3? A 2010 paper that I just came across argues that 80% of the BOLD signal is caused by internal processing, and only 20% is due to input.

They took some rats, and stimulated their whiskers. Using electrodes, they measured blood oxygenation changes in an area called the barrel cortex, which is known to deal with whisker-based sensations (they didn't actually use fMRI, but this would be seen as a BOLD signal if they had.)

But they then added a drug called muscimol to the barrel cortex. Muscimol reduces neuronal firing, but it doesn't affect synaptic input. They show that muscimol strongly reduced the blood oxygenation response, by about 80%. This suggests that 80% of the signal was not caused directly by sensory input to the cortex, but was generated within the cortex.

In many ways this is not surprising: it would be weird if the cortex were just picking up signals and doing nothing with them. However, it's good to be able to put a figure on just how much intra-cortical processing contributes to the fMRI signal. In rats, at any rate.

Harris S, Jones M, Zheng Y, & Berwick J (2010). Does neural input or processing play a greater role in the magnitude of neuroimaging signals? Frontiers in neuroenergetics, 2 PMID: 20740075

Placebos And The Brain's Own Pot

2011-10-15T10:23:00.000+01:00

According to a neat little new paper, the placebo effect relies on the brain's own marijuana-like chemicals, endocannabinoids.

Or rather, some kinds of placebo effects involve endocannabinoids. It turns out that "the placebo effect" is not one thing.

The authors, led by Fabrizio Benedetti, have previously shown that placebo "opioids" - i.e. when you expect to get a painkiller such as morphine, but actually it's just water - relieve pain via the brain's own opioid system (endorphins). Blocking endorphins with certain drugs blocks the power of placebo morphine.

But there are many painkillers that aren't opioids, leaving open the question of whether all placebo effects on pain are mediated by endorphins.

The new study claims that endocannabinoids are involved in non-opioid placebo analgesia. They used rimonabant, a weight loss drug that was pulled from the market shortly after it appeared, because it caused depression. Rimonabant worked by blocking CB1 receptors, which are the main target of the psychoactive chemicals in cannabis - and also key players in the endogenous cannabinoid system.

Here's the headline result:

The graph on the left shows the relationship between the pain relieving power of morphine, and the pain relief caused by placebo "morphine" given on a subsequent day. As you can see, there was a strong correlation. People who had a strong response to real morphine, later responded well to the fake morphine. But rimonabant had no effect at all.

Pain relief was measured using tolerance to the pain caused by a tightly fitting tourniquet.

However, rimonabant did have a strong effect on the placebo response to a different drug, ketorolac, which is related to the better-known ibuprofen (Nurofen). As you can see in the graph on the right, people given rimonabant had a much lower response to the placebo "ketorolac".

In other experiments, they showed that rimonabant alone had no effect on pain tolerance.

This is a nice result. It shows that the placebo effect is not a single thing, but that it depends upon the nature of the drug that you believe you've got. It also reminds us that the placebo effect is not some magical power of mind-over-matter, but is in fact, well, matter-over-matter.

Interestingly, ketorolac has no effect on endocannabinoids, or at least no direct effect. The mechanism of action, which is fairly well understood, has nothing to do with cannabinoids. Yet placebo "ketorolac" still seems to set endocannabinoids buzzing.

Benedetti F, Amanzio M, Rosato R, & Blanchard C (2011). Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nature medicine, 17 (10), 1228-30 PMID: 21963514

Mountains of Mental Disorders

2011-10-12T08:25:00.001+01:00

This is a story about a man who lived in a house. Here it is:

The house was a lovely thatched cabin, situated in a wooded valley between two little hills, set against the spectacular scenary of a snow-capped mountain. He'd been born there, and he'd lived there all his life.

One day, there was a knock on the man's door. He opened it to find two official-looking people carrying clipboards, with serious expressions on their faces.

