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

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

New Deep Brain Stimulation Blog

Via Dr Shock, there's a new blog just been started by an anonymous American man who will soon be undergoing deep brain stimulation (DBS) for clinical depression, as part of a blinded trial.

It sounds like it's going to be fascinating reading - to my knowledge this is the first blog of its kind. I've always been a big believer in the important of first-hand reports in psychiatry and neurology, but sadly these are often in short supply compared to the huge proliferation of MRI scans, graphs and clinical rating scales. Sometimes, you just need to listen to people.

The study, called 278-005, also known as BROADEN, will involve electrical stimulation of the subgenual cingulate cortex ("Area 25"), the most commonly chosen target for DBS in depression. The preliminary reports from subgenual cingulate DBS have been extremely positive, but there have been no large scale clinical trials to date.

New Deep Brain Stimulation Blog

Via Dr Shock, there's a new blog just been started by an anonymous American man who will soon be undergoing deep brain stimulation (DBS) for clinical depression, as part of a blinded trial.

It sounds like it's going to be fascinating reading - to my knowledge this is the first blog of its kind. I've always been a big believer in the important of first-hand reports in psychiatry and neurology, but sadly these are often in short supply compared to the huge proliferation of MRI scans, graphs and clinical rating scales. Sometimes, you just need to listen to people.

The study, called 278-005, also known as BROADEN, will involve electrical stimulation of the subgenual cingulate cortex ("Area 25"), the most commonly chosen target for DBS in depression. The preliminary reports from subgenual cingulate DBS have been extremely positive, but there have been no large scale clinical trials to date.

Lessons from the Placebo Gene

Update: See also Lessons from the Video Game Brain



The Journal of Neuroscience has published a Swedish study which, according to New Scientist (and the rest) is something of a breakthrough:

First 'Placebo Gene' Discovered

I rather like the idea of a dummy gene made of sugar, or perhaps a gene for being Brian Moloko, but what they're referring to is a gene, TPH2, which allegedly determines susceptibility to the placebo effect. Interesting, if true. Genetic Future was skeptical of the study because of its small sample size. It is small, but I'm not too concerned about that because there are, unfortunately, other serious problems with this study and the reporting on it. I should say at the outset, however, that most of what I'm about to criticize is depressingly common in the neuroimaging literature. The authors of this study have done some good work in the past and are, I'm sure, no worse than most researchers. With that in mind...



The study included 25 people diagnosed with Social Anxiety Disorder (SAD). Some people see the SAD diagnosis as a drug company ploy to sell pills (mainly antidepressants) to people who are just shy. I disagree. Either way, these were people who complained of severe anxiety in social situations. The 25 patients were all given placebo pill treatment for 8 weeks.



Before and after the treatment they each got an [H2

15O] PET scan, which measures regional blood flow (rCBF) in the brain, something that is generally assumed to correlate with neural activity. It's a bit like fMRI, although the physics are different. During the scans the subjects had to make a brief speech in front of 6 to 8 people. This was intended to make them anxious, as it would do. The patient's self-reported social anxiety in everyday situations was also assessed every 2 weeks by questionaires and clinical interviews.



The patients were then split into two groups based upon their final status: "placebo responders" were those who ended up with a "CGI" rating of 1 or 2 - meaning that they reported that their anxiety had got a lot better - and "placebo nonresponders" who didn't. (You may take issue with this terminology - if so, well done, and keep reading). Brain activation during the public speaking task was compared between these two groups. The authors also looked at two genes, 5HTTLPR and TPH2. Both are involved in serotonin signalling and both have been associated (in some studies) with vulnerability to anxiety and depression.



The results: The placebo responders reported less anxiety following treatment - unsurprisingly, because this is why they were classed as responders. On the PET scans, the placebo responders showed reduced amygdala activity during the second public speaking task compared to the first one; the non-responders showed no change. This is consistent with the popular and fairly sensible idea that the amygdala is active during the experience of emotion, especially fear and anxiety. However, in fact, this effect was marginal, and it was only significant under a region-of-interest analysis i.e. when they specifically looked at the data from the amygdala; in a more conservative whole-brain analysis they found nothing (or rather they did, but they wrote it off as uninteresting, as cognitive neuroscientists generally do when they see blobs in the cerebellum and the motor cortex):

PET data: whole-brain analyses

Exploratory analyses did not reveal significantly different treatment-induced patterns of change in responders versus nonresponders. Significant within-group alterations outside the amygdala region were noted only in nonresponders, who had increased (pre < post) rCBF in the right cerebellum ... and in a cluster encompassing the right primary motor and somatosensory cortices...

