Genes, Brains and the Perils of Publication

Much of science, and especially neuroscience, consists of the search for "positive results". A positive result is simply a correlation or a causal relationship between one thing and another. It could be an association between a genetic variant and some personality trait. It could be a brain area which gets activated when you think about something.


It's only natural that "positive results" are especially interesting. But "negative" results are still results. If you find that one thing is not correlated with another, you've found a correlation. It just happens to have a value of zero.

For every gene which causes bipolar disorder, say, there will be a hundred which have nothing to do with it. So, if you find a gene that doesn't cause bipolar, that's a finding. It deserves to be treated just as seriously as finding that a gene does cause it. In particular, it deserves to be published.

Sadly, negative results tend not to get published. There are lots of reasons for this and much has been written about it, both on this blog and in the literature, most notably by John Ionnidis (see this and this, for starters). A paper just published in Science offers a perfect example of the problem: Neural Mechanisms of a Genome-Wide Supported Psychosis Variant.

The authors, a German group, report on a genetic variant, rs1344706, which was recently found to be associated with a slightly raised risk of psychotic illness in a genome-wide association study. (Genome-wide studies can and do throw up false positives so rs1344706 might have nothing to do with psychosis - but let's assume that it does.)

They decided to see whether the variant had an effect on the brains of people who have never suffered from psychosis. That's an extremely reasonable idea, because if a certain gene causes an illness, it could well also cause subtle effects in people who don't have the full-blown disease.

So, they took 115 healthy people and used fMRI to measure neural activity while they were doing some simple cognitive tasks, such as the n-back task, a fairly tricky memory test. People with schizophrenia and other psychotic disorders often have difficulties on this test. They also used a test which involves recognizing people's emotions from pictures of their faces.
They found that -

Regional brain activation was not significantly related to genotype...Rs1344706 genotype had no impact on performance.

In other words, the gene didn't do anything. The sample size was large - with 115 people, they had an excellent chance to detect any effect, if there was one, and they didn't. That's a perfectly good finding, a useful contribution to the scientific record. It was reasonable to think that rs1344706 might affect cognitive performance or brain activation in healthy people, and it didn't.
But that's not what the paper is about. These perfectly good negative findings were relegated to just a couple of sentences - I've just quoted almost every word they say about them - and the rest of the article concerns a positive result.The positive result is that the variant was associated with differences in functional connectivity. Functional connectivity is the correlation between activity in different parts of the brain; if one part of the brain tends to light up at the same time as another part they are said to be functionally connected.

In risk-allele carriers, connectivity both within DLPFC (same side) and to contralateral DLPFC was reduced. Conversely, the hippocampal formation was uncoupled from DLPFC in non–risk-allele homozygotes but showed dose-dependent increased connectivity in risk-allele carriers. Lastly, the risk allele predicted extensive increases of connectivity from amygdala including to hippocampus, orbitofrontal cortex, and medial prefrontal cortex.

And they conclude, optimistically:

...our findings establish dysconnectivity as a core neurogenetic mechanism, where reduced DLPFC connectivity could contribute to disturbed executive function and increased coupling with HF to deficient interactions between prefrontal and limbic structures ... Lastly, our findings validate the intermediate phenotype strategy in psychiatry by showing that mechanisms underlying genetic findings supported by genome-wide association are highly penetrant in brain, agree with the pathophysiology of overt disease, and mirror candidate gene effects. Confirming a century-old conjecture by combining genetics with imaging, we find that altered connectivity emerges as part of the core neurogenetic architecture of schizophrenia and possibly bipolar disorder, identifying novel potential therapeutic targets.

I have no wish to criticize these findings as such. But the way in which this paper is written is striking. The negative results are passed over as quickly as possible. This despite the fact that they are very clear and easy to interpret - the rs1344706 variant has no effect on cognitive task performance or neural activation. It is not a cognition gene, at least not in healthy volunteers.

By contrast, the genetic association with connectivity is modest (see the graphs above - there is a lot of overlap), and very difficult to interpret, since it is clearly not associated with any kind of actual differences in behaviour.