"Hello, sir. We are officials from the Ministry of Mountains. Sorry it took us so long."
"Oh... excuse me?", the man replied, puzzled.
"We're very sorry we didn't get here earlier."
"I'm afraid that I don't know what you mean. I wasn't expecting any..."
"Hmm. Let me explain. The Ministry of Mountains exists to help people who live on mountains. So, you see, we're here to..."
"Ask for directions to the mountain? It's about 10 miles down the road. Just look up - you can't miss it."

The official looked unamused.
"No. We're here to help you, sir."
"Help you to cope with the rigors of mountain living!" the other chimed in, helpfully.
"But... I don't live on a mountain."
"I'm afraid you do. Look - " and the first official unfolded a large map. "Do you agree that there is a mountain, here?" and she pointed to a spot 10 miles down the road.
"Yes. Actually I just told you about i..."
"...and, do you agree that you live - here?"
"Of course, but..."

"So you do live on the mountain. The very ground beneath our feet right now is part of that mountain nearby."
"No it's not." The man protested. "This is a valley, miles away. I mean just look outside. We're clearly not on a mountain now, are we?"
"How old fashioned. That's what we used to think. But, thanks to advances in geology, we now appreciate that these hills and valleys are merely a part of the mountain."
"Yes!" the other said, whipping out a textbook and becoming increasingly enthusiastic. "You see, a mountain is merely a mass of rock, and this rock extends underground for a considerable distance... It's impossible, really, to draw a line on the map and say categorically, this side is mountain, this isn't. So 'mountains' are an arbitrary construct. 'Hills' are likewise just protrusions of the underlying mountain and..."

The man was even more confused now. "Umm... well, I suppose, technically...but..."
"...so yes, so you do live on a mountain. And we know that this is very difficult. You're exposed to all kinds of dangers like blizzards, altitude sickness, avalanches..."
"Not really. It's nice here. It doesn't even snow most years."
"That's unlikely. You agree that mountains have blizzards and avalanches? Right. And you earlier agreed that there's no dividing line between you and a mountain. So logically..."
"Er..."
"So you are in danger! Don't worry, though. We're here to help. To start off with, we're going to reinforce your house with six tons of cement, to protect you against rockfalls. The construction crew will arrive tomorrow morning. Now, as for those blizzards..."
The man had had enough of this.
"This is absurd. Now look - there is a guy who really does live on top of the mountain in a rickety old shack. Old Grandpa McHermit. He might actually need your help. I don't. Get out! And if I see anyone with a bag of cement tomorrow morning, I'll shove it right up their..."

---

As you may have guess, this story is a metaphor. There is a movement in psychiatry at the moment, away from a 'categorical' view of mental illness towards a 'spectrum' view. Mental disorders are not things you either have or don't - defined according to some arbitrary cut-off. Rather, they're things that everyone has, to some degree.

This has already happened, or is happening, to autism, schizophrenia, bipolar disorder, personality disorders, and more.

Now, the "spectrum" or "dimensional" approach has much to recommend it. It's true that diagnostic cutoffs are arbitrary. It's true that the categorical approach doesn't capture the true degree of variation that real people display.

My worry is that these new "spectra" are, in practice, merely the old categories, just bigger. We still think of people as being ill or not-ill, although we may call it on the spectrum or off it. Worse, we still think of "ill" in the same way as we used to i.e. as referring to the most severe end of the spectrum. The only difference is that we've expanded the old category of "ill" to cover more people.

This is evident in the fact that we still use the old categorical labels. It's the autism (or schizophrenia or bipolar) spectrum, even though "autism", in the old sense of a discrete disorder, is now supposed to be just one extreme of that spectrum. Yet the point about an extreme is that it's unusual, so why call it that?

We don't call the rainbow the red spectrum. We don't call height the midget spectrum. We don't call hills part of the mountain spectrum.

The point is, we really think of color and height and altitude as spectra, not as approximations to an extreme point, and that's good, because they are. Now it might well be possible to think of autistic or bipolar traits in the same way - but not if we call them autistic and bipolar traits. And not if we just rename them, while keeping the mental associations the same.

Not unless we can find a way of referring to what's currently called the autism spectrum without making anyone think of autism when they hear it. Similarly for "bipolar" and all the rest. Until we get to that point, there's a real risk that "spectra" will just be big categories.