As for the famous "placebo gene", they found that two genetic variants, 5HTTLPR ll and TPH2 GG, were associated with a bigger drop in amygdala activity from before treatment to after treatment. TPH2 GG was also associated with the improvement in anxiety over the 8 weeks.

In a logistic regression analysis, the TPH2 polymorphism emerged as the only significant variable that could reliably predict clinical placebo response (CGI-I) on day 56, homozygosity for the G allele being associated with better outcome. Eight of the nine placebo responders (89%), for whom TPH2 gene data were available, were GG homozygotes.

You could call this a gene correlating with the "placebo effect", although you'd probably be wrong (see below). There are a number of important lessons to take home here.



1. Dr Placebo, I presume? - Be careful what you call the placebo effect



This study couldn't have discovered a "placebo gene", even if there is one. It didn't measure the placebo effect at all.



You'll recall that the patients in this study were assessed before and after 8 weeks of placebo treatment (sugar pills). Any changes occuring during these 8 weeks might be due to a true "placebo effect" - improvement caused by the patient's belief in the power of the treatment. This is the possibility that gets some people rather excited: it's mind over matter, man! This is why the word "placebo" is often preceded by words like "Amazing", "Mysterious", or even "Magical" - as if Placebo were the stage-name of a 19th century conjuror. (As opposed to the stage name of androgynous pop-goth Brian Moloko ... I've already done that one.)



But, as they often do, more prosaic explanations suggest themselves. Most boringly, the patients might have just got better. Time is the greater healer, etc., and two months is quite a long time. Maybe one of the patients hooked up with a cute guy and it did wonders for their self-confidence. Maybe the reason why the patients volunteered for the study when they did was because their anxiety was especially bad, and by the time of the second scan it had returned to normal (regression towards the mean). Maybe the study itself made a difference, by getting the patients talking about their anxiety with sympathetic professionals. Maybe the patients didn't actually feel any better at all, but just said they did because that's what they thought were expected to say. I could go on all day.



In my opinion most likely, the patients were just less anxious having their second PET scan, once they had survived the first one. PET scans are no fun: you get a catheter inserted into your arm, through which you're injected with a radioactive tracer compound. Meanwhile, your head is fixed in place within big white box covered in hazard signs. It's not hard to see that you'd probably be much more anxious on your first scan than on your second time around.



So, calling the change from baseline to 8 weeks a "placebo response", and calling the people who got better "placebo responders", is misleading (at least it misled every commentator on this study so far). The only way to measure the true placebo effect is to compare placebo-treated people with people who get no treatment at all. This wasn't done in this study. It rarely is. This is something which confuses an awful lot of people. When people talk about the placebo effect, they're very often referring to the change in the placebo group, which as we've seen is not the same thing at all, and has nothing even vaguely magical or mysterious about it. (For example, some armchair psychiatrists like to say that since patients in the placebo group in antidepressant drug trials often show large improvements, sugar pills must be helpful in depression.) Although that said there was another study in the same issue of the same journal which did measure an actual placebo effect.



2. Beware Post Hoc-us Pocus



From the way it's been reported, you would probably assume that this was a study designed to investigate the placebo effect. However, in the paper we read:

Patients were taken from two previously unpublished RCTs that evaluated changes in regional cerebral blood flow after 56 d of pharmacological treatment by means of positron emission tomography. ... The clinical PET trials ... included a total of 108 patients with SAD. There were three treatment arms in the first study and six arms in the second. ... Only the pooled placebo data are included herein, whereas additional data on psychoactive drug treatment will be reported separately.

