The Mystical Path of Scientific Understanding

Reading and understanding the latest papers is a crucial part of being a scientist, but it's not something that we're ever taught to do, explicitly, as part of a scientific education. You take classes on genetics, and then maybe you become a grad student and you start doing genetics research: but there are no classes on reading genetics papers. It's something you pick up as you go along, if you're lucky.

But reading a paper isn't one single skill: as you learn more about a particular field your understanding of the published literature tends to progress through certain stages. At least, this is my experience. Like all such "stage models" what follows is a simplification, but it's something I think I'd have found useful to have been told when I was starting out.

Stage 0 : Huh?

You don't even understand what the paper is about. If I were to somehow find myself reading a paper on quantum chromodynamics, I would have no idea what it was trying to say, let alone whether it was right.

How to tell if you're at this level: The title has you stumped.

Next comes the most dangerous stage:

Stage 1 : Oooh!

You understand the paper's conclusions, but that's it: you don't get how the authors arrived at them, or how they relate to anything else. My understanding of chemistry is at this level: if someone claims to have found a new way of synthesizing some molecule, I know what that means, but I have to take the result or leave it: I can't criticize it, and in order to know how important the result is and what the implications are, I only have the author's word.

How to tell if you're here: you struggle with the Methods and the Results; you rely on the author's summary of their findings in the Abstract or the Discussion. The Introduction is all new to you.
How to get here: read a textbook until you grasp the basics of the field.

This is dangerous, because a paper could be completely wrong, and you wouldn't know - yet you know enough to be mislead by it, and to think you understand it. Incidentally, this is the stage inhabited by most journalists and politicians

These next two stages don't really come in any particular order. 2a does not necessarily precede 2b (it's just the one I chose to write about first.)

Stage 2a : Hmmm.

You understand the paper's conclusions and its methods, so you're able to judge how strong the argument is. If I were reading about a new cancer drug, and learned that had passed a large randomized controlled clinical trial, I'd be fairly confident that it works. Whereas, if I read that it had been "tested" in one patient (a case study), I'd be skeptical. I don't know anything about cancer drugs but I do know about clinical trials.

How to tell if you're here: you're comfortable reading the Methods and the Results.
How to get here: Read the Methods sections of papers in the field. If you don't understand the terminology, find a textbook or a review paper dealing with methods.

Stage 2b : Oh, interesting...

You understand why the authors decided to research this stuff, because you understand the specialist background literature about this sub-topic. You can judge important the research is and what the implications of it are. Note that the Introduction and the Discussion are meant to serve to explain all this context for the benefit of people who don't have this level of understanding of the topic, but in fact they're often either poorly written or actively misleading, so you can't rely on them.

How to tell if you're here: you find yourself either agreeing with, or criticizing, the Introduction and the Discussion.
How to get here: read recent review papers about the field. Textbooks are unlikely to be up-to-date enough, or detailed enough, to be of much use. Just remember that every review paper offers a different slant so make sure you don't just read one and take it as gospel.

Finally, we come to the highest stage, the moment of Enlightenment, saroti, Nirvana...

Stage 3 : Aha!

This is what happens when you have both of the previous kinds of understanding - you see what the authors did and why they did it. This is more than the sum of its parts, because it allows you to evaluate whether they chose the most appropriate way of answering the questions they set out to investigate. You can think up a better way of doing it, or design interesting follow-up work.

This is the stage at which you stop seeing papers as communications from a mysterious other world, and see them as something written by people much like yourself - which, or course, is what they are.

For example, if I were to read a paper using fMRI to study whether a new antidepressant raises dopamine levels in the brain, I'd be able to say that while that's an excellent question, fMRI is unable to show this directly, whereas PET can, so it's probably a better option; but they probably chose to use fMRI because it's a lot cheaper than PET and much less hassle.

How to tell if you're here: you pretty much know what the full paper is going to be like from the Abstract alone; you probably don't bother to read the whole thing.
How to get here: Get to 2a and 2b.

The Left Hand of Obama

Voters in the 2008 Presidential election didn't have a meaningful choice. Whichever box they ticked, they were voting for a lefty.

Yes, Obama and McCain are both sinistral, a rather unlikely occurrence since just 7-10% of adults are left handed. Netherlands-based neuroscientists Casasanto and Jasmin decided to make use of this coincidence to test the hypothesis that people tend to make "good" gestures with their dominant hand and "bad" ones with their off-hand, in a new PLoS paper: Good and Bad in the Hands of Politicians.

They analyzed the final televised debates from the '04 and '08 elections, in which the candidates discussed various topics, both positive i.e. their own policies, and negative i.e. their opponent's Vietnam War records, choice of running-mate, and association with dodgy preachers. They also examined the gestures that the speakers made to accompany their positive or negative points, and recorded which hand they used. George W. Bush and John Kerry are both right-handed, by the way.

Here's what they found:
Both lefty candidates tended to use their left hands for good gestures and their right hands for bad ones, while the right-handed showed the opposite pattern. The data also reveal some interesting facts about the overall number of gestures: Obama had a hands-off approach with only 119 gestures in total, while McCain was gesticulating all over the shop (259). Bush and Kerry, however, were essentially equal (192 vs 193). Maybe Kerry's one extra gesture was just one too many for the electorate, thus costing him the Presidency.

Anyway, does this prove that we use our dominant hands to make "good" gestures - supporting the notion that we unconsciously associate positive ideas with our dominant side of space, and negative ideas with our non-dominant side? Well, this study includes a large amount of data: it is, statistically, very likely that Obama really does tend to use his left hand over his right hand for positive gestures, i.e. this is unlikely to be due to random chance.

But does this mean that there's a correlation between handedness and good-gesture-lateralization? We actually only have 4 data points relevant to that question: Obama, McCain, Kerry and Bush. We have a lot of information on each of those people, but there are only 4 independent sets of data.