Edit: This post has been very kindly translated into Hebrew over at the alhasapa.com blog.

Mental Illness And Creativity Revisited

2011-10-11T07:51:00.002+01:00

A new study offers support for the theory that mental illness is associated with "creative" achievement.

The idea that madness is close to creative genius is a popular one. From the nutty professor to the tortured genius, there's no end of sterotypes, and pop culture seemingly offers plenty of examples, from Van Gogh and his ear to Charlie Sheen and his bi-winning.

But is it true?

A new study says yes. Kyaga et al looked at everyone in Sweden who had been treated as an inpatient for either schizophrenia, bipolar disorder, or depression, between 1973 and 2003. In total that meant about 300,000 people (two thirds of that was depression).

They then matched this up with the Swedish national census which asks people their occupation. They looked to see whether the psychiatric cases were more likely to have been employed in a "creative" profession. They defined that as visual artists (photographers, designers, etc.) non-visual artists (musicians, actors, authors) and academics (university teachers).

Finally, they pulled up the records on the patients' relatives, to see what their jobs were. This is one of those studies that could only happen in Scandinavia, because only those countries keep such comprehensive ( rather scarily so) info about their citizens.

They found that being bipolar, or being a close relative of someone who's bipolar, was associated with having a creative job. For schizophrenia, the picture was more complex: being a schizophrenia inpatient was not linked to being a creative in itself, but being related to someone with schizophrenia was. The effects were fairly modest.

For depression (not bipolar, just plain unipolar depression), there was no link at all, or even a slightly lower level.

The correlation wasn't driven by differences in IQ (yes, they had data on that too, for males, thanks to military service records.) Creative types had higher IQs on average while psych inpatients had slightly lower IQs than others. So correcting for IQ made the associations even stronger.

So it looks as though being bipolar, at any rate, is linked to creativity, and so is having bipolar and schizophrenia in the family - if you believe these findings. Should we?

This study was huge and the data are, on the face of it, very comprehensive. However, it turns out that many people didn't state their occupation, especially the patients. Only 45% of people with schizophrenia gave a valid answer, compared to 75% of the bipolar and depressed. In the controls, it was about 80%.

That's a serious issue. The authors did try to get around this by looking at the siblings of the patients with missing data. For schizophrenia, siblings of missing data schizophrenics were more creative than for the ones with full data, and for bipolar there was no difference. So the effects are not due to nonreporting of non-creative jobs.

Another possible confound is family background and environment. Indeed, the fact that people with bipolar were no more likely to be in a creative job than their relatives who weren't bipolar (or, at least, never received inpatient treatment) rather supports this view. Maybe the relatives shared genes with the patients meaning that their creativity was associated with bipolar, but we can't know that.

One reassuring piece of evidence against the idea that these results were driven by a general correlation between psychiatric hospitalization and "middle class professions" is that there was no association with the "non-creative" job of accountancy and auditing (sorry accountants and auditors).

Overall, while this is an interesting study, and while I find the proposed link between mental illness and creativity plausible, we need more detailed research to ensure that the correlation isn't just a reflection of socioeconomic factors.

Kyaga, S., Lichtenstein, P., Boman, M., Hultman, C., Langstrom, N. Landen, M. (2011). Creativity and mental disorder: family study of 300 000 people with severe mental disorder The British Journal of Psychiatry DOI: 10.1192/bjp.bp.110.085316

You Use Your Partner To Phone And Play Angry Birds. Literally.

2011-10-08T09:30:00.001+01:00

WITH lots of weddings expected on Tuesday, people in love across the world are getting ready for their latest fix.

But should we really characterize the intense devotion shown by people in love, as love? A recent experiment that I carried out using neuroimaging technology suggests that love-related terms like “romance” and “soulmates” aren’t scientifically accurate - not compared to a word we use to describe our relationships with our smartphones. That word is “owning an iPhone.”

As a branding consultant, why am I even writing this article for the NYT? Never mind. Earlier this year, I carried out an fMRI experiment to find out whether iPhones were really, truly addictive, no less so than alcohol, cocaine, shopping or video games (sic)... wait, are those last two actually addictive? Whatever, let's just say they are.