Personally, I find this odd. Why have so many groups if you're interested in just one of them? Even if the data from the drug groups are published, it's unusual to report on some aspect of the placebo data in a seperate paper before writing up the main results of an RCT. To me it seems likely that when this study was designed, no-one intended to search for genes associated with the placebo effect. I suspect that the analysis the authors report on here was post-hoc; having looked at the data, they looked around for any interesting effects in it.



To be clear, there's no proof that this is what happened here, but anyone who has worked in science will know that it does happen, and to my jaded eyes it seems probable that this is a case of it. For one thing, if this was a study intended to investigate the placebo effect, it was poorly designed (see above).



There's nothing wrong with post-hoc findings. If scientists only ever found what they set out to look for, science wouldn't have got very far. However, unless they are clearly reported as post-hoc the problem of the Texas Sharpshooter arises - findings may appear to be more significant than they otherwise would. In this case, the TPH2 gene was only a significant predictor of "placebo response" with p=0.04, which is marginal at the best of times.



The reason researchers feel the need to do this kind of thing is because of the premium the scientific community (and hence scientific publishing) places on getting "positive results". Plus, no-one wants to PET scan over 100 people (they're incredibly expensive) and report that nothing interesting happened. However, this doesn't make it right (rant continues...)



3. Science Journalism Is Dysfunctional



Sorry to go on about this, but really it is. New Scientist's write up of this study was, relatively speaking, quite good - they did at least include some caveats ("The gene might not play a role in our response to treatment for all conditions, and the experiment involved only a small number of people.") Although, they had a couple of factual errors such as saying that "8 of the 10 responders had two copies [of the TPH2 G allele], while none of the non-responders did" - actually 8 of the 15 non-responders did - but anyway.



The main point is that they didn't pick up on the fact that this experiment didn't measure the placebo effect at all, which makes their whole article misleading. (The newspapers generally did an even worse job.) I was able to write this post because I had nothing else on this weekend and reading papers like this is a major part of my day job. Ego aside, I'm pretty good at this kind of thing. That's why I write about it, and not about other stuff. And that's why I no longer read science journalism (well, except to blog about how rubbish it is.)



It would be wrong to blame the journalist who wrote the article for this. I'm sure they did the best they could in the time available. I'm sure that I couldn't have done any better. The problem is that they didn't have enough time, and probably didn't have enough specialist knowledge, to read the study critically. It's not their fault, it's not even New Scientist's fault, it's the fault of the whole idea of science journalism, which involves getting non-experts to write, very fast, about complicated issues and make them comprehensible and interesting to the laymen even if they're manifestly not. I used to want to be a science journalist, until I realised that that was the job description.



T. Furmark, L. Appel, S. Henningsson, F. Ahs, V. Faria, C. Linnman, A. Pissiota, O. Frans, M. Bani, P. Bettica, E. M. Pich, E. Jacobsson, K. Wahlstedt, L. Oreland, B. Langstrom, E. Eriksson, M. Fredrikson (2008). A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety Journal of Neuroscience, 28 (49), 13066-13074 DOI: 10.1523/JNEUROSCI.2534-08.2008

Lessons from the Placebo Gene

Update: See also Lessons from the Video Game Brain



The Journal of Neuroscience has published a Swedish study which, according to New Scientist (and the rest) is something of a breakthrough:

First 'Placebo Gene' Discovered

I rather like the idea of a dummy gene made of sugar, or perhaps a gene for being Brian Moloko, but what they're referring to is a gene, TPH2, which allegedly determines susceptibility to the placebo effect. Interesting, if true. Genetic Future was skeptical of the study because of its small sample size. It is small, but I'm not too concerned about that because there are, unfortunately, other serious problems with this study and the reporting on it. I should say at the outset, however, that most of what I'm about to criticize is depressingly common in the neuroimaging literature. The authors of this study have done some good work in the past and are, I'm sure, no worse than most researchers. With that in mind...



The study included 25 people diagnosed with Social Anxiety Disorder (SAD). Some people see the SAD diagnosis as a drug company ploy to sell pills (mainly antidepressants) to people who are just shy. I disagree. Either way, these were people who complained of severe anxiety in social situations. The 25 patients were all given placebo pill treatment for 8 weeks.



