A Gene for Power-Line Leukemia?

Some people believe that living near high-voltage power lines raises the risk of childhood cancer. Most people are skeptical. A Chinese group have just published a paper in the journal Leukemia and Lymphoma, claiming that a genetic polymorphism in the XRCC1 gene, which has been previously linked to various cancers, raises the risk of electromagnetic field (EMF)-related leukemia. People who believe in EMF-related leukemia are happy. The Daily Mail report on this study quoting no less than three such people.

What's the real story? The authors took 123 childhood leukemia patients living near Shanghai. They took blood samples for DNA analysis and asked the parents to report on a wide range of possible environmental risk factors, not just EMF:

The mothers of the patients were interviewed at the hospital by specifically trained medical doctors using a questionnaire. Visits to the present (or previous) residential areas of 66 cases were arranged, and the actual values of magnetic field intensities were measured using an EMF detector (TriField Meter, AlphaLab, USA). Questionnaires covered information about the parents’ sociodemographic characteristics, the children’s pre and postnatal characteristics and the familial history of cancer and autoimmune diseases. The questions related to environmental exposure covered pregnancy and the period from birth to diagnosis and detailed information including: Was there a television set/refrigerator/ microwave oven in the children’s rooms? Did you regularly use insecticides at home? Did you use gardening chemicals such as, fertilisers, herbicides, insecticides, fungicides, others? Were there chemical factories/telecommunication transmitters/electric transformers/power lines around your house?

Relying on self-report like this raises the risk of recall bias, but to be honest, this doesn't seem like a major problem. Certainly there is a much bigger problem with this study (see below). The authors genotyped the children for six different SNPs (genetic variants) which have been previously implicated in cancer

The MassARRAY technology platform (Sequenom, San Diego, California, USA) was used to detect the SNPs in hMLH1 Ex8–23A4G (rs1799977), APEX1 Ex5þ5T4G (rs1130409), MGMTEx7þ 13A4G (rs2308321), XRCC1 Ex9þ16G4A (rs25489), XPD Ex10–16G4A (rs1799793) and XPD Ex23þ61 T4G (rs13181)

See the problem that's developing here? Six SNPs, who knows how many different environmental factors (the paper isn't clear, but it seems to be at least seven, see below) - that's a textbook example of multiple comparisons. Any statistical comparison has a chance of giving a positive result just by chance. If you do enough comparisons, you will find something, just by chance.

The authors do not report making an attempt to correct for this (although there are plenty of ways of doing so). They never even acknowledge the problem. They simply report on their only positive result - an association between the XRCC1 risk allele and "proximity to electrical transformers and power lines" - and relegate all the negative results to a brief summary

No significant interactions between the proximity of the electric transformers and power lines and other genotypes were observed. No significant interactions were observed between genotypes and the presence of television sets, refrigerators or microwave ovens in children’s rooms, pesticides use or the presence of chemical factories or telecommunication transmitter within 500 m of the houses.

The positive result was that out of the children with leukemia, those living within 100m of electrical transformers and power lines were more likely to carry the XRCC1 risk allele than those not living within this proximity. Those living within 50m were slightly more likely than that. Under the assumption that genotype is not correlated with environment in the general population (a reasonable assumption, and they did test this in a control sample), this indicates a G x E interaction for leukemia / lymphoma risk, with p below 0.01.

One such result from what seems like at least 42 such comparisons is not especially impressive. It's certainly not proof of an interaction between XRCC1 and EMF, it's not even "suggestive evidence", it's at best a prompt for further research. Even being generous, and assuming that they would not have reported on an association with any risk factor other than proximity to power lines, this is still 6 comparisons with different polymorphisms (more if you count the fact that children living at differing distances from power lines were tested seperately).

Postscript: I hope that I'm wrong about this. It would be great if XRCC1 raised the risk of childhood cancer, because it would mean that we could prevent some childhood cancers by keeping at-risk children away from power-lines. This post is just something I hacked together in an hour and a half on a Sunday morning, and I'm not a statistician - it would be awful if I've just spotted a serious problem with an important paper which went un-noticed by journal editors and peer reviewers. So if someone wants to disagree with me please, please do - I'll provide the PDF of the paper on request if you need it. Until then, I think that this is especially bad example of the problem of multiple comparisons and a tragic case of sloppy science which could end up having serious consequences for health, in terms of acting as a red herring distracting from more valuable research.

[BPSDB]

You Yang, Xingming Jin, Chonghuai Yan, Ying Tian, Jingyan Tang, Xiaoming Shen (2008). Case-only study of interactions between DNA repair genes (hMLH1, APEX1, MGMT, XRCC1 and XPD) and low-frequency electromagnetic fields in childhood acute leukemia Leukemia and Lymphoma, 49 (12), 2344-2350 DOI: 10.1080/10428190802441347

A Gene for Power-Line Leukemia?