Suppose that everyone has a hand-they-use-for-good-gestures, and that it's 50/50 whether it's left or right - that is to say, suppose it has nothing to do with your general handedness. Clearly, there's then a 50% chance that any given person's good-gesture-hand will match their handedness, just by coincidence. There's a 1 in 4 chance that, for any two people, both will have a match; it's 1 in 8 for three people and 1 in 16 for four people. Which implies that there's a 1 in 16 chance that these results would have happened purely by chance.

Maybe we need to look back to the Clinton / Dole debates to get some more data...

Daniel Casasanto and Kyle Jasmin1 (2010). Good and Bad in the Hands of Politicians: Spontaneous Gestures during Positive and Negative Speech PLoS ONE

Inception for Dummies

If you haven't watched Inception yet, don't read this post. It's great and I don't want to spoil it for you. So stop. You didn't though, did you, you're still reading this right now. Well, I warned you.

Inception as everyone knows is about people who can hack into other people's dreams to access their subconcious. The plot concerns their attempts to achieve, well, inception - putting an idea into someone's mind, which makes what they usually do, stealing secret ideas, seem easy by comparison.

The problem is that it's easy to plant an idea, but the victim always knows that it's an external imposition - they don't really believe it. Leonardo DiCaprio comes up with the plan of going into the victim's subconcious's subconcious, and planting an emotional idea about his father, in order to lead him to conclude, on his own, that he should break up his father's business empire. I'm not sure what Freud would have thought of this plan.

Could you actually do this? Well. Hacking into people's dreams is high fantasy: we have absolutely no idea how you'd do that, and in the movie the only explanation we get is that it involves fancy machines and unspecified drugs. It's safe to say no-one will be gatecrashing your dream party any time soon.

But here's one way to achieve the same kind of effect, inspired by two recent papers: this one that I wrote about in my last post, finding that electrical stimulation of the hippocampus produces temporary amnesia, and this one covered at Neurophilosophy, finding that stimulating a mouse's lateral amygdala at the same time as playing it a noise makes it fear that noise.

Simple fear conditioning happens in the amygdala, not the hippocampus (although conditioned fear to some partiuclarly complex stimuli, like places, does.) So assuming you were a neurosurgeon with a desire to do some inception and no ethical scruples whatsoever, here's what you might decide to do.

Knock your victim out with a sedative. Keep them unconscious while you implant electrodes in their hippocampus and their amygdala. Wake them up, but make sure that you constantly stimulate their hippocampus to disrupt it, from the moment they awake. This will leave them fully aware, but will mean they'll have no subsequent concious memory of what you do, because such concious declarative memories depend upon the hippocampus.

Now, you condition them to fear something, by showing it to them whilst stimulating their lateral amygdala. (To be honest, you could just give them a slap in the face and it would probably be just as effective - but that would be a bit unrefined. This is a high-tech evil medical procedure, not a common punch-up.) Maybe you could make them scared of the face of a business rival who you don't want them to cut a deal with. Or you could make a terrorist leader abhor the symbols of his own ideology. The possibilities are endless.

Once you're done, sedate them again and return them to their house. Yeah, you'd have to do this all in the course of one night, but no-one said Inception was going to be easy. With any luck, they'll wake up with no concious recollection of anything, but with the emotional conditioning still intact.

The lack of memory is of course crucial: if they remembered what had happened, they'd realize that the conditioning was an external imposition, and wouldn't be swayed by it. And they'd bust you to the cops, obviously. But without that concious knowledge as to the true source of the feelings, they'd have no alternative interpretation of the fear they now feel - they'd take it as their own, and really start to dislike whatever it was you'd made them afraid of, constructing elaborate rationalizations along the way. The dream is real...

Zapping Memories Away

Imagine you're about to have to do something horrible or embarrasing, like say, admitting that you read Neuroskeptic. Wouldn't it be nice to be able to switch off your memory for a while, so you at least didn't have to remember it?

Well, now you can, as long as you have electrodes implanted in your brain. Lacruz et al, based at London's Institute of Psychiatry, report that Single pulse electrical stimulation of the hippocampus is sufficient to impair human episodic memory.

They took 12 people who were undergoing neurosurgery for severe epilepsy, and found that giving a single brief electrical pulse to the hippocampus caused momentary amnesia. Patients were much less likely to remember seeing a word or a picture presented immediately (within 150 milliseconds) after the pulse.

It only worked if you zapped the hippocampus on both the left and the right side simultaneously; if you only disrupt one, memory is unaffected, suggesting that one can compensate for the lack of the other.

It's been known for 60 years that damage to the hippocampus causes amnesia (e.g.), and previous electrode stimulation studies have shown amnesia after a few minutes of repeated shocks, but this is the first study to show that a single pulse can cause ultra-short memory impairment.

Follow up work confirmed that the stimulation only affected memory, rather than the perception of the items. Stimulation immediately before asking people to remember the items had no effect, showing that the hippocampus is only required for encoding, not retrieval.

This is a great study which adds to our knowledge of the memory functions of the hippocampus - although we need to avoid the temptation to see the hippocampus as purely a "memory module", since it's also known to be involved in space perception.

It's also a good example of why epilepsy patients are the unsung heroes of modern neuroscience - because they're basically the only people in whom it's ethical to do this kind of experiments. Surgeons need to stimulate their brains in order to optimize their treatment. It would be unethical to open someone's skull and poke around their grey matter purely for research purposes, but given that it's going to happen anyway for medical reasons, you might as well do a little research too...