And yet this positive result got the experiment published in no less a journal than Science! The negative results alone would have struggled to get accepted anywhere, and would probably have ended up either unpublished, or published in some rubbish minor journal and never read. It's no wonder the authors decided to write their paper in the way they did. They were just doing the smart thing. And they are perfectly respectable scientists - Andreas Meyer-Lindenberg, the senior author, has done some excellent work in this and other fields.

The fault here is with a system which all but forces researchers to search for "positive results" at all costs.

[BPSDB]

Esslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Arnold, C., Haddad, L., Mier, D., Opitz von Boberfeld, C., Raab, K., Witt, S., Rietschel, M., Cichon, S., & Meyer-Lindenberg, A. (2009). Neural Mechanisms of a Genome-Wide Supported Psychosis Variant Science, 324 (5927), 605-605 DOI: 10.1126/science.1167768

Genes, Brains and the Perils of Publication

Much of science, and especially neuroscience, consists of the search for "positive results". A positive result is simply a correlation or a causal relationship between one thing and another. It could be an association between a genetic variant and some personality trait. It could be a brain area which gets activated when you think about something.


It's only natural that "positive results" are especially interesting. But "negative" results are still results. If you find that one thing is not correlated with another, you've found a correlation. It just happens to have a value of zero.

For every gene which causes bipolar disorder, say, there will be a hundred which have nothing to do with it. So, if you find a gene that doesn't cause bipolar, that's a finding. It deserves to be treated just as seriously as finding that a gene does cause it. In particular, it deserves to be published.

Sadly, negative results tend not to get published. There are lots of reasons for this and much has been written about it, both on this blog and in the literature, most notably by John Ionnidis (see this and this, for starters). A paper just published in Science offers a perfect example of the problem: Neural Mechanisms of a Genome-Wide Supported Psychosis Variant.

The authors, a German group, report on a genetic variant, rs1344706, which was recently found to be associated with a slightly raised risk of psychotic illness in a genome-wide association study. (Genome-wide studies can and do throw up false positives so rs1344706 might have nothing to do with psychosis - but let's assume that it does.)

They decided to see whether the variant had an effect on the brains of people who have never suffered from psychosis. That's an extremely reasonable idea, because if a certain gene causes an illness, it could well also cause subtle effects in people who don't have the full-blown disease.

So, they took 115 healthy people and used fMRI to measure neural activity while they were doing some simple cognitive tasks, such as the n-back task, a fairly tricky memory test. People with schizophrenia and other psychotic disorders often have difficulties on this test. They also used a test which involves recognizing people's emotions from pictures of their faces.
They found that -

Regional brain activation was not significantly related to genotype...Rs1344706 genotype had no impact on performance.

In other words, the gene didn't do anything. The sample size was large - with 115 people, they had an excellent chance to detect any effect, if there was one, and they didn't. That's a perfectly good finding, a useful contribution to the scientific record. It was reasonable to think that rs1344706 might affect cognitive performance or brain activation in healthy people, and it didn't.
But that's not what the paper is about. These perfectly good negative findings were relegated to just a couple of sentences - I've just quoted almost every word they say about them - and the rest of the article concerns a positive result.The positive result is that the variant was associated with differences in functional connectivity. Functional connectivity is the correlation between activity in different parts of the brain; if one part of the brain tends to light up at the same time as another part they are said to be functionally connected.

In risk-allele carriers, connectivity both within DLPFC (same side) and to contralateral DLPFC was reduced. Conversely, the hippocampal formation was uncoupled from DLPFC in non–risk-allele homozygotes but showed dose-dependent increased connectivity in risk-allele carriers. Lastly, the risk allele predicted extensive increases of connectivity from amygdala including to hippocampus, orbitofrontal cortex, and medial prefrontal cortex.

And they conclude, optimistically:

...our findings establish dysconnectivity as a core neurogenetic mechanism, where reduced DLPFC connectivity could contribute to disturbed executive function and increased coupling with HF to deficient interactions between prefrontal and limbic structures ... Lastly, our findings validate the intermediate phenotype strategy in psychiatry by showing that mechanisms underlying genetic findings supported by genome-wide association are highly penetrant in brain, agree with the pathophysiology of overt disease, and mirror candidate gene effects. Confirming a century-old conjecture by combining genetics with imaging, we find that altered connectivity emerges as part of the core neurogenetic architecture of schizophrenia and possibly bipolar disorder, identifying novel potential therapeutic targets.

