Neuroskeptic

Book: Deep Brain Stimulation

2009-11-10T20:06:00.003Z

Jamie Talan's Deep Brain Stimulation: A New Treatment Shows Promise In The Most Difficult Cases is the first book to offer a popular look at DBS, one of the more exciting emerging treatments in neurology and psychiatry.

Deep Brain Stimulation is not a textbook and the depth of scientific detail is kept pretty low, but the breadth of the material is good. Talan reviews the many kinds of disorders for which DBS has been trialled, from the early 1990s when it was used in Parkinson's disease up to the past five years where it's been tried for everything from epilepsy, depression and Tourette's Syndrome up to lifting patients out of persistent vegetative states (maybe).

Unfortunately, Talan doesn't discuss the controversial history of the first era of human brain stimulation, including the morally murky work of Robert G. Heath at Tulane University in the 1960s. She mentions Tulane once in passing but more detail would have been welcome, if only because it's a rather spicy tale.

The book's most engaging passages are the stories of individual patients. There's the man with Parkinson's who experienced amazing benefits from DBS, and who was so keen to keep them that he didn't tell doctors about the infection which developed a few weeks after surgery, in case they took the electrode out. After literally keeping the infected site under his hat for a few days, it progressed to a brain abscess, and he nearly died. Happily, he not only survived but was able to get the electrodes reimplanted.

Then there's the most moving case, that of the woman suffering from severe OCD and depression, who was given experimental DBS for the former condition. She died by suicide several months later, but said in her suicide note that the DBS had worked - her OCD symptoms were gone. Her depression was as bad as ever, though, and this is what led her to suicide. She wanted people to know that deep brain stimulation helped her, and didn't want her death to go down in the records as a mark against it.

The precursor to DBS was ablative neurosurgery - destroying particular parts of the brain in order to relieve symptoms. Talan describes its use in movement disorders such as Parkinson's, but she glosses over the history of "psychosurgery", the use of surgery to treat mental illness. People using DBS in psychiatry often prefer not to talk about psychosurgery - it's not exactly good PR. But clearly it is relevant. For all its faults, psychosurgery did seem to help some patients, which is why it's still used today in rare cases, although DBS may soon replace it.

DBS for depression and OCD usually target the same prefrontal white matter pathways that psychosurgery severed, so scientifically, psychosurgery has lessons for DBS. The ethical issues overlap too. Although DBS is reversible, unlike brain lesioning, it carries the same risks of serious complications like infection or brain bleeding. And there's the same question of whether seriously mentally ill people can give informed consent.

The book's strongest chaper is the last, which covers the ethical and practical difficulties of DBS. The danger is that enthusiastic doctors with no experience of the procedure, encouraged by the tales from other hospitals, might start doing it inappropriately. There's also a risk that patients or their families might volunteer for DBS prematurely or have impossibly high expectations. The initial results have been very promising, but there have been no large placebo-controlled trials so far (except in some movement disorders). And even with the best surgeons, in most disorders the response rate seems to hover around the 50-60% mark. Talan warns that DBS risks being a victim of its own hype. That's an important message.

The Needle and the Damage (Not) Done

2009-11-09T13:11:00.004Z

You may already have heard about Desiree Jennings.

If not, here's a summary, although for the full story you should consult Steven Novella or Orac, whose expert analyses of the case are second to none. Desiree Jennings is a 25 year old woman from Ashburn, Virginia who developed horrible symptoms following a seasonal flu vaccination in August. As she puts it:

In a matter of a few short weeks I lost the ability to walk, talk normally, and focus on more than one stimuli at a time. Whenever I eat I know, without fail, that my body will soon go into uncontrollable convulsions coupled with periods of blacking out.

For some weeks the problems were so bad that she was almost completely disabled, and feared the damage was permanent. Vaccines had destroyed her life. You can see a video here - American TV has covered the story in a lot of detail (the fact that she is quite... photogenic can't have put them off). Desiree and the media described her illness as dystonia, a neurological condition characterised by uncontrollable muscle contractions. Dystonia is caused by damage to certain motor pathways in the brain.

However, Desiree Jennings does not have dystonia. The symptoms look a bit like dystonia to the untrained eye, but they're not it. This is the unanimous opinion of dystonia experts who've seen the footage of Jennings. A blogger discovered that it was also seemingly the view of the neurologist who originally examined her.

So what's wrong with her? The answer, according to experts, is that her symptoms are psychogenic - "neurological" or "medical" symptoms caused by psychological factors rather than organic brain damage. It's important to be clear on what exactly this implies. It doesn't mean that Jennings is "making up" or "faking" the symptoms or that they're a "hoax". The symptoms are as "real" as any others, the only thing psychological about them is the cause. Nor are psychogenic symptoms delusions - Jennings isn't mentally ill or "crazy".