Lacruz ME, Valentín A, Seoane JJ, Morris RG, Selway RP, & Alarcón G (2010). Single pulse electrical stimulation of the hippocampus is sufficient to impair human episodic memory. Neuroscience PMID: 20643192

Clever New Scheme

CNS Response are a California-based company who offer a high-tech new approach to the personalized treatment of depression: "referenced EEG" (rEEG).

This is not to be confused with qEEG, which I have written about previously. What is rEEG? It involves taking an EEG recording of resting brain activity and sending it - along with a cheque, naturally - to CNS Response, who compare it to their database of over 1,800 psychiatric patients who likewise had EEGs taken before they started on various drugs. They look to see which drugs worked best in people with an EEG profile similar to yours, and give you a fancy report with their recommendations.

That's not completely implausible. It could work. Does it? CNS Response and some academic collaborators have just published a paper saying yes: The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression. How solid is it? Well, it would be wrong to say that there are many problems with this study. But then if you run off a cliff and plummet into a volcano, you've only made one mistake.

Depressed patients were randomized to one of two groups: treatment-as-usual, which generally meant the common antidepressants bupropion, citalopram, or venlafaxine, vs. rEEG-guided personalized drug treatment. The trial was pretty large, with 114 patients randomized, and pretty long, 12 weeks. The patients had failed to respond to at least one antidepressant (mean: 1.5) during the current episode, so they were slightly "treatment-resistant", though not extremely so.

What happened? The rEEG-guided group did better on the QIDS16SR self-report scale, and on most other measures. Not enormously: take a look at the graph, notice that the vertical axis doesn't start at zero. But better.
Great, they did better. But why? The problem with this study is that the rEEG-guided group got a very different set of drugs to the control group. No less than 55% of them got stimulants, either methylphenidate (Ritalin) and dexamphetamine (speed). These drugs make you feel good. That's why they're illegal, that's why people pay good money for them on the street.

It's debatable whether stimulants are clinically useful as antidepressants in the long term, but they've got a good chance of making you feel nice for a few weeks, and make you say you feel better on a rating scale. Plus there's nothing like a pep pill to drive active placebo effects.

The authors say that "Almost all of the studies with depression not associated with medical disorders have reported minimal or no antidepressant effect of stimulants", and refer to some 1980s studies - yet their own trial has just shown that they do work in more than 50% of patients, and the latest Cochrane meta-analysis finds stimulants do work in the short term...

The other big names in the EEG group were MAOis (selegiline or tranylcypromine). These are often effective in treatment-resistant depression. Not necessarily more so than other drugs, but remember that these patients had already failed at least one SSRI(*). Yet the control group were, it seems, almost all given SSRIs - either citalopram, or venlafaxine, which is effectively an SSRI at low doses, e.g. the average dose used here, 141 mg. (It does other stuff, but only at higher doses of 225 mg or 300 mg.)

In summary, there were two groups in this trial and they got entirely different sets of drugs. One group also got rEEG-based treatment personalization. That group did better, but that might have nothing to do with the rEEG: they might have done equally well if they'd just been assigned to stimulants or MAOis etc. by flipping a coin. We cannot tell, from these data, whether rEEG offered any benefits at all.

What's curious is that it would have been very simple to avoid this issue. Just give everyone rEEG, but shuffle the assignments in the control group, so that everyone was guided by someone else's EEG. So you'd give control Patient 2 the drugs that Patient 1 should have got, and vice versa; swap 3 and 4, 5 and 6, etc.

This would be a genuinely controlled test of the personalized rEEG system, because both groups would get the same kinds of drugs. It would have been a lot easier too. For one thing it wouldn't require the additional step of deciding what drugs to give the control group. The authors decided to follow the STAR*D treatment protocol in this study, which is not unreasonable, but that must have been a bit of a hard decision.

Second, it would allow the trial to be double-blind: in this study the investigators knew which group people were in, because it was obvious from the drug choice. Thirdly, it wouldn't have meant they had to exclude people whose rEEG recommended they get the same treatment that they would have got in the control group... and so on.

Hmm. Mysterious. Anyway, we may be hearing more about CNS Response soon, so watch this space.

(*) - Technically, some of them had failed an SSRI and some had failed "2 or more classes of antidepressants", but one of those classes will almost certainly have been an SSRI, because they're the first-line treatment.

DeBattista, C., Kinrys, G., Hoffman, D., Goldstein, C., Zajecka, J., Kocsis, J., Teicher, M., Potkin, S., Preda, A., & Multani, G. (2010). The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression Journal of Psychiatric Research DOI: 10.1016/j.jpsychires.2010.05.009

What You Really Feel

Arthur Schopenhauer is my favorite 19th century German philosopher. Not that this is enormous praise given my attitude to the others, but anyway, here's one of his pearls of wisdom (source):

If you want to find out your real opinion of anyone, observe the impression made upon you by the first sight of a letter from him.

Does your heart leap, does it sink, do you get butterflies in your stomach, in the moment when you first see a message from that person? That's how you really feel, and if you didn't think you felt that way, you thought wrong.

Schopenhauer's trick relies on the fact that emotion is faster than thought. A letter takes you by surprise: even if you're expecting to hear from someone, you don't know exactly when it will arrive. It arrives: in that first second your emotions have a chance to show through, before your thoughts have got into gear. It works with emails and phone calls as well, of course, but not with any encounter which is planned out in advance.

The point is that you do not enjoy direct and perfect knowledge of your own feelings. You can be wrong about them, just like you could misjudge anyone else's feelings. Maybe you think that you like someone, when you really find them annoying. You believe that you like someone as a friend, but you really feel more than that.

In fact, it's not clear that we have any special insight into our own emotions, beyond that which is available to others. We tend to assume that we do. For one thing, we say they're our emotions: we own them. I'm the one who feels my emotions, and emotions are just feelings, so I must be the expert on them, right?