Some people believe that living near high-voltage power lines raises the risk of childhood cancer. Most people are skeptical. A Chinese group have just published a paper in the journal Leukemia and Lymphoma, claiming that a genetic polymorphism in the XRCC1 gene, which has been previously linked to various cancers, raises the risk of electromagnetic field (EMF)-related leukemia. People who believe in EMF-related leukemia are happy. The Daily Mail report on this study quoting no less than three such people.

What's the real story? The authors took 123 childhood leukemia patients living near Shanghai. They took blood samples for DNA analysis and asked the parents to report on a wide range of possible environmental risk factors, not just EMF:

The mothers of the patients were interviewed at the hospital by specifically trained medical doctors using a questionnaire. Visits to the present (or previous) residential areas of 66 cases were arranged, and the actual values of magnetic field intensities were measured using an EMF detector (TriField Meter, AlphaLab, USA). Questionnaires covered information about the parents’ sociodemographic characteristics, the children’s pre and postnatal characteristics and the familial history of cancer and autoimmune diseases. The questions related to environmental exposure covered pregnancy and the period from birth to diagnosis and detailed information including: Was there a television set/refrigerator/ microwave oven in the children’s rooms? Did you regularly use insecticides at home? Did you use gardening chemicals such as, fertilisers, herbicides, insecticides, fungicides, others? Were there chemical factories/telecommunication transmitters/electric transformers/power lines around your house?

Relying on self-report like this raises the risk of recall bias, but to be honest, this doesn't seem like a major problem. Certainly there is a much bigger problem with this study (see below). The authors genotyped the children for six different SNPs (genetic variants) which have been previously implicated in cancer

The MassARRAY technology platform (Sequenom, San Diego, California, USA) was used to detect the SNPs in hMLH1 Ex8–23A4G (rs1799977), APEX1 Ex5þ5T4G (rs1130409), MGMTEx7þ 13A4G (rs2308321), XRCC1 Ex9þ16G4A (rs25489), XPD Ex10–16G4A (rs1799793) and XPD Ex23þ61 T4G (rs13181)

See the problem that's developing here? Six SNPs, who knows how many different environmental factors (the paper isn't clear, but it seems to be at least seven, see below) - that's a textbook example of multiple comparisons. Any statistical comparison has a chance of giving a positive result just by chance. If you do enough comparisons, you will find something, just by chance.

The authors do not report making an attempt to correct for this (although there are plenty of ways of doing so). They never even acknowledge the problem. They simply report on their only positive result - an association between the XRCC1 risk allele and "proximity to electrical transformers and power lines" - and relegate all the negative results to a brief summary

No significant interactions between the proximity of the electric transformers and power lines and other genotypes were observed. No significant interactions were observed between genotypes and the presence of television sets, refrigerators or microwave ovens in children’s rooms, pesticides use or the presence of chemical factories or telecommunication transmitter within 500 m of the houses.

The positive result was that out of the children with leukemia, those living within 100m of electrical transformers and power lines were more likely to carry the XRCC1 risk allele than those not living within this proximity. Those living within 50m were slightly more likely than that. Under the assumption that genotype is not correlated with environment in the general population (a reasonable assumption, and they did test this in a control sample), this indicates a G x E interaction for leukemia / lymphoma risk, with p below 0.01.

One such result from what seems like at least 42 such comparisons is not especially impressive. It's certainly not proof of an interaction between XRCC1 and EMF, it's not even "suggestive evidence", it's at best a prompt for further research. Even being generous, and assuming that they would not have reported on an association with any risk factor other than proximity to power lines, this is still 6 comparisons with different polymorphisms (more if you count the fact that children living at differing distances from power lines were tested seperately).

Postscript: I hope that I'm wrong about this. It would be great if XRCC1 raised the risk of childhood cancer, because it would mean that we could prevent some childhood cancers by keeping at-risk children away from power-lines. This post is just something I hacked together in an hour and a half on a Sunday morning, and I'm not a statistician - it would be awful if I've just spotted a serious problem with an important paper which went un-noticed by journal editors and peer reviewers. So if someone wants to disagree with me please, please do - I'll provide the PDF of the paper on request if you need it. Until then, I think that this is especially bad example of the problem of multiple comparisons and a tragic case of sloppy science which could end up having serious consequences for health, in terms of acting as a red herring distracting from more valuable research.

[BPSDB]

You Yang, Xingming Jin, Chonghuai Yan, Ying Tian, Jingyan Tang, Xiaoming Shen (2008). Case-only study of interactions between DNA repair genes (hMLH1, APEX1, MGMT, XRCC1 and XPD) and low-frequency electromagnetic fields in childhood acute leukemia Leukemia and Lymphoma, 49 (12), 2344-2350 DOI: 10.1080/10428190802441347

The Lonely Grave of Galileo Galilei

Galileo would be turning in his grave. His achievement was to set science on the course which has made it into an astonishingly successful means of generating knowledge. Yet some people not only reject the truths of the science that Galileo did so much to advance; they do it in his name.