In conjunction with the San Diego-based firm MindSign Neuromarketing (kerching! Wait, did I write that, or just think it?), I enlisted eight men and eight women between the ages of 18 and 25. Our 16 subjects were exposed separately to audio and to video of a wife or husband.

In each instance, the results showed activation in both the audio and visual cortices of the subjects’ brains. In other words, when they were exposed to the video, our subjects’ brains didn’t just see their partner, they “heard” them, too. This powerful cross-sensory phenomenon is known as "the brain storing information about people and objects, and retrieving it in response to related stimuli", or "memory" to use the technical term.

But most striking of all was the flurry of activation in the insular cortex of the brain, which has also been associated with seeing an iPhone. The subjects’ brains responded to the sound of their partner as they would respond to the presence or proximity of a top of the range smartphone (with free WiFi in thousands of locations!)

In short, the subjects didn’t demonstrate the classic brain-based signs of addiction when they were shown pictures of their lovers. Instead, they made calls and played Angry Birds on them.

---

The silliness of equating insula activation on fMRI with love and using this to argue that we love our iPhones as a recent crap OpEd in the New York Times did, has been excellently covered over at [Citation Needed], Neurocritic and many others. I'm sure you've heard plenty about this story already.

But let's set aside the fact that loads of other things, by no means limited to disgust and drug addiction, are known to involve the insula in fMRI. Let's assume (as the NYT piece did) that the only two things that had ever been shown to activate the insula were seeing an iPhone and seeing someone you love.

This study still wouldn't show that people love their phones. You could equally well turn the whole thing on its head and argue that it shows that we think of people we love as something to make phone calls with. Hey, the brain activity is the same as when you look at an iPhone.

This might strike you as implausible, but given the fMRI data alone, you have no grounds for saying one interpretation is more or less plausible than the other.

There are countless other interpretations, each equally plausible given the imaging data. Maybe the insula is only about love, and the activation to the iPhone is due to conditioned association (you call people you love on it). Maybe it's about objects you see every day, which includes your phone and people you love. Maybe...

The only reason to prefer any particular interpretation would be because you have evidence from outside neuroimaging - from other areas of neuroscience or psychology. So if you discovered that insula lesions cause people to be unable to fall in love (they don't, as far as I know) then you could make a case for the love interpretation. But only then.

Neuroimaging, on its own, can't tell us anything about the brain. It's like a peek under the hood of your car. If you already know how a car works, you can look under the hood and work out what's going on, and what's gone wrong. But only if you have that prior knowledge. Otherwise, it's just a big set of metal pipes.

Le Pack It In

2011-10-06T19:39:00.001+01:00

Earlier this year, a large group of autism experts signed a consensus statement condemning "Le Packing", a certain procedure used in children with autism.

They said:

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...

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..."

We have reached the consensus that practitioners and families around the world should consider this approach unethical.

Le Packing is almost unheard of outside France, where it was invented some years ago by M. A. Woodbury, an American psychiatrist. It's controversial even there.

Now Pierre Delion, a French packer who's previously defended the approach, and even wrote the book on it, has penned an article which discusses the towel-based treatment: Towards a dialogue between psychoanalysis and neuroscience: Connections that are both possible and necessary

The piece (part of a special issue on psychoanalysis and neuroscience) starts out with some general scholarly remarks about previous authors who have discussed Freud and the brain, but it moves on to autism, with some, well, puzzling remarks:

During the ﬁrst months of life, an infant will actively practice his or her archaic reﬂexes. Of these, the grasping, which will progressively disappear as voluntary prehension emerges around the age of 4–5 months, is of great interest. The facilitation and/or anaclitic relationships between this reﬂex and adhesive identiﬁcation are even more interesting to study together because, for instance, in an autistic child, the ﬁrst model will integrate under the form of pathological adhesive identiﬁcation.