Before and after the treatment they each got an [H2

15O] PET scan, which measures regional blood flow (rCBF) in the brain, something that is generally assumed to correlate with neural activity. It's a bit like fMRI, although the physics are different. During the scans the subjects had to make a brief speech in front of 6 to 8 people. This was intended to make them anxious, as it would do. The patient's self-reported social anxiety in everyday situations was also assessed every 2 weeks by questionaires and clinical interviews.



The patients were then split into two groups based upon their final status: "placebo responders" were those who ended up with a "CGI" rating of 1 or 2 - meaning that they reported that their anxiety had got a lot better - and "placebo nonresponders" who didn't. (You may take issue with this terminology - if so, well done, and keep reading). Brain activation during the public speaking task was compared between these two groups. The authors also looked at two genes, 5HTTLPR and TPH2. Both are involved in serotonin signalling and both have been associated (in some studies) with vulnerability to anxiety and depression.



The results: The placebo responders reported less anxiety following treatment - unsurprisingly, because this is why they were classed as responders. On the PET scans, the placebo responders showed reduced amygdala activity during the second public speaking task compared to the first one; the non-responders showed no change. This is consistent with the popular and fairly sensible idea that the amygdala is active during the experience of emotion, especially fear and anxiety. However, in fact, this effect was marginal, and it was only significant under a region-of-interest analysis i.e. when they specifically looked at the data from the amygdala; in a more conservative whole-brain analysis they found nothing (or rather they did, but they wrote it off as uninteresting, as cognitive neuroscientists generally do when they see blobs in the cerebellum and the motor cortex):

PET data: whole-brain analyses

Exploratory analyses did not reveal significantly different treatment-induced patterns of change in responders versus nonresponders. Significant within-group alterations outside the amygdala region were noted only in nonresponders, who had increased (pre < post) rCBF in the right cerebellum ... and in a cluster encompassing the right primary motor and somatosensory cortices...

As for the famous "placebo gene", they found that two genetic variants, 5HTTLPR ll and TPH2 GG, were associated with a bigger drop in amygdala activity from before treatment to after treatment. TPH2 GG was also associated with the improvement in anxiety over the 8 weeks.

In a logistic regression analysis, the TPH2 polymorphism emerged as the only significant variable that could reliably predict clinical placebo response (CGI-I) on day 56, homozygosity for the G allele being associated with better outcome. Eight of the nine placebo responders (89%), for whom TPH2 gene data were available, were GG homozygotes.

You could call this a gene correlating with the "placebo effect", although you'd probably be wrong (see below). There are a number of important lessons to take home here.



1. Dr Placebo, I presume? - Be careful what you call the placebo effect



This study couldn't have discovered a "placebo gene", even if there is one. It didn't measure the placebo effect at all.



You'll recall that the patients in this study were assessed before and after 8 weeks of placebo treatment (sugar pills). Any changes occuring during these 8 weeks might be due to a true "placebo effect" - improvement caused by the patient's belief in the power of the treatment. This is the possibility that gets some people rather excited: it's mind over matter, man! This is why the word "placebo" is often preceded by words like "Amazing", "Mysterious", or even "Magical" - as if Placebo were the stage-name of a 19th century conjuror. (As opposed to the stage name of androgynous pop-goth Brian Moloko ... I've already done that one.)



But, as they often do, more prosaic explanations suggest themselves. Most boringly, the patients might have just got better. Time is the greater healer, etc., and two months is quite a long time. Maybe one of the patients hooked up with a cute guy and it did wonders for their self-confidence. Maybe the reason why the patients volunteered for the study when they did was because their anxiety was especially bad, and by the time of the second scan it had returned to normal (regression towards the mean). Maybe the study itself made a difference, by getting the patients talking about their anxiety with sympathetic professionals. Maybe the patients didn't actually feel any better at all, but just said they did because that's what they thought were expected to say. I could go on all day.



In my opinion most likely, the patients were just less anxious having their second PET scan, once they had survived the first one. PET scans are no fun: you get a catheter inserted into your arm, through which you're injected with a radioactive tracer compound. Meanwhile, your head is fixed in place within big white box covered in hazard signs. It's not hard to see that you'd probably be much more anxious on your first scan than on your second time around.