Intro: In Denial?

Scientific truth is increasingly disbelieved, and this is a new phenomenon, so much so that new words have been invented to describe it. Leah Ceccarelli defines manufacturoversy as a public controversy over some question (usually scientific) which is not considered by experts on the topic to be in dispute; the controversy is not a legitimate scientific debate but a PR tool created by commercial or ideological interests.

Probably the best example is the attempts by tobacco companies to cast doubt on the association between tobacco smoking and cancer. The techniques involved are now well known. The number of smokers who didn't quit smoking because there was "doubt" over the link with cancer is less clear. More recently, there have been energy industry-sponsored attempts to do the same to the science on anthropogenic global warming. Other cases often cited are the MMR-autism link, Intelligent Design, and HIV/AIDS denial, although the agendas behind these "controversies" are less about money and more about politics and cultural warfare.

Many manufacturoversies are also examples of denialism, which Wikipedia defines as

the position of governments, political parties, business groups, interest groups, or individuals who reject propositions on which a scientific or scholarly consensus exists

although the two terms are not synonymous; one could be a denialist without having any ulterior motives, while conversely, one could manufacture a controversy which did not involve denying anything (e.g. the media-manufactured MMR-causes-autism theory, while completely wrong, didn't contradict any established science, it was just an assertion with no evidence and plenty of reasons to think it was wrong.) Denialism is very often accompanied by invokations of Galileo (or occasionally other "rebel scientists"), in an attempt to rhetorically paint the theory under attack as no more than an established dogma.

Just a caveat: in the wrong hands, the concepts of manufacturoversy and denialism could become a means of rubbishing legitimate dissent. The slogan of the denialism blog is "Don't mistake denialism for debate", but the line is sometimes very fine(*). For example, I'm critical of the idea that psychiatric medications and electroconvulsive therapy are of little or no benefit to patients. If one wanted to, it would be possible to make a coherent-sounding case as to why this debate was a manufacturoversy on the part of the psychotherapy industry to undermine confidence in a competing form of treatment which is overwhelmingly supported by the scientific evidence. This would be wrong (mostly).

A History of Error

Anyway. What's interesting is that the idea of inappropriate or manufactured doubt about scientific or historical claims is a very new phenomenon. Indeed, it's very hard to think of any examples before 1950, with the possible exception of the first wave of Creationism in the 1920s. Leah Ceccarelli points out that many of the rhetorical tricks used go back to the Greek Sophists but until recently the concept of denialism would have been almost meaningless, for the simple reason that this requires a truth to be inappropriately called into question and before about the 19th century, to a first approximation, we didn't have access to any such truths.

It's easy to forget just how ignorant we were until recently. The average schoolkid today has a more accurate picture of the universe than the greatest genius of 500 years ago, or of 300 years ago, and even of 100 years ago (assuming that the schoolkid knows about the Big Bang, plate tectonics, and DNA - all 20th century discoveries).

To exaggerate, but not very much: until the last couple of centuries of human history, no-one correctly believed in anything, and people had many beliefs that were actively wrong - they believed in ghosts, and witches, and Hiranyagarbha, and Penglai. People erred by believing. Those who disbelieved were likely to be right.

Things have changed. There is more knowledge now; today, when people err, it is increasingly because they reject the truth. No-one in the West now believes in witches, but hundreds of millions of us don't believe that the visible universe originated in a singularity about 13.5 billion years ago, although this is arguably a much bigger mistake to make. In other words, whereas in the past the main problem was belief in false ideas ("dogma"); increasingly the problem is doubting true ones ("denialism").

Myths & Legends of Science

The problem is that the way most people think about science hasn't caught up with the pace of scientific change. In just a couple of hundred years, science has gone from being an assortment of separate, largely bad notions, to being a vast construct of interlinking and mutually supporting theories, the foundations of which are supported by mountains of evidence. Yet all of our most popular myths about science are Robin Hood stories - the hero is the underdog, the rebel, the Maverick who stands up to authority, battles the entrenched beliefs of the Establishment, and challenges dogma. In other words, the hero is a denialist - albeit one who turns out to be right.

Once, this was realistic. Galileo was an Aristotelean cosmology denier; Pasteur was a miasma theory denier; Einstein was a Newtonian physics denier. (In fact, the historical facts are a bit more complicated, as they often are, but this is true enough.) But these stories are out of date. Thanks to the great deniers of the past, there are few, if any, inappropriate dogmas in mainstream science. There, I said it. Thanks to the efforts of scientists past and present, science has become a professional activity with, generally, a very good success rate.