In such an example, a strategy for thinking about these two phenomena and making them compatible is using a third term (e.g., Peircean logic, in which adhesive identiﬁcation is an icon of grasping). If we refer to this important principle from this great American semiotician, the icon is part of the logical representation scheme from the most elementary, the icon, to the most evolved, the symbol, passing by the intermediate, the index...

The relationships between neurological wiring and pre-wiring enable the effective installation of the theory of mind and the phenomenon of projective identiﬁcation described by Melanie Klein and her students...

Hmm.

On Le Packing itself we get a curious paragraph which seems to be saying that the therapy itself works via a neurophysiological mechanism, but that Freudian theory can explain why the child and their caregivers are anxious. What the anxiety in question is about is not clear. About the packing? That seems the most natural reading:

Another example taken from Pierre Delion’s practice as a therapist for children with autistic disorder is the ‘‘packing’’ technique (Goeb et al., 2008). This is the use of humid wrapping to prevent self-mutilation by using these two different levels [i.e. neuroscience and psychoanalysis] that are nonetheless joint during treatment. This technique uses a neurophysiological hypothesis to try to explain the therapeutic effects, but, at the same time, the psychopathological hypothesis that is given by psychoanalysis helps to format the anxieties that are experienced by the children and invariably shared by their caretakers.

Clinical research regarding this topic is currently being undertaken in Pierre Delion’s child psychiatry department following a hospital program for clinical research (PHRC, NoEudra CT: 2007-A01376-47) entitled ‘‘Demonstration of the efﬁciency of packing treatments in children affected by autistic disorders with severe behavioral disorders’’.

Delion P (2011). Towards a dialogue between psychoanalysis and neuroscience: Connections that are both possible and necessary. Journal of physiology, Paris PMID: 21963531

To Catch A Predator... With A Brain Scanner?

2011-10-05T08:18:00.002+01:00

With the help of an MRI scanner and some child pornography, a new study claims to be able to tell whether someone is a paedophile: Assessment of Pedophilia Using Hemodynamic Brain Response to Sexual Stimuli.

It was an fMRI study of 24 self-identified paedophiles (recruited through a clinic offering anonymous treatment) and 32 male controls. Everyone was shown a series of images of naked men, women, boys and girls. The neural response to child vs. adult images was the main outcome measure.

Respect to the authors for getting that past the ethics committee.

The blob-o-grams above show that the paedophile's brains reacted differently to the control brains, when shown images of naked children, which is not surprising because the brain is what makes you a paedophile (and everything else.)

However, what's more interesting is that by comparing each individual's brain activity to the average activity of the paedophile group and the control group, it was possible to diagnose people as paedophiles or not with high accuracy (90+%).

Plotting the "typical paedophile"-ness of the neural response to girls vs women and boys vs men, the paedophiles (triangles) form a clear cluster. There were also some differences between homosexual and heterosexuals in both groups.

The statistics seem kosher: they used leave-one-out cross-validation to avoid the error of double dipping.

What's not clear is whether this was measuring sexual attraction as such. All it's measuring is how much each person's activity correlated with the paedophile group average. Maybe it's picking up on the shame paedophiles feel over being reminded of what they've done. Maybe the controls were just averting their eyes when the child porn came on.

However, you could say that if you're just interested in the practical business of catching paedophiles, that's academic. More concerning is the question of whether it would be possible to fool the technique. A recent study showed that it's easy to fool a brain scan designed to detect lying.

But let's suppose it does work out. Would that be a good thing? What is "a paedophile", anyway? Is it someone's who's attracted to children, or someone who acts on that attraction?

For example, there are people who are caught with child porn, and who admit they downloaded it, but who deny being attracted to children. The Who shredder Pete Townsend and comedian Chris Langham being two British examples. Both admit downloading illegal images, but say it was for 'research purposes'.

Now it might be possible, using fMRI, to find out if they're telling the truth. Let's suppose it was doable.

So what? Downloading child pornography is a crime - whatever your motivation. Being attracted to children is legal, in itself. So from a legal perspective it should make no difference at all in cases like this.