Yes, but feeling an emotion and understanding it are entirely separate. As I wrote previously, we all interpret our feelings in various ways, and like any act of interpretation, we can be either right or wrong. Suppose I love you and I think "I love you". In that case I'm right. But I could love you and think I don't (maybe I think it's just lust), or then again I could not love you (it is just lust) but think that I do. Any combination of feelings and thoughts is possible.

The notion that our mind is a single monolithic thing, and that we know everything that's in our own mind, is a stubborn one, but quite misleading. In fact we know very little about what goes on in our own heads; 100 billion cells are firing all the time, and we're not aware of any of them. Sometimes we can achieve self-knowledge, but it is never guaranteed.

Pepsi No Evil

So the web's leading science blogs hub, scienceblogs.com, tried to open a big bottle of Pepsi, but someone had shaken it up and it sprayed all over their face. Or something.

The PepsiGate Affair aka #sbfail has been covered elsewhere in great detail. Basically, SB announced they were going to host a new blog by Pepsi where Pepsi could talk about the "nutritional research" they're doing. A number of their best known bloggers decided they didn't want to be a part of that, and moved their blogs off the site. SB backtracked, and the PepsiBlog is no more, but the damage has been done.

Now that the dust has settled somewhat, I wonder: what exactly was wrong with the idea?

Well, the Pepsi blog would have been crap. Almost by definition. And the whole thing was undeniably an ill-thought decision, as shown by the fact that SB U-turned when the backlash hit. If they'd been serious, they'd have stuck to their guns.

But would it have been so bad? Take this from the response that SB made to their critics:

We think the conversation should include scientists from academia and government; we also think it should include scientists from industry.

I agree with this. It reflects the real world, and to the extent that science blogs are there to educate about science, that's a good thing. It would be lovely if all research was done by tenured academics with absolutely no ulterior motives except to uncover the truth. Unfortunately, it isn't. Most research is either done by non-tenured academics, whose ulterior motive is to advance our own careers, or by industry. (Of course most tenured academics have conflicts of interest too, but at least they could be impartial and still make a living.)

Now it could be said that industrial researchers shouldn't be bloggers because their conflict of interest is so glaring that their blogs would be mere propaganda. Well, they almost certainly would, but the point about blogging is that it's peer reviewed by default: if someone writes something crap, then either no-one will read it, or they'll criticize it, probably in the comments.

This is why if someone has a "blog" with no comments I don't think it's really a blog (comment moderation is iffy too in my book). So the fact that we're rarely perfectly impartial isn't a fatal flaw, because we get grilled. And we get grilled if we're wrong for reasons other than impartiality.

I'd love it if every major company had an official blog, so long as it had genuinely open comments, because I think they would get ripped to shreds and that would, eventually, undermine their credibility. This is presumably why most companies don't. As Jack of Kent said, "they are exposed to a huge reputational risk by seeking to blog in the full glare of the blogosphere."

Now there is a big question as to whether scienceblogs.com should play host to such blogs. I agree that it feels wrong. But I suspect that this feeling stems from the fear that it wouldn't just be a new PepsiBlog, it would also lead to a chilling effect on any of their other bloggers preventing them from criticizing Pepsi. That it would fundamentally change the character of the whole site.

If that happened, then I'd stop reading SB, and I'd hope that any blogger with integrity would quit - but let's be fair, we just don't know whether it would have happened or not. And if it didn't, what harm would have been done? The non-Pepsi blogs would be able to continue blogging as happily as ever, PepsiBlog would get ripped to shreds, and Pepsi would, I suspect, have pulled it before too long anyway, realizing it had become a joke.

SB's pristine reputation for only hosting the best science would be dirtied. But I'm not sure that reputation was intact anyway. Look at Pharyngula. Let's be honest, most Pharyngula posts are not actually about science, they're about religion. Not that there's anything wrong with that, it's one of the leading blogs of its kind, but it's pretty obvious that the reason SB host it is because it brings in a ton of hits, and hence advertising money. And the owners of ScienceBlogs have allowed advertisers to dictate editorial policy before (personally I find this incident more disturbing than the Pepsi one).

In my mind, there is however, one excellent reason for opposing the PepsiBlog, and that's that it is a slippery slope away from high quality writing. As it stands, SB recruits blogs on merit. At least nominally. Maybe they also accept sexual favors. But not openly. Pharyngula has plenty of merit, although as I said, it's not exactly science, but that's the big difference between Pharyngula and a corporate blog: Pharyngula brings in the hits because it's good at what it does.

The PepsiBlog, while not a disaster in itself, would have sent the signal that you don't need to be good to blog at SB, you can also blog there if you're rich. This would have inevitably led to the erosion of SB's own reputation, which was extremely good until this happened because most of their blogs were excellent. The very fact that there has been such outcry over all this proves it - people didn't expect this from SB because we thought: they are above this.

SB was a great site. It may still be one, I hope it is, and I suspect they have learned their lesson now. If not, then the biggest damage from PepsiGate will be that we've lost a great site. But I don't think that's happened yet. SB still has a lot of great blogs, although it has just lost some of its best, but I for one am hopeful that it will recover.

Autism And Wealth

We live in societies where some people are richer than others - though the extent of wealth inequality varies greatly around the world.

In general, it's sad but true that poor people suffer more diseases. Within a given country almost all physical and mental illnesses are more common amongst the poor, although this isn't always true between countries.

So if a certain disease is more common in rich people within a country, that's big news because it suggests that something unusual is going on. Autism spectrum disorders (ASDs) have long been known to show this pattern, at least in some countries, but this has often been thought to be a product of diagnostic ascertainment bias. Maybe richer and better-educated parents are more likely to have access to services that can diagnose autism. This is a serious issue because autism often goes undiagnosed and diagnosis is rarely clear-cut.