I have no wish to criticize these findings as such. But the way in which this paper is written is striking. The negative results are passed over as quickly as possible. This despite the fact that they are very clear and easy to interpret - the rs1344706 variant has no effect on cognitive task performance or neural activation. It is not a cognition gene, at least not in healthy volunteers.

By contrast, the genetic association with connectivity is modest (see the graphs above - there is a lot of overlap), and very difficult to interpret, since it is clearly not associated with any kind of actual differences in behaviour.

And yet this positive result got the experiment published in no less a journal than Science! The negative results alone would have struggled to get accepted anywhere, and would probably have ended up either unpublished, or published in some rubbish minor journal and never read. It's no wonder the authors decided to write their paper in the way they did. They were just doing the smart thing. And they are perfectly respectable scientists - Andreas Meyer-Lindenberg, the senior author, has done some excellent work in this and other fields.

The fault here is with a system which all but forces researchers to search for "positive results" at all costs.

[BPSDB]

Esslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Arnold, C., Haddad, L., Mier, D., Opitz von Boberfeld, C., Raab, K., Witt, S., Rietschel, M., Cichon, S., & Meyer-Lindenberg, A. (2009). Neural Mechanisms of a Genome-Wide Supported Psychosis Variant Science, 324 (5927), 605-605 DOI: 10.1126/science.1167768

Legal Highs

The past couple of weeks has seen British newspapers and politicians fretting about "legal highs". Legal highs are perfectly legal substances that "help people get out of their minds yet stay within the law" as the Guardian puts it.

Like Ritalin and booze, you mean? No, they're talking about things like spice arctic synergy. You know, spice arctic synergy, the famous drug. No? Well, you know about it now, and so does everyone who reads the Guardian. I would be interested to see what the sales of spice arctic synergy are like in the next few weeks.

From what I can tell "spice" is just the latest of the many brands of "herbal highs" that can be bought in head shops and other such "alternative" retailers. Other famous brands are Druid's Fantasy, Aztec Acid, and Wizard's Willy. (I may have made some of those up.) These are blends of possibly psychoactive plants which can be smoked or eaten; the effects are supposedly a bit like cannabis or magic mushrooms but, at least so far as I'm told, mostly consist of nausea and headache. And wasting £20.

The consumer base for these silly products largely consists of teenagers who aren't cool enough to buy any proper drugs. On the drug credibility scale, most "legal highs" rank somewhere between sniffing glue and drinking your own pee after taking mushrooms in order to recapture some of the hallucinogens. (That works, allegedly.) No self-respecting drug user would be seen dead with any. Ban them, on the other hand, and everyone will want some.

To be fair, there are some genuinely potent legal drugs out there. Salvia divinorum, for example, contains a pharmacologically unique dissociative hallucinogen called salvinorin. Back when I was an uncool teenager a few friends of mine tried it, but they only ever took it once. The experience apparently amounted to ten minutes of terror and indescribable visions that seem to last hours; no-one I know who's taken it enjoyed it, and in the case of one of them it let him to vow never to take any hallucinogens ever again. I tried some, but it did nothing at all (except waste my money.) So it's a bit unpredictable.

Should it be banned? Maybe. It's certainly not stuff I would want my kids to go near, if I had any. Hypocritical as that might be. But that doesn't mean it's actually harmful, still less that prohibiting it would prevent harm overall (I suspect people would just find another drug to take, maybe an even dodgier one.) It would be worth a serious and evidence-based look, like all areas of drug policy, but given that the government have a history of hysterical shrieking whenever their own appointed experts try to do that, I'm not hopeful.

And when I read that one MP has made it his personal mission to stop Salvia, I just couldn't stop thinking of bisturbile cranabolic amphetamoids.

Legal Highs

The past couple of weeks has seen British newspapers and politicians fretting about "legal highs". Legal highs are perfectly legal substances that "help people get out of their minds yet stay within the law" as the Guardian puts it.

Like Ritalin and booze, you mean? No, they're talking about things like spice arctic synergy. You know, spice arctic synergy, the famous drug. No? Well, you know about it now, and so does everyone who reads the Guardian. I would be interested to see what the sales of spice arctic synergy are like in the next few weeks.