Of course, we don't in fact go around seeing things from a purely legal perspective. We care whether someone is attracted to children or not. But should we care? Is that fair? You don't choose your sexual orientation. What you choose is whether to break the law by commiting the crime.

There are surely people out there - no-one knows how many - who are attracted the children, and never act on it. Do we want to be able to "catch" them?

Edit: The original version of this post linked to the wrong paper, an older paper by the same authors. This has been fixed now.

Ponseti, J., Granert, O., Jansen, O., Wolff, S., Beier, K., Neutze, J., Deuschl, G., Mehdorn, H., Siebner, H., & Bosinski, H. (2011). Assessment of Pedophilia Using Hemodynamic Brain Response to Sexual Stimuli Archives of General Psychiatry DOI: 10.1001/archgenpsychiatry.2011.130

Failed Drug Company... Failed Drug?

2011-10-03T09:20:00.003+01:00

The pharmaceutical industry is in trouble at the moment, with many companies pulling out of development in certain areas and psychiatry is high on the list.

The tale of one troubled would-be antidepressant has just been published in the form of a clinical trial that was terminated early when the parent company went under. But another company came along to save the day, so the drug might live on.

Amitifadine is a triple reuptake inhibitor (TRI). What's that? Prozac and other SSRI antidepressants work by blocking the reuptake of serotonin in the brain thus increasing levels of serotonin. Some other antidepressants block the reuptake of serotonin and noradrenaline, and these dual reuptake inhibitors may be slightly better than SSRIs (although maybe not).

TRIs take this one step further: they add a third monoamine neurotransmitter, dopamine, to the list. If two monoamines are better than one, three ought to be even better... right?

This was a clinical trial of amitifadine vs placebo in depressed adults. It was originally designed to have 200 depressed people, but it only got to 63 patients before the money ran out:

The study was initiated in April 2008 and was halted by the sponsor, DOV Pharmaceuticals, early in December 2008 due to lack of funding.

DOV were a small company best known in the financial world for the fact that their stock crashed spectacularly on the first day they went public on the markets. Investors who lost out subsequently sued the company and their main underwriters, a certain outfit you may have heard of called Lehman Brothers.

After various (non-psychiatry) projects failed, DOV were bought out by a certain Euthymics Bioscience. DOV's old website, dovpharm.com, now offers Canadian Cialis. Don't wait! Order the cheapest medications now!

What a sad fate.

When Euthymics bought DOV, they also bought the rights to DOV 21,947 which they dubbed amitifadine. The takeover happened in June 2010, so I guess that after DOV pulled the plug on the trial in 2008, Euthymics came along and decided to try to finish the development of amitifadine. The lead author on the present paper is Chief Medical Officer at Euthymics.

So what did they get for their money? Is amitifadine a goose that will lay some golden eggs, or the latest turkey?

Take a look:

People on amitifadine did slightly better than the ones on placebo over 6 weeks, on the MADRS depression scale (p=0.028). On the HAMD17 scale, which is more popular, there was no significant benefit (p=0.125), although it might have worked had the trial managed to recruit more people.

The non-significant benefit over placebo on the HAMD was 3.1 points. How does that compare to other drugs? It's impossible to say for sure, but there are some reasons to think that it's nothing special.

Patients in this study had very severe depression, with a baseline HAMD17 score of about 29.5. We know that the effect of antidepressants over placebo is correlated with severity. For what it's worth, with existing antidepressants, a baseline HAMD score of 29.5 would be expected to translate into a drug-placebo difference of about 4 HAMD points according to Fournier et al or about 5 in Kirsch et al.

Plus, the odds were stacked in the drug's favour in this study. To get into the trial, patients needed to have shown a "significant clinical improvement" to at least one previous antidepressant. Anyone who'd failed to improve on two or more different drugs was excluded.

In terms of side effects, there weren't many, and people on the drug actually reported no more adverse effects than those on placebo, in total. It lowered blood pressure and raised heart rate slightly. However, the small sample size is an issue here as well. The only way to know whether it's really better tolerated than other drugs would be to do a direct comparison.

