Depression, Neurogenesis and Herpes

Previously, I've discussed the neurogenesis theory of depression in two rather skeptical posts. Not that I'm on some kind of anti-neurogenesis theory crusade, but a study just published adds to the evidence that all's not well with that hypothesis.

The paper is Singer et. al.'s Conditional ablation and recovery of forebrain neurogenesis in the mouse. Via some cunning genetic engineering, the authors created mice with a gene for a protein called herpes simplex virus thymidine kinase. As the name suggests, this is a protein normally found in, er, herpes. Ganciclovir is a drug which can be used to treat herpes and related viral infections. And, as you might expect, cells engineered to express the herpes protein die when exposed to ganciclovir.

The authors engineered mice which expressed herpes simplex virus thymidine kinase, but only in neural progenitor cells. These are the cells which eventually become new neurones in the adult brain. They found that injections of gancyclovir devasasted the production of new neurones in the engineered mice. (It had no effect on normal mice, of course, because their brain cells weren't half mouse, half herpes). That's not all that surprising.

However, they also found that gancyclovir treatment had no effect on the ability of 28 days treatment imipramine, an antidepressant, to affect the mice's behaviour. (The measure of antidepressant action was the Tail Suspension Test). That's a result, because a lot of people are interested in the theory that antidepressants work by boosting neurogenesis in the hippocampus. If that were true, blocking neurogenesis should also block the effects of antidepressants.

Some rather exciting experiments found that it does, most famously the much-cited Santarelli et al (2003). But a growing number of other studies, such as this one, have not confirmed this finding. This doesn't mean that Santarelli et al were wrong, but it does suggest that there's more to antidepressants than neurogenesis. The seemingly-contradictory findings of the various studies might be due to important differences in the methods used. For example, the authors of this paper say that Santarelli et al's way of blocking neurogenesis - using x-rays - may have also caused inflammation and blocked the formation of non-neural cells, such as those which go to make up blood-vessels.

Of course, it's easy enough for us to speculate along such lines - rather harder to work out what exactly is going on. With any luck, the next few years will see more progress on this important topic.

Singer, B., Jutkiewicz, E., Fuller, C., Lichtenwalner, R., Zhang, H., Velander, A., Li, X., Gnegy, M., Burant, C., & Parent, J. (2009). Conditional ablation and recovery of forebrain neurogenesis in the mouse The Journal of Comparative Neurology, 514 (6), 567-582 DOI: 10.1002/cne.22052

Depression, Neurogenesis and Herpes

Previously, I've discussed the neurogenesis theory of depression in two rather skeptical posts. Not that I'm on some kind of anti-neurogenesis theory crusade, but a study just published adds to the evidence that all's not well with that hypothesis.

The paper is Singer et. al.'s Conditional ablation and recovery of forebrain neurogenesis in the mouse. Via some cunning genetic engineering, the authors created mice with a gene for a protein called herpes simplex virus thymidine kinase. As the name suggests, this is a protein normally found in, er, herpes. Ganciclovir is a drug which can be used to treat herpes and related viral infections. And, as you might expect, cells engineered to express the herpes protein die when exposed to ganciclovir.

The authors engineered mice which expressed herpes simplex virus thymidine kinase, but only in neural progenitor cells. These are the cells which eventually become new neurones in the adult brain. They found that injections of gancyclovir devasasted the production of new neurones in the engineered mice. (It had no effect on normal mice, of course, because their brain cells weren't half mouse, half herpes). That's not all that surprising.

However, they also found that gancyclovir treatment had no effect on the ability of 28 days treatment imipramine, an antidepressant, to affect the mice's behaviour. (The measure of antidepressant action was the Tail Suspension Test). That's a result, because a lot of people are interested in the theory that antidepressants work by boosting neurogenesis in the hippocampus. If that were true, blocking neurogenesis should also block the effects of antidepressants.