The HIV/AIDS hypothesis and anti-retroviral drugs were developed by orthodox career scientists with proper qualifications working within the mainstream of biology and medicine. They probably wore boring, conventional white coats. There were no exciting paradigm shifts in HIV science. There was no Galileo of HIV; there was Robert Gallo. Yet orthodox science has been successful in delivering treatments for HIV and understanding of the disease (anti-retrovirals are not perfect, but they're a hell of a lot better than untreated AIDS, and just 20 years ago that was what all patients faced.) The skeptics, the rebels, the Robin Hoods of HIV/AIDS - they have been a disaster. If global warming deniers succeed, the consequences will be much worse.

Of coure, we do still need intelligent rebels. It would be a foolhardy person(**) who predicted that there will never be another paradigm shifts in science; neuroscience, at least, is due at least one more and there are parts of the remoter provinces of science, such as behavioural genetics, which are in serious need of a critical eye. But the vast majority of modern science, unlike the science of the past, is actually quite good. Hence, rebels are most likely wrong. To make a foolhardy prediction: there will never be another Galileo in the sense of a single figure who denies the scientific consensus and turns out to be right. There can only be a finite number of Galileos in history - once one succeeds in reforming some field, there is no need for another - and we may well have run out. My previous post on this topic included the bold claim that

if most scientists believe something you probably should believe it, just because scientists say so.

Yet this wasn't always true. To pluck a nice round number out of the air, I'd say that science has only been this trustworthy for 50 years. Most of our myths and ideas about science date from before that era. Science has moved on since the time of Galileo, thanks to his efforts and those of they who came after him, but he is still invoked as a hero by those who deny scientific truth. He would be turning in his grave, in the earth which, as we now know, turns around the sun.

(*) and of course as we know, "it's such a fine line between stupid and clever".
(**) As foolhardy as Francis Fukuyama who in 1989 proclaimed that history had ended and that the world was past the era of ideological struggles.

[BPSDB]

The Lonely Grave of Galileo Galilei

Galileo would be turning in his grave. His achievement was to set science on the course which has made it into an astonishingly successful means of generating knowledge. Yet some people not only reject the truths of the science that Galileo did so much to advance; they do it in his name.

Intro: In Denial?

Scientific truth is increasingly disbelieved, and this is a new phenomenon, so much so that new words have been invented to describe it. Leah Ceccarelli defines manufacturoversy as a public controversy over some question (usually scientific) which is not considered by experts on the topic to be in dispute; the controversy is not a legitimate scientific debate but a PR tool created by commercial or ideological interests.

Probably the best example is the attempts by tobacco companies to cast doubt on the association between tobacco smoking and cancer. The techniques involved are now well known. The number of smokers who didn't quit smoking because there was "doubt" over the link with cancer is less clear. More recently, there have been energy industry-sponsored attempts to do the same to the science on anthropogenic global warming. Other cases often cited are the MMR-autism link, Intelligent Design, and HIV/AIDS denial, although the agendas behind these "controversies" are less about money and more about politics and cultural warfare.

Many manufacturoversies are also examples of denialism, which Wikipedia defines as

the position of governments, political parties, business groups, interest groups, or individuals who reject propositions on which a scientific or scholarly consensus exists

although the two terms are not synonymous; one could be a denialist without having any ulterior motives, while conversely, one could manufacture a controversy which did not involve denying anything (e.g. the media-manufactured MMR-causes-autism theory, while completely wrong, didn't contradict any established science, it was just an assertion with no evidence and plenty of reasons to think it was wrong.) Denialism is very often accompanied by invokations of Galileo (or occasionally other "rebel scientists"), in an attempt to rhetorically paint the theory under attack as no more than an established dogma.

Just a caveat: in the wrong hands, the concepts of manufacturoversy and denialism could become a means of rubbishing legitimate dissent. The slogan of the denialism blog is "Don't mistake denialism for debate", but the line is sometimes very fine(*). For example, I'm critical of the idea that psychiatric medications and electroconvulsive therapy are of little or no benefit to patients. If one wanted to, it would be possible to make a coherent-sounding case as to why this debate was a manufacturoversy on the part of the psychotherapy industry to undermine confidence in a competing form of treatment which is overwhelmingly supported by the scientific evidence. This would be wrong (mostly).

A History of Error

Anyway. What's interesting is that the idea of inappropriate or manufactured doubt about scientific or historical claims is a very new phenomenon. Indeed, it's very hard to think of any examples before 1950, with the possible exception of the first wave of Creationism in the 1920s. Leah Ceccarelli points out that many of the rhetorical tricks used go back to the Greek Sophists but until recently the concept of denialism would have been almost meaningless, for the simple reason that this requires a truth to be inappropriately called into question and before about the 19th century, to a first approximation, we didn't have access to any such truths.

It's easy to forget just how ignorant we were until recently. The average schoolkid today has a more accurate picture of the universe than the greatest genius of 500 years ago, or of 300 years ago, and even of 100 years ago (assuming that the schoolkid knows about the Big Bang, plate tectonics, and DNA - all 20th century discoveries).