So, calling the change from baseline to 8 weeks a "placebo response", and calling the people who got better "placebo responders", is misleading (at least it misled every commentator on this study so far). The only way to measure the true placebo effect is to compare placebo-treated people with people who get no treatment at all. This wasn't done in this study. It rarely is. This is something which confuses an awful lot of people. When people talk about the placebo effect, they're very often referring to the change in the placebo group, which as we've seen is not the same thing at all, and has nothing even vaguely magical or mysterious about it. (For example, some armchair psychiatrists like to say that since patients in the placebo group in antidepressant drug trials often show large improvements, sugar pills must be helpful in depression.) Although that said there was another study in the same issue of the same journal which did measure an actual placebo effect.



2. Beware Post Hoc-us Pocus



From the way it's been reported, you would probably assume that this was a study designed to investigate the placebo effect. However, in the paper we read:

Patients were taken from two previously unpublished RCTs that evaluated changes in regional cerebral blood flow after 56 d of pharmacological treatment by means of positron emission tomography. ... The clinical PET trials ... included a total of 108 patients with SAD. There were three treatment arms in the first study and six arms in the second. ... Only the pooled placebo data are included herein, whereas additional data on psychoactive drug treatment will be reported separately.

Personally, I find this odd. Why have so many groups if you're interested in just one of them? Even if the data from the drug groups are published, it's unusual to report on some aspect of the placebo data in a seperate paper before writing up the main results of an RCT. To me it seems likely that when this study was designed, no-one intended to search for genes associated with the placebo effect. I suspect that the analysis the authors report on here was post-hoc; having looked at the data, they looked around for any interesting effects in it.



To be clear, there's no proof that this is what happened here, but anyone who has worked in science will know that it does happen, and to my jaded eyes it seems probable that this is a case of it. For one thing, if this was a study intended to investigate the placebo effect, it was poorly designed (see above).



There's nothing wrong with post-hoc findings. If scientists only ever found what they set out to look for, science wouldn't have got very far. However, unless they are clearly reported as post-hoc the problem of the Texas Sharpshooter arises - findings may appear to be more significant than they otherwise would. In this case, the TPH2 gene was only a significant predictor of "placebo response" with p=0.04, which is marginal at the best of times.



The reason researchers feel the need to do this kind of thing is because of the premium the scientific community (and hence scientific publishing) places on getting "positive results". Plus, no-one wants to PET scan over 100 people (they're incredibly expensive) and report that nothing interesting happened. However, this doesn't make it right (rant continues...)



3. Science Journalism Is Dysfunctional



Sorry to go on about this, but really it is. New Scientist's write up of this study was, relatively speaking, quite good - they did at least include some caveats ("The gene might not play a role in our response to treatment for all conditions, and the experiment involved only a small number of people.") Although, they had a couple of factual errors such as saying that "8 of the 10 responders had two copies [of the TPH2 G allele], while none of the non-responders did" - actually 8 of the 15 non-responders did - but anyway.



The main point is that they didn't pick up on the fact that this experiment didn't measure the placebo effect at all, which makes their whole article misleading. (The newspapers generally did an even worse job.) I was able to write this post because I had nothing else on this weekend and reading papers like this is a major part of my day job. Ego aside, I'm pretty good at this kind of thing. That's why I write about it, and not about other stuff. And that's why I no longer read science journalism (well, except to blog about how rubbish it is.)



It would be wrong to blame the journalist who wrote the article for this. I'm sure they did the best they could in the time available. I'm sure that I couldn't have done any better. The problem is that they didn't have enough time, and probably didn't have enough specialist knowledge, to read the study critically. It's not their fault, it's not even New Scientist's fault, it's the fault of the whole idea of science journalism, which involves getting non-experts to write, very fast, about complicated issues and make them comprehensible and interesting to the laymen even if they're manifestly not. I used to want to be a science journalist, until I realised that that was the job description.