An important new PLoS paper from Wisconsin's Durkin et al suggests that, while ascertainment bias does happen, it doesn't explain the whole effect in the USA: richer American families really do have more autism than poorer ones. The authors made use of the ADDM Network which covers about 550,000 8 year old children from several sites across the USA. (This paper also blogged about here at C6-H12-O6 blog.)

ADDM attempts to count the number of children with autism based on

abstracted data from records of multiple educational and medical sources to determine the number of children who appear to meet the ASD case definition, regardless of pre-existing diagnosis. Clinicians determine whether the ASD case definition is met by reviewing a compiled record of all relevant abstracted data.

Basically, this allowed them to detect autism even in kids who haven't got a formal diagnosis, based on reports of behavioural problems at school etc indicative of autism. Clearly, this is going to underestimate autism somewhat, because some autistic kids do well at school and don't cause any alarm bells, but it has the advantage of reducing ascertainment bias.

What happened? The overall prevalence of autism was 0.6%. This is a lot lower than recent estimates in 5-9 year olds in the UK (1.5%), but the UK estimates used an even more detailed screening technique which was less likely to leave kids undetected.

The headline result: autism was more common in kids of richer parents. This held true within all ethnic groups: richer African-American or Hispanic parents were more likely to have autistic children compared to poorer people of the same ethnicity. So it wasn't a product of ethnic disparities.

Crucially, the pattern held true in children who had never been diagnosed with autism, although the effects of wealth were quite a bit smaller:

The difference in the slope of the two lines suggests that there is some ascertainment bias, with richer parents being more likely to get a diagnosis for their children, but this can't explain the whole story. There really is a correlation with wealth.

So what does this mean? This is a correlation - the causality remains to be determined. There are two obvious possibilities: to put it bluntly, either being rich makes your kids autistic, or having autistic kids makes you rich.

How could being rich make your children autistic? There could be many reasons, but a big one is paternal age: it's known that the risk of autism rises with the age of the father, maybe because the sperm of older men accumulates more genetic damage, and this damage can cause autism. In general richer people wait longer to have kids (I think, although I can't actually find the data on this) so maybe that's the cause.

How could having autistic kids make you richer? Well, unfortunately I don't think it does directly, but maybe being the kind of person who is likely to have an autistic child could. Autism is highly heritable, so the parents of autistic children are likely to carry some "autism genes". These could give them autistic traits, or indeed autism, and autistic traits, like being intensely interested in complex intellectual matters, can be a positive advantage in many relatively well paid professions like scientific research, or computing. Marginal Revolution's Tyler Cowen recently wrote a book all about that. I hope I will not offend too many when I say that in my experience it's rare to meet a scientist, IT person or, say, neuroscience blogger, who doesn't have a few...

Durkin, M., Maenner, M., Meaney, F., Levy, S., DiGuiseppi, C., Nicholas, J., Kirby, R., Pinto-Martin, J., & Schieve, L. (2010). Socioeconomic Inequality in the Prevalence of Autism Spectrum Disorder: Evidence from a U.S. Cross-Sectional Study PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011551

I Feel X, Therefore Y

I'm reading Le Rouge et le Noir ("The Red and the Black"), an 1830 French novel by Stendhal...

One passage in particular struck me. Stendhal is describing two characters who are falling in love (mostly); both are young, have lived all their lives in a backwater provincial town, and neither has been well educated.

In Paris, the nature of [her] attitude towards [him] would have very quickly become plain - but in Paris, love is an offspring of the novels. In three or four such novels, or even in a couplet or two of the kind of song they sing at the Gymnase, the young tutor and his shy mistress would have found a clear explanation of their relations with each other. Novels would have traced out a part for them to play, given them a model to imitate.

The idea that reading novels could change the way people fall in love might strange today, but remember that in 1830 the novel as we know it was still a fairly new invention, and was seen in conservative quarters as potentially dangerous. Stendhal was of course pro-novels (he was a novelist), but he accepts that they have a profound effect on the minds of readers.

Notice that his claim is not that novels create entirely new emotions. The two characters had feelings for each other despite never having read any. Novels suggest roles to play and models to follow: in other words, they provide interpretations as to what emotions mean and expectations as to what behaviours they lead to. You feel that, therefore you'll do this.

This bears on many things that I've written about recently. Take the active placebo phenomenon. This refers to cases in which a drug creates certain feelings, and the user interprets these feelings as meaning that "the drug is working", so they expect to improve, which leads them to feel better and behave as if they are getting better.

As I said at the time, active placebos are most often discussed in terms of drug side effects creating the expectation of improvement, but the same thing also happens with real drug effects. Valium (diazepam) produces a sensation of relaxation and reduces anxiety as a direct pharmacological effect but if someone takes it expecting to feel better, this will also drive improvement via expectation: the Valium is working, I can cope with this.

The same process can be harmful, though, and this may be even more common. The cognitive-behavioural theory of recurrent panic attacks is that they're caused by vicious cycles of feelings and expectations. Suppose someone feels a bit anxious, or notices their heart is racing a little. They could interpret that in various ways. They might write it off and ignore it, but they might conclude that they're about to have a panic attack.

If so, that's understandably going to make them more anxious, because panic is horrible. Anxiety causes adrenaline released, the heart beats ever faster etc., and this causes yet more anxiety until a full-blown panic attack occurs. The more often this happens, the more they come to fear even minor symptoms of physical arousal because they expect to suffer panic. Cognitive behavioural therapy for panic generally consists of breaking the cycle by changing interpretations, and by gradual exposure to physical symptoms and "panic-inducing" situations until they no longer cause the expectation of panic.