To exaggerate, but not very much: until the last couple of centuries of human history, no-one correctly believed in anything, and people had many beliefs that were actively wrong - they believed in ghosts, and witches, and Hiranyagarbha, and Penglai. People erred by believing. Those who disbelieved were likely to be right.

Things have changed. There is more knowledge now; today, when people err, it is increasingly because they reject the truth. No-one in the West now believes in witches, but hundreds of millions of us don't believe that the visible universe originated in a singularity about 13.5 billion years ago, although this is arguably a much bigger mistake to make. In other words, whereas in the past the main problem was belief in false ideas ("dogma"); increasingly the problem is doubting true ones ("denialism").

Myths & Legends of Science

The problem is that the way most people think about science hasn't caught up with the pace of scientific change. In just a couple of hundred years, science has gone from being an assortment of separate, largely bad notions, to being a vast construct of interlinking and mutually supporting theories, the foundations of which are supported by mountains of evidence. Yet all of our most popular myths about science are Robin Hood stories - the hero is the underdog, the rebel, the Maverick who stands up to authority, battles the entrenched beliefs of the Establishment, and challenges dogma. In other words, the hero is a denialist - albeit one who turns out to be right.

Once, this was realistic. Galileo was an Aristotelean cosmology denier; Pasteur was a miasma theory denier; Einstein was a Newtonian physics denier. (In fact, the historical facts are a bit more complicated, as they often are, but this is true enough.) But these stories are out of date. Thanks to the great deniers of the past, there are few, if any, inappropriate dogmas in mainstream science. There, I said it. Thanks to the efforts of scientists past and present, science has become a professional activity with, generally, a very good success rate.

The HIV/AIDS hypothesis and anti-retroviral drugs were developed by orthodox career scientists with proper qualifications working within the mainstream of biology and medicine. They probably wore boring, conventional white coats. There were no exciting paradigm shifts in HIV science. There was no Galileo of HIV; there was Robert Gallo. Yet orthodox science has been successful in delivering treatments for HIV and understanding of the disease (anti-retrovirals are not perfect, but they're a hell of a lot better than untreated AIDS, and just 20 years ago that was what all patients faced.) The skeptics, the rebels, the Robin Hoods of HIV/AIDS - they have been a disaster. If global warming deniers succeed, the consequences will be much worse.

Of coure, we do still need intelligent rebels. It would be a foolhardy person(**) who predicted that there will never be another paradigm shifts in science; neuroscience, at least, is due at least one more and there are parts of the remoter provinces of science, such as behavioural genetics, which are in serious need of a critical eye. But the vast majority of modern science, unlike the science of the past, is actually quite good. Hence, rebels are most likely wrong. To make a foolhardy prediction: there will never be another Galileo in the sense of a single figure who denies the scientific consensus and turns out to be right. There can only be a finite number of Galileos in history - once one succeeds in reforming some field, there is no need for another - and we may well have run out. My previous post on this topic included the bold claim that

if most scientists believe something you probably should believe it, just because scientists say so.

Yet this wasn't always true. To pluck a nice round number out of the air, I'd say that science has only been this trustworthy for 50 years. Most of our myths and ideas about science date from before that era. Science has moved on since the time of Galileo, thanks to his efforts and those of they who came after him, but he is still invoked as a hero by those who deny scientific truth. He would be turning in his grave, in the earth which, as we now know, turns around the sun.

(*) and of course as we know, "it's such a fine line between stupid and clever".
(**) As foolhardy as Francis Fukuyama who in 1989 proclaimed that history had ended and that the world was past the era of ideological struggles.

[BPSDB]

We Really Are Sorry, But Your Soul is Still Dead

Over the past few weeks, Christian neurosurgeon Michael Egnor, who writes on Evolution News & Views, and atheist neurologist Steve Novella (Neurologica) have been having an, er, vigorous debate about what neuroscience can tell us about materialism and the soul. As reported in New Scientist, this is part of an apparant attempt to undermine the materialist position (that all mental processes are the product of neural processes), on the part of the same people who brought you Intelligent Design. Many are calling it the latest front in the Culture War.

A couple of days ago Denyse O'Leary, a Canadian journalist who writes the blog Mindful Hack(*), posted some comments from Egnor about the great Wilder Penfield and his idea of "double consciousness" (my emphasis)

[By stimulating points on the cerebral cortex with electrodes during surgery] Penfield found that he could invoke all sorts of things- movements, sensations, memories. But in every instance ... 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.

I generally find arguing about religion boring, and I've no wish to enlist in any Culture Armies (I'm British - we're a nation of Culture Pacifists), but I'm going to say something about this, because it's just bad neuroscience. Maybe there are good arguments against materialism, but this isn't one.