T. Furmark, L. Appel, S. Henningsson, F. Ahs, V. Faria, C. Linnman, A. Pissiota, O. Frans, M. Bani, P. Bettica, E. M. Pich, E. Jacobsson, K. Wahlstedt, L. Oreland, B. Langstrom, E. Eriksson, M. Fredrikson (2008). A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety Journal of Neuroscience, 28 (49), 13066-13074 DOI: 10.1523/JNEUROSCI.2534-08.2008

Alas, Poor Noradrenaline

Previously I posted about the much-maligned serotonin theory of depression and tentatively defended it, while making it clear that "low serotonin" was certainly not the whole story. Critics have noted that the serotonin-is-happiness hypothesis has become folk wisdom, despite being clearly incomplete, and this is generally ascribed to the marketing power of the pharmaceutical industry. What's also interesting is that a predecessor and rival to the serotonin hypothesis, the noradrenaline theory, failed to achieve such prominence.

Everyone's heard of serotonin. Only doctors and neuroscientists have heard of noradrenaline (called norepinephine if you're American), which is another monoamine neurotransmitter. Chemically the two molecules are rather different, but they both play roughly parallel roles in the brain, in the sense that both are released from a small number of cells originating in the brain stem onto areas throughout the brain in what's often described as a "sprinkler system" arrangement.

Forty years ago, noradrenaline was seen by most psychopharmacologists as being the key chemical determinant of mood, and the leading theory on the cause of depression was some kind of noradrenaline deficiency. At this time, serotonin was generally seen as being at best of uncertain importance. In 1967 two superstars of psychopharmacology, Joseph Schildkraut and Seymour Kety, wrote a review article in Science in which they summarized the evidence for a noradrenaline theory of depression. It still makes quite convincing reading, and since 1967, more evidence has come to light; reboxetine, which selectively inhibits the reuptake of noradrenaline, is at least as effective as Prozac, which is selective for serotonin. Although it's slightly controversial, it also seems as though antidepressants which target both monoamines are slightly more effective than those which only target either.

So what happened to the noradrenaline theory? If pressed, most experts will admit that there must be something in it, and it is still discussed - but noradrenaline just doesn't get talked about as much as serotonin in the context of depression and mood. So far as I can see there is little good reason for this - given that both serotonin and noradrenaline seem to be involved in mood, the best thing would be to study both, and in particular to study their interactions. Yet this is not what most scientists are doing. Noradrenaline has just dropped off the scientific radar.

Because everyone likes graphs, and because I had nothing better to do today, I knocked together a couple to show the rise and fall of noradrenaline. The first shows the total number of PubMed entries for each year from 1969 to 2007, containing hits in the Title or Abstract for [noradrenaline OR norepinephrine] AND [depression OR depressive OR antidepressant OR antidepressants OR antidepressive] vs. [Serotonin OR 5HT OR 5-hydroxytryptamine] AND [depression OR depressive OR antidepressant OR antidepressants OR antidepressive]. As you can see, the two lines track each other very closely until about 1990, when interest in serotonin in the context of depression / antidepressants suddenly takes off, leaving noradrenaline languishing far behind.

What's fascinating is that the total amount of published research about noradrenaline also peaked around 1990 and has since declined markedly, while publications about serotonin and dopamine (another monoamine neurotransmitter) have been steadily growing.

What happened around 1990? Prozac, the first commercially successful selective serotonin reuptake inhibitor (SSRI), was released onto the U.S. market in late 1987. Bearing in mind that science generally takes a year or so to make it from the lab to the journal page, it's tempting to see 1990 as the year of the onset of the "Prozac Effect". Prozac notoriously achieved a huge amount of publicity, far more than was granted to older antidepressants such as imipramine, despite its probably being less effective. Could this be one reason why serotonin has eclipsed noradrenaline in the eyes of scientists?

A couple of caveats: All I've shown here are historical trends, which is not in itself proof of causation. Also, the fall in the total number of publications mentioning noradrenaline is much too large to be directly due to the stall in the number of papers about noradrenaline and depression / antidepressants. However, there could be indirect effects (scientists might be less interested in basic research on noradrenaline if they see it as having no relevance to medicine.)

Note 16/12/08: I've realized that it would have been better to include the term "5-HT" in the serotonin searches as this is a popular way of referring to it. I suspect that had I done this the serotonin lines would have been higher, but the trends over time would be the same.

J. J. Schildkraut, S. S. Kety (1967). Biogenic Amines and Emotion Science, 156 (3771), 21-30 DOI: 10.1126/science.156.3771.21