This also harks back to Ethan Watters' book Crazy Like Us which I praised a few months back. Watters argued that much mental illness is shaped by culture in the following way: culture tells us what to expect and how people behave when they feel distressed in certain ways, and thus channels distress into recognizable "syndromes" - a part to play, a model to imitate, though probably quite unconsciously. The most common syndromes in Western culture can be found in the DSM-IV, but this doesn't mean that they exist in the rest of the world.

Like Stendhal's, this theory does not attempt to explain everything - it assumes that there are fundamental feelings of distress - and I do not think that it explains the core symptoms of severe mental illness such as bipolar disorder and schizophrenia. But people with bipolar and schizophrenia have interpretations and expectations just like everyone else, and these may be very important in determining long-term prognosis. If you expect to be ill forever and never have a normal life, you probably won't.

The World Turned Upside Down

This map is not “upside down”. It looks that way to us; the sense that north is up is a deeply ingrained one. It's grim up north, Dixie is away down south. Yet this is pure convention. The earth is a sphere in space. It has a north and a south, but no up and down.

There’s a famous experiment involving four guys and a door. An unsuspecting test subject is lured into a conversation with a stranger, actually a psychologist. After a few moments, two people appear carrying a large door, and they walk right between the subject and the experimenter.

Behind the door, the experimenter swaps places with one of the door carriers, who may be quite different in voice and appearance. Most subjects don't notice the swap. Perception is lazy: whenever it can get away with it, it merely tells us that things are as we expect, rather than actually showing us stuff. We often do not really perceive things at all. Did the subject really see the first guy? The second? Either?

The inverted map makes us actually see the Earth's geography, rather than just showing us the expected "countries" and "continents". I was struck by how parochial Europe is – the whole place is little more than a frayed end of the vast Eurasian landmass, no more impressive than the one at the other end, Russia's Chukotski. Africa dominates the scene: it can no longer be written off as that poor place at the bottom.

One of the most common observations in psychotherapy of people with depression or anxiety is that they hold themselves to impossibly high standards, although they have a perfectly sensible evaluation of everyone else. Their own failures are catastrophic; other people's are minor setbacks. Other people's successes are well-deserved triumphs; their own are never good enough, flukes, they don't count.

The first step in challenging these unhelpful patterns of thought is to simply point out the double-standard: why are you such a perfectionist about yourself, when you're not when it comes to other people? The idea being to help people to think about themselves in more like healthy way they already think about others. Turn the map of yourself upside down - what do you actually see?

Brain Stimulation Can Stop the Rock

Isn't it annoying when you get a song stuck in your head? Like, say, this one:

Stop the rock, stop the rock
Stop the rock, stop the rock
Stop the rock, can't stop the rock
You can't stop the rock, stop the rock
Stop the rock, can't stop the rock
You can't stop the rock, can't stop the rock. etc.

- Apollo 440, "Stop the Rock"

You'll probably be stuck with that tune for a few minutes, but with any luck it'll go away eventually. However, for the 63-year old Italian man reported on in a new paper by Cosentino et al., the melodic misery never stopped.

The patient had suffered from partial hearing loss for 20 years, probably as a result of his work as a stonemason, which involved a lot of loud noise. His real problems started, however, when he suffered a car accident which cause damage to his right temporal pole. This caused

continuous musical hallucinations in the form of popular songs by Renato Carosone ... the songs were the ones he often used to listen to when he was younger. The volume of the musical hallucinations was initially low, and then became progressively louder; it was perceived in the middle of head and changed in severity over the course of the day. The intensity of the hallucinations evaluated through an arbitrary scale ranging from 0 (no hallucinations) to 10 (unbearable hallucinations) varied from 5 to 8 during the day.

The spectral songs didn't directly interfere with his life, but they were extremely annoying. He reported no other symptoms, his hearing was no worse than it had been before the accident, all neuropsychological tests were normal, and he had no history of any neurological or psychiatric problems.

Doctors tried to control the harmonic hallucinations with a range of anti-epileptic drugs, but they didn't work. A PET scan showed reduced brain activity in the area which was damaged, but increased activity in the posterior temporal lobe. Maybe this was to blame for the problems.

So Cosentino et al. decided to use repetitive transcranial magnetic stimulation (rTMS) to suppress activity in the offending part of the brain. rTMS uses strong magnetic fields to stimulate the brain; through some unknown neurobiological process, it can, in the long term, lead to reduced activity.

rTMS was given 5 days per week for 2 weeks. After the first week, the patient reported that the music had got a lot quieter and after another week, it was gone. A few months later it started again, but far quieter than before and only occasionally. The patient was offered more treatment but he said it wouldn't be worth it, because the hallucinations were no longer annoying. A second PET scan showed normalization of the activity...maybe (see the picture above; A=before B=after.)

There was no placebo condition, so it's hard to know whether this was a true effect of the magnetic stimulation, but the fact that a number of drugs hadn't worked suggests that it wasn't merely a placebo effect. So it turns out that you can Stop the Rock. Or at least, you can Stop the Canzone Napoletana of Renato Carosone. Whether the Rock is harder to Stop is a topic for future research.

Cosentino, G., Giglia, G., Palermo, A., Panetta, M., Lo Baido, R., Brighina, F., & Fierro, B. (2010). A case of post-traumatic complex auditory hallucinosis treated with rTMS Neurocase, 16 (3), 267-272 DOI: 10.1080/13554790903456191

XMRV and Chronic Fatigue Syndrome, Continued (Again)

Yet more twists have emerged in the already serpentine tale of XMRV, the virus that may or may not be responsible for causing some cases of chronic fatigue syndrome (CFS), aka myalgic encephalomyelitis, (ME).

First off, on Saturday 2nd July, a news item in Science magazine reported that two papers on XMRV were about to be published, but that the publication of both was "on hold" because they contradicted each other. One paper, from the US federal Centers for Disease Control (CDC), supposedly found no evidence of XMRV infection while the other one, from the National Institutes of Health and Food and Drug Administration (NIH/FDA), did.