From what I can tell "spice" is just the latest of the many brands of "herbal highs" that can be bought in head shops and other such "alternative" retailers. Other famous brands are Druid's Fantasy, Aztec Acid, and Wizard's Willy. (I may have made some of those up.) These are blends of possibly psychoactive plants which can be smoked or eaten; the effects are supposedly a bit like cannabis or magic mushrooms but, at least so far as I'm told, mostly consist of nausea and headache. And wasting £20.

The consumer base for these silly products largely consists of teenagers who aren't cool enough to buy any proper drugs. On the drug credibility scale, most "legal highs" rank somewhere between sniffing glue and drinking your own pee after taking mushrooms in order to recapture some of the hallucinogens. (That works, allegedly.) No self-respecting drug user would be seen dead with any. Ban them, on the other hand, and everyone will want some.

To be fair, there are some genuinely potent legal drugs out there. Salvia divinorum, for example, contains a pharmacologically unique dissociative hallucinogen called salvinorin. Back when I was an uncool teenager a few friends of mine tried it, but they only ever took it once. The experience apparently amounted to ten minutes of terror and indescribable visions that seem to last hours; no-one I know who's taken it enjoyed it, and in the case of one of them it let him to vow never to take any hallucinogens ever again. I tried some, but it did nothing at all (except waste my money.) So it's a bit unpredictable.

Should it be banned? Maybe. It's certainly not stuff I would want my kids to go near, if I had any. Hypocritical as that might be. But that doesn't mean it's actually harmful, still less that prohibiting it would prevent harm overall (I suspect people would just find another drug to take, maybe an even dodgier one.) It would be worth a serious and evidence-based look, like all areas of drug policy, but given that the government have a history of hysterical shrieking whenever their own appointed experts try to do that, I'm not hopeful.

And when I read that one MP has made it his personal mission to stop Salvia, I just couldn't stop thinking of bisturbile cranabolic amphetamoids.

Science vs. Free Will, Again

The question of whether we have "free will" has kept philosophers occupied for at least 2000 years. Wouldn't it be nice if science came along and sorted the whole thing out?
That's the reason why so many people are excited about reports like the one just published in Science, Movement Intention After Parietal Cortex Stimulation in Humans. The report itself is extremely straightforward. The authors, a team of French neurosurgeons, used electrodes to stimulate various points on the surface of the brains of seven patients. The patients were all suffering from brain tumours in various places, and they were undergoing surgery to remove them. As often happens, the authors decided to try to squeeze a little research out of the procedure as well.

The authors stimulated points in various areas of the brain, but the most interesting results came from the premotor cortex (the blue area on the picture above) and the posterior parietal cortex (red and yellow).

When certain points on the premotor cortex were stimulated, the patients moved. But they were not aware that they had done so. For example:

...during stimulation patient PM1 exhibited a large multijoint movement involving flexion of the left wrist, fingers, and elbow ... He did not spontaneously comment on this, and when asked whether he had felt a movement he responded negatively.

That's pretty interesting in itself, but even more so is what happened when the posterior parietal cortex got zapped. Stimulation here produced a desire or intention to move, although no movement actually occured:

Stimulation of all these sites produced a pure intention, that is, a felt desire to move without any overt movement being produced... Without prompting by the examiner, all three patients spontaneously used terms such as “will,” “desire,” and “wanting to,” which convey the voluntary character of the movement intention and its attribution to an internal source, that is, located within the self.

And as if that wasn't enough philosophically-provocative fun, high intensity stimulation of the same area made the patients believe that they had in fact moved, although they didn't move a muscle:

[with higher electrode currents] conscious motor intentions were replaced by a sensation that a movement had been accomplished [but] no actual movement was observed. Thus, these patients experienced awareness of an illusory movement. For example, patient PP3 reported after low-intensity stimulation of one site (5 mA, 4 s; site a in Fig. 1), “I felt a desire to lick my lips” and at a higher intensity (8 mA, 4 s), “I moved my mouth, I talked, what did I say?”

Wow. What are we to make of all this?