Unfortunately, neither O'Leary nor Egnor allow comments on their blogs, but immediately after posting this I emailed them both with a link to this post. We'll see what happens.

Anyway, Penfield, whom you can read about in great detail at Neurophilosophy, was a pioneer in the functional mapping of the cerebral cortex. He was a neurosurgeon, and as part of his surgical procedures he would systematically stimulate different points of the cerebral cortex with an electrode, so as to locate which areas were responsible for important functions and avoid damaging them. Michael Egnor, following Penfield, is correct that this kind of point stimulation of the cortex tends to evoke sensations or motor responses which are experienced by the patient as external. Point stimulation is not reported to be able to effect our "higher" mental faculties such as our beliefs, desires, decisions, and "will"; it might evoke a movement of the arm, say, but the subject will report that this felt like an involuntary reflex, not a willed action.

However, to take this as evidence for some kind of a dualism between a form of conciousness which can be manipulated via the brain and another, non-material level of conciousness which can't (the "soul" in other words), is like saying that because hammering away at one key of a piano produces nothing but an annoying noise, there must be something magical going on when a pianist plays a Mozart concerto. Stimulating a single small part of the brain is about the crudest manipulation imaginable; all we can conclude from the results of point-stimulation experiments is that some kinds of mental processes are not controlled by single points on the cortex. This should not be surprising, since the brain is a network of 100 billion cells; what's interesting, in fact, is that stimulating a few million of these cells with the tip of an electrode can do anything.

Neuroskeptic is frequently critical of fMRI, but one of my favorite papers is an fMRI study, Reading Hidden Intentions in the Human Brain. In this experiment the authors got volunteers to freely decide on one of two courses of action several seconds before they were required to actually do the chosen act. (It was deciding betweening adding vs. subtracting two numbers on a screen.) They discovered that it was possible to determine (albeit with less than 100% accuracy) what subjects were planning to do on any given trial, before they actually did it, through an analysis of the pattern of neural activity across a large area of the medial prefrontal cortex.

The green area on this image shows the area over which activity predicts the future action. Importantly, no one point on the cortex is associated with one choice over another, but the combination of activity across the whole area is (once you put it through some brilliant maths).

Based on this evidence, it's reasonable to suppose that we could manipulate human intentions if, instead of just one electrode, we had several thousand (or million), and if we knew exactly which pattern of stimulation to apply. Or to run with the piano analogy: we could play a wonderful tune if we were skilled enough to play the right notes in the right combinations in the right order.

In fact, there are plenty of things which already are known to alter "higher" processes. At the correct doses, acetylcholine receptor antagonists such as scopolamine and atropine can produce a state of delerium with hallucinations which are experienced as being indistingishable from reality. Someone might talk to a non-existent friend or try to smoke a non-existent cigarette, without any knowledge of having taken a drug at all. Erowid has many first-hand accounts from people who have taken such drugs "recreationally" (a very bad idea, as you'll gather if you read a few.)

Then there's psychiatric illness. Someone who's psychotic may hear voices and believe them to be real communications from God, or the dead, or a radio transmitter in his head. A bipolar patient in a manic state may believe herself to have incredible talents or supernatural powers and dismiss as nonsense any suggestion that this is a result of her illness. In general those suffering from acute abnormal mental states may behave in a manner which is completely out of character, or think and talk in bizarre ways, without being aware of doing so. This is called "lacking in insight".

We don't yet know the neurobiological basis of these states, but that they (often) have one is beyond doubt; give the appropriate drugs - or use electricity to induce seizures - and they (usually) vanish. Many people in the advanced phases of dementia, especially Alzheimer's disease, as a result of neurodegeneration, are similarly unaware of being ill - hence the sad sight of formerly intelligent men and women wandering the streets, not knowing how they got there. Brain damage, or stimulation of deep brain structures (not the cortex which Penfield studied), can lead to profound alterations in personality and emotion. To summarize - if you seek the soul in the data of neuroscience, you will need to look harder than Penfield did.

Links : Sorry, But Your Soul Just Died - Tom Wolfe. A classic.

(*) - Mindful Hack - not to be confused with Mind Hacks.

[BPSDB]

We Really Are Sorry, But Your Soul is Still Dead

Over the past few weeks, Christian neurosurgeon Michael Egnor, who writes on Evolution News & Views, and atheist neurologist Steve Novella (Neurologica) have been having an, er, vigorous debate about what neuroscience can tell us about materialism and the soul. As reported in New Scientist, this is part of an apparant attempt to undermine the materialist position (that all mental processes are the product of neural processes), on the part of the same people who brought you Intelligent Design. Many are calling it the latest front in the Culture War.

A couple of days ago Denyse O'Leary, a Canadian journalist who writes the blog Mindful Hack(*), posted some comments from Egnor about the great Wilder Penfield and his idea of "double consciousness" (my emphasis)

[By stimulating points on the cerebral cortex with electrodes during surgery] Penfield found that he could invoke all sorts of things- movements, sensations, memories. But in every instance ... 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.