The papers were only rumored to exist at that stage, and the story behind the NIH/FDA paper was particularly complicated. A Dutch magazine called ORTHO reported (see also) that NIH virologist Harvey Alter had given a presentation in Zagreb, Croatia, in which he reportedly said that the original Lombardi et al 2009 results, which first implicated XMRV in CFS

are extremely strong and likely true, despite the controversy...We (FDA & NIH) have independently confirmed the Lombardi group findings.

This was in reference to the still unpublished NIH/FDA paper, which according to Science, has been accepted for publication but currently put "on hold" by the journal PNAS.

However, the Science news was obsolete as soon as it appeared, because the other "on hold" paper, the negative one from the CDC, turned out not to be on hold for very long, if at all. It's now available online at the journal Retrovirology: Switzer et al's Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States. It's listed as being published on the 1st July.

The CDC paper Switzer et al, as the rumors predicted, is negative. The authors tested blood plasma from 51 CFS cases and 53 healthy controls and found no evidence of anti-XMRV antibodies; they sent the same samples to a German lab and they confirmed the results. They then tested DNA extracted from blood samples in the same CFS patients and 97 controls, finding no evidence of XMRV DNA using a number of analytical methods; again, a second lab confirmed this. The paper is open access, so you can read it for more details (there are lots).

This is a big deal, because this is the first paper to attempt to replicate Lombardi et al's results in American patients. Several studies have appeared in the months following the original paper, and none of them found XMRV infection in any of their patients or controls. This is mysterious because Lombardi et al found XMRV in 67% of patients, but also in 4% of controls. However, these studies all used European people, raising the possibility that XMRV is just not found in Europe, for whatever reason.


So what exactly is going on here? Maybe only Lombardi et al used the appropriate methods which were able to detect XMRV, and everyone else has been failing to pick it up. However, in my opinion, while this was a reasonable suspicion months ago, it's very unlikely now because (by my count) 6 labs have not found XMRV in CFS patients, using lots of different approaches.

In most cases these labs showed that they were able to detect small quantities of XMRV added into a sample, as a positive control. Switzer et al, for example, say that they were able to detect 10 copies of the virus (not many) mixed into a sample of human DNA; one of the labs they used for a confirmation analysis could detect 4 copies.

There's another possibility - maybe only Lombardi et al were studying the right people. Lombardi et al used a carefully selected subgroup of CFS patients with various neurological and immunological abnormalities suggestive of a "medical" as opposed to a "psychological" disorder. However, the most popular 1994 criteria for CFS are a lot broader than this. Supporters of the XMRV-CFS link say that XMRV is probably associated only with some cases of CFS, and the various failed attempts to confirm XMRV have been looking in the wrong people.

Bearing this in mind, it's notable that the latest Switzer et al paper didn't recruit patients by approaching those who considered themselves to have CFS. Rather they identified cases through population screening: calling random numbers from the telephone directory of Wichita, Kansas, and of sites in Georgia, and asking people whether they were suffering from CFS-like symptoms such as fatigue. People who answered "yes" to enough questions were invited for a medical exam and interview and were diagnosed with CFS if they met the 1994 criteria (though in the abstract these are described as the revised 1994 criteria), as long as their symptoms weren't explained by a known, current medical or psychiatric disorder.

It's fair to say that this will have recruited a very different cross-section of patients than Lombardi et al did. However, in my opinion, while this is important, it doesn't resolve the fundamental mystery of why no-one had XMRV, not even the healthy controls, given that Lombardi et al found XMRV in 4% of healthy people. To my knowledge, this question remains unexplained. Maybe the "on hold" NIH/FDA paper will shed some light...

Finally, those interested in this topic may find my running summary of (I hope) all human XMRV research useful.

Link: virologyblog is also on the case...


Switzer, W., Jia, H., Hohn, O., Zheng, H., Tang, S., Shankar, A., Bannert, N., Simmons, G., Hendry, R., Falkenberg, V., Reeves, W., & Heneine, W. (2010). Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States Retrovirology, 7 (1) DOI: 10.1186/1742-4690-7-57

Enserink, M. (2010). Conflicting Papers on Hold as XMRV Frenzy Reaches New Heights Science, 329 (5987), 18-19 DOI: 10.1126/science.329.5987.18

Fingers

How many fingers do you have?

10, obviously, unless you've been the victim of an accident or a birth defect. Everyone knows that. You count up to ten on your fingers, for one thing.

But look at your left hand - how many fingers are on it? Little finger, ring finger, middle finger, first finger... thumb. So that's 4. But then we'd only have 8 fingers, and we all know we have 10. Unless the thumb is a finger, but is it?

Hmm. Hard to say. Wikipedia has some interesting facts about this question, and on Google if you start to type in "is the thumb", the top suggested search terms are all about this issue. It's a tricky one. People don't seem to know for sure.

But does that mean there's any real mystery about the thumb? No - we understand it as well as any other part of the body. We know all about the bones and muscles and joints and nerves of the thumb, we know how it works, what it does, even its evolutionary history (see The Panda's Thumb by Steven J Gould, still one of the greatest popular science books ever.) Science has got thumbs covered.

The mystery is in the English language, which isn't quite clear on whether the word "finger" encompasses the human thumb; for some purposes it does, i.e. we have 10 fingers, but for other purposes it probably doesn't, although even English speakers seem to be in two minds about the details (see Google, above).

Notice that although the messiness seems to focus on the thumb, the word "thumb" is perfectly clear. The ambiguity is rather in the word "finger", which can mean either any of the digits of the hand, or, the digits of the hand with three joints. Take a look at your hand again and you'll notice that your thumb lacks a joint compared to the fingers; something I must admit I'd forgotten until Wikipedia reminded me.