A while back I wrote about Wilder Penfield's idea of "double conciousness" which Christian neurosurgeon Michael Egnor described approvingly as

Penfield found that he could invoke all sorts of things- movements, sensations, memories. But in every instance (hundreds of thousands of individual stimulations- in different locations in each patient- during his career), the patients were aware that the stimulation was being done to them, but not by them. There was a part of the mind that was independent of brain stimulation and that constituted a part of subjective experience that Penfield was not able to manipulate with his surgery.

Penfield called this "double consciousness", meaning that there was a part of subjective experience that he could invoke or modify materially, and a different part that was immune to such manipulation.

So Penfield, one of the great pioneers of 20th century neuroscience, claimed that stimulation of the brain could never produce desires or intentions which were experienced as the subject's "own". The person whose brain you were stimulating always felt that whatever happened to them came from outside.

But this French report directly contradicts that. We can only speculate as to why. It could be that Penfield just never hit the right spot, but this seems extremely unlikely, as he did a lot of stimulating over the course of his career. A cynic might ask whether Penfield did observe similar phenomena and just never reported them, but if we're going to go down that road, it's equally likely that these neurosurgeons just made it all up. Fortunately, any neurosurgeon should be able to try to replicate these results with a few prods of an electrode, so it shouldn't take long before the truth becomes clearer.

If these present results hold up, they'll certainly suggest some interesting ideas about the organisation of the brain - such as that the perception of movement depends upon the neurones encoding the intention to move rather than those involved in producing the actual motor act.

It would also be interesting to find out what happens when you simulataneously stimulate the premotor spot which makes your arm move, and the posterior parietal spot which makes you want to move your arm. Would that make you want to move your arm - and do so? If so, that would suggest that something very similar to that is going on whenever we do anything. What is life, but wanting to move, and moving?

But whether that's true or not, intentions (and everything else) are still something that happens in the brain, and the brain is a material object subject to the laws of physics. Neuroscience can tell us how exactly it all fits together, but at the end of the day, it's all a bunch of cells. Free will, in other words, appears to be in trouble, whatever the details of the brain's mechanisms happen to be.

Desmurget, M., Reilly, K., Richard, N., Szathmari, A., Mottolese, C., & Sirigu, A. (2009). Movement Intention After Parietal Cortex Stimulation in Humans Science, 324 (5928), 811-813 DOI: 10.1126/science.1169896

Science vs. Free Will, Again

The question of whether we have "free will" has kept philosophers occupied for at least 2000 years. Wouldn't it be nice if science came along and sorted the whole thing out?
That's the reason why so many people are excited about reports like the one just published in Science, Movement Intention After Parietal Cortex Stimulation in Humans. The report itself is extremely straightforward. The authors, a team of French neurosurgeons, used electrodes to stimulate various points on the surface of the brains of seven patients. The patients were all suffering from brain tumours in various places, and they were undergoing surgery to remove them. As often happens, the authors decided to try to squeeze a little research out of the procedure as well.

The authors stimulated points in various areas of the brain, but the most interesting results came from the premotor cortex (the blue area on the picture above) and the posterior parietal cortex (red and yellow).

When certain points on the premotor cortex were stimulated, the patients moved. But they were not aware that they had done so. For example:

...during stimulation patient PM1 exhibited a large multijoint movement involving flexion of the left wrist, fingers, and elbow ... He did not spontaneously comment on this, and when asked whether he had felt a movement he responded negatively.

That's pretty interesting in itself, but even more so is what happened when the posterior parietal cortex got zapped. Stimulation here produced a desire or intention to move, although no movement actually occured:

Stimulation of all these sites produced a pure intention, that is, a felt desire to move without any overt movement being produced... Without prompting by the examiner, all three patients spontaneously used terms such as “will,” “desire,” and “wanting to,” which convey the voluntary character of the movement intention and its attribution to an internal source, that is, located within the self.

And as if that wasn't enough philosophically-provocative fun, high intensity stimulation of the same area made the patients believe that they had in fact moved, although they didn't move a muscle:

[with higher electrode currents] conscious motor intentions were replaced by a sensation that a movement had been accomplished [but] no actual movement was observed. Thus, these patients experienced awareness of an illusory movement. For example, patient PP3 reported after low-intensity stimulation of one site (5 mA, 4 s; site a in Fig. 1), “I felt a desire to lick my lips” and at a higher intensity (8 mA, 4 s), “I moved my mouth, I talked, what did I say?”