Overall, while amitifadine looks like it works to some extent, it's anyone's guess whether it will offer any advantages over existing, cheap drugs - a verdict that Neuroskeptic readers have heard before.

Tran P, Skolnick P, Czobor P, Huang NY, Bradshaw M, McKinney A, & Fava M (2011). Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Journal of psychiatric research PMID: 21925682

The Recession and Death

2011-10-01T12:51:00.000+01:00

The present economic crisis has led to more suicides in Europe - but fewer deaths in road traffic accidents.

So says a brief report in The Lancet. The authors show that suicide rates in people under the age of 65, which have been falling for several years in Europe, rose in 2008 and again in 2009, in line with unemployment figures. The overall effect was fairly small - 2009 was no worse than 2006. It still corresponds to a 5% annual increase in most countries. In Greece, Ireland, and Latvia the rise was about 15%.

That's sad but not perhaps very surprising.

What's interesting though is that road traffic fatalities fell sharply. In Lithuania, they dropped by nearly half, although they were very high to begin with, and in Spain and Ireland they fell by 25%.

This presumably reflects the fact that people are just driving less, and perhaps slower. We've got less money to spend on fuel, and fewer jobs and things to need to drive to.

The authors note that although fewer road deaths is generally a good thing, there's one downside - a shortage of donor organs for transplantation. Road accidents are a prime source of organs because they're one of the few times that young, healthy people die leaving most of the body intact.

Stuckler D, Basu S, Suhrcke M, Coutts A, & McKee M (2011). Effects of the 2008 recession on health: a first look at European data. Lancet, 378 (9786), 124-5 PMID: 21742166

Why Brain Scanners Make Your Head Spin

2011-09-29T10:57:00.003+01:00

Here at Neuroskeptic we see a lot of dizzyingly bad (and sometimes even good) neuroscience, but did you know that brain scanners can literally send your head into a spin? A new paper explains why, with implications for all MRI researchers.

MRI scanners rely on extremely powerful magnetic fields. This is why you can't take metal objects into the scanner room, as they'd be pulled into it. Yet the fields can also exert other kinds of effects on the body.

I'd always been told that static, unchanging magnetic fields are biologically inert. But moving through the field too quickly can cause side effects. When an object moves through a magnetic field, induction happens - electrical currents are produced.

In the case of the human body, these small currents can activate nerve cells. Depending on which cells they hit this can cause you to feel dizzy, see flashes of light, experience tingling sensations, and so on. Or so I thought.

However, a new paper from Dale Roberts et al of Johns Hopkins shows that just being in a powerful magnetic field can cause dizziness and vertigo - with no movement required. They noticed that lying still in or near an MRI scanner causes nystagmus, abnormal horizontal eye movements, and that the amount of eye movement is directly correlated with the angle at which the head is positioned relative to the field.

The nystagmus was caused by an automatic reflex in response to effects in the vestibular ("balance") system of the ear. Roberts et al realized that the static magnetic field causes electrical currents that activate vestibular cells, even when the head is perfectly still. It happens because there's a natural flow of electrically charged ions into these cells in a part of the ear called the semicircular canal. The magnetic field interacts with this ion current, in what's called a Lorentz force.

The semicircular canals normally allow us to sense when our head is moving. Our eyes automatically compensate for head movement to keep us looking in the same direction. The MRI magnet fooled the ear into thinking the head was rotating, and the eyes produced nystagmus as a result.

Two patients who had suffered damage to their semicircular canals were immune to the effect.

This has important implications for functional MRI studies of brain function. Many people are interesting in measuring eye movements during MRI scans. This finding suggests that these movements may be unusual, compared to normal eye movements outside the scanner. Worst, the vestibular stimulation could alter brain activity:

Vestibular stimulation induced by the magnetic field in healthy subjects simply lying in the bore could activate many brain areas related to vision, eye movements, and the perception of the position and motion of the body.

Roberts, D., Marcelli, V., Gillen, J., Carey, J., Della Santina, C., & Zee, D. (2011). MRI Magnetic Field Stimulates Rotational Sensors of the Brain Current Biology DOI: 10.1016/j.cub.2011.08.029