Some rather exciting experiments found that it does, most famously the much-cited Santarelli et al (2003). But a growing number of other studies, such as this one, have not confirmed this finding. This doesn't mean that Santarelli et al were wrong, but it does suggest that there's more to antidepressants than neurogenesis. The seemingly-contradictory findings of the various studies might be due to important differences in the methods used. For example, the authors of this paper say that Santarelli et al's way of blocking neurogenesis - using x-rays - may have also caused inflammation and blocked the formation of non-neural cells, such as those which go to make up blood-vessels.

Of course, it's easy enough for us to speculate along such lines - rather harder to work out what exactly is going on. With any luck, the next few years will see more progress on this important topic.

Singer, B., Jutkiewicz, E., Fuller, C., Lichtenwalner, R., Zhang, H., Velander, A., Li, X., Gnegy, M., Burant, C., & Parent, J. (2009). Conditional ablation and recovery of forebrain neurogenesis in the mouse The Journal of Comparative Neurology, 514 (6), 567-582 DOI: 10.1002/cne.22052

More on that Homeopathy Analysis

As promised, I emailed the authors of that Cochrane Review of homeopathy for reducing the side effects of cancer treatment. I asked them to clarify why they had included the Pommier et al trial of Calendula ointment - a decision which attracted some criticism. Their (very prompt) response included this statement:

"...We contacted the manufacturer of the calendula ointment and they confirmed that it had been prepared in accordance with the German Homeopathic Pharmacopoeia, therefore the trial met our inclusion criteria..."

Which is a reference to the inclusion criteria as set out in their paper, i.e.:

Homeopathy (also spelt homoeopathy) was defined, for the purpose of this review, as the use of homeopathic medicines prepared in accordance with officially recognised homeopathic pharmacopoeias. Where there was doubt about the classification of the medicine, we contacted authors or the product manufactures for confirmation. Any homeopathic prescribing strategy was included (pp. 3-4).

So it looks like the debate over the inclusion of this trial boils down to a difference of opinion over the definition of "homeopathy". Critics (myself included) who questioned the inclusion of this trial did so because we hold a rather narrower concept of "homeopathy" than the authors do. Of course, there is no right or wrong definition of homeopathy - no-one holds a trademark on the term - so I think that this is where the debate is going to have to rest.

[BPSDB]

More on that Homeopathy Analysis

As promised, I emailed the authors of that Cochrane Review of homeopathy for reducing the side effects of cancer treatment. I asked them to clarify why they had included the Pommier et al trial of Calendula ointment - a decision which attracted some criticism. Their (very prompt) response included this statement:

"...We contacted the manufacturer of the calendula ointment and they confirmed that it had been prepared in accordance with the German Homeopathic Pharmacopoeia, therefore the trial met our inclusion criteria..."

Which is a reference to the inclusion criteria as set out in their paper, i.e.:

Homeopathy (also spelt homoeopathy) was defined, for the purpose of this review, as the use of homeopathic medicines prepared in accordance with officially recognised homeopathic pharmacopoeias. Where there was doubt about the classification of the medicine, we contacted authors or the product manufactures for confirmation. Any homeopathic prescribing strategy was included (pp. 3-4).

So it looks like the debate over the inclusion of this trial boils down to a difference of opinion over the definition of "homeopathy". Critics (myself included) who questioned the inclusion of this trial did so because we hold a rather narrower concept of "homeopathy" than the authors do. Of course, there is no right or wrong definition of homeopathy - no-one holds a trademark on the term - so I think that this is where the debate is going to have to rest.

[BPSDB]

BBC: Homeopathy Works, Oh Wait...

According to a BBC headline today, the Cochrane Collaboration says that:

Homeopathy 'eases cancer therapy'

Wow. The Cochrane Collaboration, the very embodiment of evidence-based medicine, says that homeopathy works! That would really be something to write home about. If it were true. What a recent Cochrane Review, Homeopathic medicines for adverse effects of cancer treatments, in fact concluded was that:

This review found preliminary data in support of the efficacy of topical calendula for prophylaxis of acute dermatitis during radiotherapy and Traumeel S mouthwash in the treatment of chemotherapy-induced stomatitis. These trials need replicating. There is no convincing evidence for the efficacy of homeopathic medicines for other adverse effects of cancer treatments. Further research is required.