Wow. What are we to make of all this?

A while back I wrote about Wilder Penfield's idea of "double conciousness" which Christian neurosurgeon Michael Egnor described approvingly as

Penfield found that he could invoke all sorts of things- movements, sensations, memories. But in every instance (hundreds of thousands of individual stimulations- in different locations in each patient- during his career), the patients were aware that the stimulation was being done to them, but not by them. There was a part of the mind that was independent of brain stimulation and that constituted a part of subjective experience that Penfield was not able to manipulate with his surgery.

Penfield called this "double consciousness", meaning that there was a part of subjective experience that he could invoke or modify materially, and a different part that was immune to such manipulation.

So Penfield, one of the great pioneers of 20th century neuroscience, claimed that stimulation of the brain could never produce desires or intentions which were experienced as the subject's "own". The person whose brain you were stimulating always felt that whatever happened to them came from outside.

But this French report directly contradicts that. We can only speculate as to why. It could be that Penfield just never hit the right spot, but this seems extremely unlikely, as he did a lot of stimulating over the course of his career. A cynic might ask whether Penfield did observe similar phenomena and just never reported them, but if we're going to go down that road, it's equally likely that these neurosurgeons just made it all up. Fortunately, any neurosurgeon should be able to try to replicate these results with a few prods of an electrode, so it shouldn't take long before the truth becomes clearer.

If these present results hold up, they'll certainly suggest some interesting ideas about the organisation of the brain - such as that the perception of movement depends upon the neurones encoding the intention to move rather than those involved in producing the actual motor act.

It would also be interesting to find out what happens when you simulataneously stimulate the premotor spot which makes your arm move, and the posterior parietal spot which makes you want to move your arm. Would that make you want to move your arm - and do so? If so, that would suggest that something very similar to that is going on whenever we do anything. What is life, but wanting to move, and moving?

But whether that's true or not, intentions (and everything else) are still something that happens in the brain, and the brain is a material object subject to the laws of physics. Neuroscience can tell us how exactly it all fits together, but at the end of the day, it's all a bunch of cells. Free will, in other words, appears to be in trouble, whatever the details of the brain's mechanisms happen to be.

Desmurget, M., Reilly, K., Richard, N., Szathmari, A., Mottolese, C., & Sirigu, A. (2009). Movement Intention After Parietal Cortex Stimulation in Humans Science, 324 (5928), 811-813 DOI: 10.1126/science.1169896

Annotated Links #2

In the NY Times, Daphne Merkin writes about her life with recurrent and "treatment-resistant" depression. A Journey Through Darkness is eloquent and honest, but it offers no convincing explanations as to the origin of her bouts of melancholy. Sometimes she is depressed and then eventually the state passes. In Merkin's account, and in my personal experience, being depressed is a brute fact. It is experienced, not understood. To call it a "journey" or anything else which implies some kind of narrative is misleading. And when a depression passes, it goes with a whimper not a bang:

It was about 4:30, the time of day that, by mid-August, brings with it a whiff of summer’s end. I looked up into the startlingly blue sky; one of the dogs was sitting at my side, her warm body against my leg, drying me off after the swim I had recently taken. I could begin to see the curve of fall up ahead. There would be new books to read, new films to see and new restaurants to try. I envisioned myself writing again, and it didn’t seem like a totally preposterous idea. I had things I wanted to say. Everything felt fragile and freshly come upon, but for now, at least, my depression had stepped back, giving me room to move forward. I had forgotten what it was like to be without it, and for a moment I floundered, wondering how I would recognize myself. I knew for certain it would return, sneaking up on me when I wasn’t looking, but meanwhile there were bound to be glimpses of light if only I stayed around and held fast to the long perspective. It was a chance that seemed worth taking.

The Royal Swedish Academy of Sciences issues a welcome statement condemning "lie-detector" peddlers Nemesysco for their attempt to gag two Swedish scientists. (See also Ministry of Truth for an extensive take-down of Nemesysco and all who use their products). Although, given that this happened several months ago, they certainly took their time about it...

Incidents of this kind are a threat to research freedom and, by extension, to the free dissemination of information in society. Threats to sue must not be used to restrict scientific discussion.

Finally, I know I said I don't believe in music reviews, but Neko Case is brilliant.