I generally find arguing about religion boring, and I've no wish to enlist in any Culture Armies (I'm British - we're a nation of Culture Pacifists), but I'm going to say something about this, because it's just bad neuroscience. Maybe there are good arguments against materialism, but this isn't one.

Unfortunately, neither O'Leary nor Egnor allow comments on their blogs, but immediately after posting this I emailed them both with a link to this post. We'll see what happens.

Anyway, Penfield, whom you can read about in great detail at Neurophilosophy, was a pioneer in the functional mapping of the cerebral cortex. He was a neurosurgeon, and as part of his surgical procedures he would systematically stimulate different points of the cerebral cortex with an electrode, so as to locate which areas were responsible for important functions and avoid damaging them. Michael Egnor, following Penfield, is correct that this kind of point stimulation of the cortex tends to evoke sensations or motor responses which are experienced by the patient as external. Point stimulation is not reported to be able to effect our "higher" mental faculties such as our beliefs, desires, decisions, and "will"; it might evoke a movement of the arm, say, but the subject will report that this felt like an involuntary reflex, not a willed action.

However, to take this as evidence for some kind of a dualism between a form of conciousness which can be manipulated via the brain and another, non-material level of conciousness which can't (the "soul" in other words), is like saying that because hammering away at one key of a piano produces nothing but an annoying noise, there must be something magical going on when a pianist plays a Mozart concerto. Stimulating a single small part of the brain is about the crudest manipulation imaginable; all we can conclude from the results of point-stimulation experiments is that some kinds of mental processes are not controlled by single points on the cortex. This should not be surprising, since the brain is a network of 100 billion cells; what's interesting, in fact, is that stimulating a few million of these cells with the tip of an electrode can do anything.

Neuroskeptic is frequently critical of fMRI, but one of my favorite papers is an fMRI study, Reading Hidden Intentions in the Human Brain. In this experiment the authors got volunteers to freely decide on one of two courses of action several seconds before they were required to actually do the chosen act. (It was deciding betweening adding vs. subtracting two numbers on a screen.) They discovered that it was possible to determine (albeit with less than 100% accuracy) what subjects were planning to do on any given trial, before they actually did it, through an analysis of the pattern of neural activity across a large area of the medial prefrontal cortex.

The green area on this image shows the area over which activity predicts the future action. Importantly, no one point on the cortex is associated with one choice over another, but the combination of activity across the whole area is (once you put it through some brilliant maths).

Based on this evidence, it's reasonable to suppose that we could manipulate human intentions if, instead of just one electrode, we had several thousand (or million), and if we knew exactly which pattern of stimulation to apply. Or to run with the piano analogy: we could play a wonderful tune if we were skilled enough to play the right notes in the right combinations in the right order.

In fact, there are plenty of things which already are known to alter "higher" processes. At the correct doses, acetylcholine receptor antagonists such as scopolamine and atropine can produce a state of delerium with hallucinations which are experienced as being indistingishable from reality. Someone might talk to a non-existent friend or try to smoke a non-existent cigarette, without any knowledge of having taken a drug at all. Erowid has many first-hand accounts from people who have taken such drugs "recreationally" (a very bad idea, as you'll gather if you read a few.)

Then there's psychiatric illness. Someone who's psychotic may hear voices and believe them to be real communications from God, or the dead, or a radio transmitter in his head. A bipolar patient in a manic state may believe herself to have incredible talents or supernatural powers and dismiss as nonsense any suggestion that this is a result of her illness. In general those suffering from acute abnormal mental states may behave in a manner which is completely out of character, or think and talk in bizarre ways, without being aware of doing so. This is called "lacking in insight".

We don't yet know the neurobiological basis of these states, but that they (often) have one is beyond doubt; give the appropriate drugs - or use electricity to induce seizures - and they (usually) vanish. Many people in the advanced phases of dementia, especially Alzheimer's disease, as a result of neurodegeneration, are similarly unaware of being ill - hence the sad sight of formerly intelligent men and women wandering the streets, not knowing how they got there. Brain damage, or stimulation of deep brain structures (not the cortex which Penfield studied), can lead to profound alterations in personality and emotion. To summarize - if you seek the soul in the data of neuroscience, you will need to look harder than Penfield did.

Links : Sorry, But Your Soul Just Died - Tom Wolfe. A classic.

(*) - Mindful Hack - not to be confused with Mind Hacks.

[BPSDB]

No ventral prefrontal cortex? No problem!