In other words, they found two high-quality positive trials. One of them, the trial of "Traumeel S", included just 30 patients, 15 on placebo and 15 on the homeopathic treatment. Which is not very many. Still, at least it actually was a trial of a homeopathic treatment. The other positive trial, the one on "topical calendula", wasn't.

No, really. The second trial, a fairly large French study (254 patients), used an ointment made from a herb, Calendula officinalis, aka the Pot Marigold. Unlike homeopathic treatments, which are just water, the Calendula ointment used in the study in question was apparantly

fabricated from a plant of the marigold family, Calendula officinalis. The digest is obtained by incubation at 75°C in petroleum jelly to extract the liposoluble components of the plant.

In other words, it contained plenty of chemicals from the plant, and would be better described as a herbal product, not a homeopathic one. Unlike in a homeopathic remedy, the herb wasn't diluted in water several times until no molecules of the original product remained. It's not homeopathy. The word "homeopathy" doesn't appear anywhere in the paper!

So why on earth was this study included in the Cochrane Review? This is where things get weird. The Cochrane authors describe the paper as "a study of a homeopathic ointment". But how did they even hear about the paper, given that the word homeopathy appears nowhere in the paper, or the abstract, or the PubMed keywords? They say that "One potential study was identified by an expert in the field (Pommier 2004)."

So the best evidence that homeopathy works for alleviating the symptoms of cancer therapy is a paper that isn't about homeopathy, identified by "an expert" in homeopathy. And the Cochrane Collaboration took his word for it. And the BBC reported on it as fact (although to their credit they do include a scathing comment from Prof. Edward Ernst.) A great job all round!

If anyone has any ideas about why this paper was included in the Cochrane review, I'd be interested to hear them. I will be in contact with the authors of the review to try to find out why, because if the Cochrane Collaboration has really just published a review about homeopathy which includes a trial which is nothing to do with homeopathy, it's something of a scandal. I find it somewhat hard to believe just on the basis that Cochrane reviews are generally very competent. So, stay tuned for more on this.

Update 18 4 2009: The authors have kindly responded to my email.

[BPSDB]

BBC: Homeopathy Works, Oh Wait...

According to a BBC headline today, the Cochrane Collaboration says that:

Homeopathy 'eases cancer therapy'

Wow. The Cochrane Collaboration, the very embodiment of evidence-based medicine, says that homeopathy works! That would really be something to write home about. If it were true. What a recent Cochrane Review, Homeopathic medicines for adverse effects of cancer treatments, in fact concluded was that:

This review found preliminary data in support of the efficacy of topical calendula for prophylaxis of acute dermatitis during radiotherapy and Traumeel S mouthwash in the treatment of chemotherapy-induced stomatitis. These trials need replicating. There is no convincing evidence for the efficacy of homeopathic medicines for other adverse effects of cancer treatments. Further research is required.

In other words, they found two high-quality positive trials. One of them, the trial of "Traumeel S", included just 30 patients, 15 on placebo and 15 on the homeopathic treatment. Which is not very many. Still, at least it actually was a trial of a homeopathic treatment. The other positive trial, the one on "topical calendula", wasn't.

No, really. The second trial, a fairly large French study (254 patients), used an ointment made from a herb, Calendula officinalis, aka the Pot Marigold. Unlike homeopathic treatments, which are just water, the Calendula ointment used in the study in question was apparantly

fabricated from a plant of the marigold family, Calendula officinalis. The digest is obtained by incubation at 75°C in petroleum jelly to extract the liposoluble components of the plant.

In other words, it contained plenty of chemicals from the plant, and would be better described as a herbal product, not a homeopathic one. Unlike in a homeopathic remedy, the herb wasn't diluted in water several times until no molecules of the original product remained. It's not homeopathy. The word "homeopathy" doesn't appear anywhere in the paper!