Yet it would be very easy to blame the thumb for the confusion. After all, the other 4 fingers are definitely fingers. The fingers are playing by the rules. Only the thumb is a troublemaker. So it comes as somewhat of a surprise to realize that it's the fingers, not the thumb, that are the problem.

*

So words or phrases can be ambiguous, and when they are, they can lead to confusion, but not always in the places you'd expect. Specifically, the confusion seems to occur at the borderlines, the edge cases, of the ambiguous terminology, but the ambiguity is really in the terminology itself, not the edge cases. To resolve the confusion you need to clarify the terminology, and not get bogged down in wondering whether this or that thing is or isn't covered by the term.

It's important to bear in this in mind when thinking about psychiatry, because psychiatry has an awful lot of confusion, and a lot of it can be traced back to ambiguous terms. Take, for example, the question of whether X "is a mental illness". Is addiction a mental illness, or a choice? Is mild depression a mental illness, or a normal part of life? Is PTSD a mental illness, or a normal reaction to extreme events? Is... I could go on all day.

The point is that you will never be able to answer these questions until you stop focussing on the particular case and first ask, what do I mean by mental illness? If you can come up with a single, satisfactory definition of mental illness, all the edge cases will become obvious. But at present, I don't think anyone really knows what they mean by this term. I know I don't, which is why I try to avoid using it, but often I do still use it because it seems to be the most fitting phrase.

It might seem paradoxical to use a word without really knowing what it means, but it isn't, because being able to use a word is procedural knowledge, like riding a bike. The problem is that many of our words have confusion built-in, because they're ambiguous. We can all use them, but that means we're all risking confusing each other, and ourselves. When this gets serious enough the only solution is to stop using the offending word and create new, unambiguous ones. With "finger", it's hardly a matter of life or death. With "mental illness", however, it is.

It's Like Cocaine, But No Fun

In a very interesting paper, Dutch pharmaceutical company NeuroSearch, in conjunction with Canadian research corporation Kendle Early Stage, report on Subjective and Objective Effects of the Novel Triple Reuptake Inhibitor Tesofensine in Recreational Stimulant Users.

Tesofensine is a drug NeuroSearch are developing for obesity, and they report that it's shown excellent weight-loss-inducing properties in early clinical trials, although of course they would say that. What makes "tes-fens" so interesting is how it works: it's a triple reuptake inhibitor or SNDRI, acting on three neurotransmitters: serotonin, dopamine, and noradrenaline. The only drug of this class in widespread use is, er, cocaine. As you can see, the two drugs are chemically pretty similar.

Experimental SNDRIs are hot right now. It's hoped that they could be effective treatments for obesity, depression, and who knows what else. SNRIs, that inhibit the reuptake of serotonin and noradrenaline but not dopamine, are well known as antidepressants (e.g. venlafaxine aka Effexor) and weight-loss drugs (sibutramine). The thinking goes that if two monoamines are good, three's got to be even better.

But the problem is that drugs that inhibit the reuptake of dopamine are powerful stimulants with the ability to get you as high as a kite. Or to put it technically they "have a strong abuse potential". The best known are amphetamine, methamphetamine, and, yes, cocaine. Here's a Mickey Mouse comic from 1951 showing what amphetamine does...

This is why this new paper is so interesting. The authors gave tesofensine, at a variety of doses, to 52 volunteers, all of whom were recreational users of illegal stimulants: the idea being that such experienced people are best placed to be able to tell you whether a certain drug is an abusable stimulant or not. Which seems like an excellent idea.

What happened? Not much: in the opinion of the expert judges, a single dose of tesofensine at 1, 6 or 9 mg, is a complete washout, man. 1 mg had no noticeable effects at all above placebo. 6 mg and 9 mg did but they were not perceived as enjoyable or as amphetamine-like; if anything, they were slightly unpleasant.

By contrast, the volunteers really liked 30 mg of d-amphetamine - no surprise there - but they did not like the antidepressant bupropion, or the ADHD drug atomoxetine. Everything was double-blind, by the way, and the fact that there was not one but three comparator drugs, as well as inert placebo, means that this study will have avoided active placebo effects.

No serious adverse events occurred, but the higher doses of tesofensine raised blood pressure and caused insomnia. Bear in mind that for obesity the lowest dose 1 mg is looking to be the most promising and this dose didn't cause many side effects. Overall, these results seem pretty convincing: tesofensine is no fun.

Why not, given that it's so similar to cocaine? The answer is almost certainly that it's just too slow. After taking it orally, it takes 5 to 8 h for blood levels to peak, and it persists in the body for weeks (halflife of ~220 h.) With cocaine, if you snort it, peak blood levels are achieved in minutes and the halflife is less than one hour.

In general, the faster a drug gets into the blood the more pleasurable it is: this is why people tend to snort, smoke, and inject recreational drugs, rather than swallowing them. Crack is the same drug as normal cocaine, but it can be smoked, which is even faster than snorting. Compared to drugs of abuse tesofensine is ridiculously slow to enter and leave the body.

But this does raise the question of whether, with repeated use, levels might build up and produce effects very different to those seen in this study, which only used a single dose. It has a half-life of 220 hours which means that 9 days after you take some, half of it is still in your bloodstream! In the obesity trials, it was given at a dose of up to 1 mg per day. This is unlikely to give it an abuse potential per se but it could cause a lot of side effects down the line. We'll just have to wait and see...

Schoedel, K., Meier, D., Chakraborty, B., Manniche, P., & Sellers, E. (2010). Subjective and Objective Effects of the Novel Triple Reuptake Inhibitor Tesofensine in Recreational Stimulant Users Clinical Pharmacology & Therapeutics, 88 (1), 69-78 DOI: 10.1038/clpt.2010.67