The Google of Negative Results

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?

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

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

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

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?

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:

1. It's sending more outputs
2. It's getting more inputs
3. 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

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

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

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.

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

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?

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?

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

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