So why on earth was this study included in the Cochrane Review? This is where things get weird. The Cochrane authors describe the paper as "a study of a homeopathic ointment". But how did they even hear about the paper, given that the word homeopathy appears nowhere in the paper, or the abstract, or the PubMed keywords? They say that "One potential study was identified by an expert in the field (Pommier 2004)."

So the best evidence that homeopathy works for alleviating the symptoms of cancer therapy is a paper that isn't about homeopathy, identified by "an expert" in homeopathy. And the Cochrane Collaboration took his word for it. And the BBC reported on it as fact (although to their credit they do include a scathing comment from Prof. Edward Ernst.) A great job all round!

If anyone has any ideas about why this paper was included in the Cochrane review, I'd be interested to hear them. I will be in contact with the authors of the review to try to find out why, because if the Cochrane Collaboration has really just published a review about homeopathy which includes a trial which is nothing to do with homeopathy, it's something of a scandal. I find it somewhat hard to believe just on the basis that Cochrane reviews are generally very competent. So, stay tuned for more on this.

Update 18 4 2009: The authors have kindly responded to my email.

[BPSDB]

The Voodoo Strikes Back

Just when you thought it was safe to compute a correlatation between a behavioural measure and a cluster mean BOLD change...

The fMRI voodoo correlations controversy isn't over. Ed Vul and collegues have just responded to their critics in a new article (pdf). The critics appear to have scored at least one victory, however, since the original paper has now been renamed. So it's goodbye to "Voodoo Correlations in Social Neuroscience" - now it's "Puzzlingly high correlations in fMRI studies of emotion, personality and social cognition" by Vul et. al. 2009. Not quite as catchy, but then, that's the point...

Just in case you need reminding of the story so far: A couple of months ago, MIT grad student Ed Vul and co-authors released a pre-publication manuscript, then titled Voodoo Correlations in Social Neuroscience. This paper reviewed the findings of a number of fMRI studies which reported linear correlations between regional brain activity and some kind of measure of personality. Vul et. al. argued that many (but by no means all) of these correlations were in fact erroneous, with the reported correlations being much higher than the true ones. Vul et. al. alleged that the problem arose due to a flaw in the statistical analysis used, the "non-independence error". For my non-technical explanation of the issue, see my previous post, or go read the original paper (it really doesn't require much knowledge of statistics).

Vul's paper attracted a lot of praise and also a lot of criticism, both in the blogosphere and in the academic literature. Many complained that it was sensationalistic and anti-fMRI. Others embraced it for the same reasons. My view was that while the paper's style was certainly journalistic, and while many of those who praised the paper did so for the wrong reasons, the core argument was both valid and important. While not representing a radical challenge to social neuroscience or fMRI in general, Vul et. al. draws attention to a widespread and potentially serious technical issue with the analysis of fMRI data, one which all neuroscientists should be aware of.

That's still my opinion. Vul et. al.'s response to their critics is a clearly worded and convincing defense. Interestingly, their defense is in many ways just a clarificiation of the argument. This is appropriate, because I think the argument is pretty much just common sense once it is correctly understood. As far as I can see the only valid defence against it is to say that a particular paper did not in fact commit the error - while not disputing that the error itself is a problem. Vul et. al. say that to their knowledge no accused papers have turned out to be innocent - although I'm sure we haven't heard the last of that.

Vul et. al. also now make explicit something which wasn't very clear in their original paper, namely that the original paper made accusations of two completely seperate errors. One, the non-independence error, is common but probably less serious than the second, the "Forman error", which is pretty much fatal. Fortunately, so far, only two papers are known to have fallen prey to the Forman error - although there could be more. Go read the article for more details on what could be Vul's next bombshell...

EDWARD VUL, CHRISTINE HARRIS, PIOTR WINKIELMAN, AND, & HAROLD PASHLER (2009). Reply to comments on “Puzzlingly high correlations in fMRI studies of emotion, personality, and social cognition” Perspectives in Psychological Science