Brain damage - it's not much fun when it's your brain, but for science, it's often good news. While neuroimaging can find the neural correlates of mental processes - areas of the brain which become active during the experience of an emotion, say - lesion studies are often necessary to establish the direction of causality. Just because somewhere in the brain is activated during the experience of fear, for example, doesn't mean that this area is responsible for our feelings of fright; it might just happen to be lighting up as a side effect. Neuroimaging can't tell the difference, but if someone suffers damage to some part of the brain and then becomes fearless, it becomes possible to establish which parts do what. Localizing a function to a certain region of the brain is not the same as understanding it, of course, but it's a start.

The main problem with lesion studies is that there aren't enough of them. Because of those pesky ethical considerations, you can't just go around poking holes in people's brains - you have to wait until damage occurs naturally. In many interesting parts of the brain, localized damage is frustratingly uncommon.

Yet good things come to those who wait. The Journal of Neuroscience have just published a landmark lesion study by Koenigs et. al.(*) who studied two separate, large groups of people who had suffered brain damage to a range of areas - Vietnam veterans with combat head injuries, and Iowa citizens who had suffered tumors, strokes, and other medical conditions. In both samples they measured symptoms of depression and attempted to correlate them with the location of the lesions.

They succeeded. In both samples, patients who had suffered damage to the ventro-medial prefrontal cortex (vmPFC), which sits a few inches behind the center of the forehead, seemed to be protected against depression. Compared to people who had suffered lesions to all of the other parts of the brain, people with vmPFC damage on both sides of the brain were rated as having fewer depressive symptoms, both according to their own report and the observations of the experimenters. In particular, they reported being almost completely free of emotional or subjective symptoms such as feelings of guilt, sadness, or self-dislike. For illustration, they describe the incredible (and ironic) case of a woman with a self-inflicted vmPFC lesion:

We identified one patient in the Iowa registry who represents an intriguing case of an apparent alleviation of severe depression after a bilateral vmPFC lesion. ... per secondary report the patient was being treated for depression when she attempted suicide 11 years ago by means of a gunshot to the head. The gunshot destroyed most of ventral PFC, including vmPFC bilaterally, but left intact most of dorsal PFC. The patient’s neuropsychologist, neurosurgeon, and long-term boyfriend all remarked that her depression was markedly diminished after the brain injury (boyfriend, speaking 16 months after the injury: “no sign of depression whatsoever since the accident”; neuropsychologist: “she never shows distress, worry, or anger”).

Overall, these results are exciting, but unsurprising - the vmPFC is commonly thought of as being involved in emotion and emotional decision making; Antonio Damasio famously inferred this from the case of Phineas Gage, who after losing his medial prefrontal cortex to an iron rod, became impulsive, reckless, and unconcerned for himself or others. It's not difficult to see that someone with such characteristics might be resistant to such emotional difficulties as depression, or, say, post-traumatic stress - and indeed Koenigs et. al. previously reported that such lesions also protect against PTSD in combat veterans.

Fascinatingly, old-fashioned psychosurgery frequently ended up destroying much the same areas of the brain; the desired result, sometimes achieved, was a patient who no longer cared or worried about anything - which was thought preferable to someone paralyzed by despair or anxiety. The point is that the vmPFC is not specifically a "depression area of the brain" - although these results suggest that it is necessary for the experience of depression, it is probably also responsible for a broad range of other emotions, and patients lacking a vmPFC clearly lack more than just sadness. (If there is a "depression area", which is possible, my money's on the subgenual cingulate cortex.)

The paper also reported that damage to another part of the brain, the dorsal prefrontal cortex (bilateral), seemed to cause depression - however, there were only 5 patients with this kind of damage, of whom 2 were clinically depressed, so it's harder to interpret this result:

The proportion of individuals meeting DSM-IV criteria for "current" MDD was significantly greater for the dorsal PFC lesion group (2 of 5) than for the non-PFC lesion group (1 of 101; p = 0.005) or non-brain-damaged group (0 of 54; p = 0.006). Thus, bilateral dorsal PFC lesions were associated with a relatively high prevalence of subsequent major depression.

A few things to note: Case histories are anecdotes, not data - and the brain of the woman described above is extensively abnormal; CT scans, not for the squeamish. The total number of vmPFC patients here was just twenty. This is the largest group of these patients studied so far, because this kind of injury is very rare, but this is still a smallish sample. Most importantly, levels of depression in the control groups in this study were fairly low. The vmPFC group showed essentially zero depressive symptoms, but even the control patients only showed mild symptoms on average, and only a couple of them were diagnosed with actual clinical depression. So the between-group differences were, while statistically significant, modest.

(*) Annoyingly, pretty much every paper from Mike Koenigs is a landmark lesion study. It's always the same lesion patients. Not that this is a major problem, I'm just annoyed that he gets to study them and not me.

M. Koenigs, E. D. Huey, M. Calamia, V. Raymont, D. Tranel, J. Grafman (2008). Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression Journal of Neuroscience, 28 (47), 12341-12348 DOI: 10.1523/JNEUROSCI.2324-08.2008