Almost certainly, she is in her right mind, and she sincerely believes that she is a victim of brain damage caused by the flu shot. The belief is false, but it's not crazy - in 1976 one flu vaccine may have caused neurological disorders and today many, many otherwise sane people believe that vaccines cause all kinds of damage. (It could well be that this belief is actually driving Jennings' symptoms, but we can't know that - there could be other psychological factors at work.)

One of the hallmarks of psychogenic symptoms is that they improve in response to psychological factors. Neurologist blogger Steven Novella predicted that:

I predict that they will be able to “cure” her, because psychogenic disorders can and do spontaneously resolve. They will then claim victory for their quackery in curing a (non-existent) vaccine injury.

They being anti-vaccination group Generation Rescue who were swift to offer Jennings their support and, er, expertise. And this is exactly what seems to be happening: Dr Rashid Buttar, a prominent anti-vaccine doctor who treats "vaccine damage" cases, began giving Jennings (amongst other things) chelation therapy to flush out toxic metals from her body, on the theory that her dystonia was caused by mercury in the vaccine. It worked! Dr. Buttar tells us - 15 minutes after the chelation solution started entering her body through an IV drip, all of the symptoms had disappeared (on the podcast it's about 6:00 onwards).

It's completely implausible that mercury in the vaccine could have caused dystonia, and even if it somehow did, it's impossible that chelation could reverse mercury-induced brain damage so quickly. If you are unfortunate enough to get mercury poisoning the neurological damage is permanent; flushing out the mercury wouldn't cure you. There's now no question that Jennings is a textbook case of psychogenic illness.

On this blog I've often written about the mysterious "placebo effect". A few weeks ago, I said -

People seem more willing to accept the mind-over-matter powers of "the placebo" than they are to accept the existence of psychosomatic illness.

We certainly seem to talk about placebos more than we talk about psychosomatic or psychogenic illness. There are 20 million Google hits for "placebo", just 1.6 million for "psychosomatic", and 500,000 for "psychogenic". (Even "placebo -music -trial" gives 8.7 million, which excludes all of the many placebo-controlled clinical trials and also hits about the band.)

Why? One important factor is surely that it's very difficult to prove that any given illness is "psychosomatic". Even if a patient has symptoms with no apparent medical cause, leading to suspicions that they're psychogenic, there could always be an organic cause waiting to be discovered. Just as we can never prove that there were no WMDs in Iraq, we can never prove that a given illness is purely psychological in origin.

But occasionally, there are cases where the psychogenic nature of an illness is so patent that there can be little doubt, and this is one of them. Watch the videos, listen to the account of the cure, and marvel at the mysteries of the mind.

[BPSDB]

The Politics of Psychopharmacology

2009-11-05T23:59:00.010Z

It's always nice when a local boy makes good in the big wide world. Many British neuroscientists and psychiatrists have been feeling rather proud this week following the enormous amount of attention given to Professor David Nutt, formerly the British government's chief adviser on illegal drugs.

Formerly being the key word. Nutt was sacked (...write your own "nutsack" pun if you must) last Friday, prompting a remarkable amount of condemnation. Critics included the rest of his former organisation, the Advisory Council on the Misuse of Drugs (ACMD), and the Government's Science Minister. The UK's Chief Scientist also spoke in favour of Nutt's views. Journalists joined in the fun with headlines like "politicians are intoxicated by cowardice".

Even Nature today ran a bluntly-worded editorial -

"The sacking of a government adviser on drugs shows Britain's politicians can't cope with intelligent debate... the position of the Labour government and of the leading opposition party, the Conservatives, which vigorously supported Nutt's sacking, has no merit at all. It deals a significant blow both to the chances of an informed and reasoned debate over illegal drugs, and to the parties' own scientific credibility."

They also have an interview with the man himself.

What happened? The short answer is a lecture Nutt gave on the 10th October, Estimating Drug Harms: A Risky Business? I'd recommend reading it (it's free). The Government's dismissal e-mail gave two reasons why he had to go - firstly, "Your recent comments have gone beyond [matters of evidence] and have been lobbying for a change of government policy" and secondly, "It is important that the government's messages on drugs are clear and as an advisor you do nothing to undermine public understanding of them."

Many people believe that Nutt was fired because he argued for the liberalization of drug laws, or because he claimed that the harms of some illegal drugs, such as cannabis, are less severe than those of legal substances like tobacco and alcohol. On this view, the government's actions were "shooting the messenger", or dismissing an expert because they didn't like to hear to the facts. It seems to me, however, that the truth is a little more nuanced, and even more stupid.

Nutt's lecture, if you read the whole thing as opposed to the quotes in the media, is remarkably mild. For instance, at no point does he suggest that any drug which is currently illegal should be made legal. The changes he "lobbies for" are ones that the ACMD have already recommended, and this lobbying consists of nothing more than tentative criticism of the stated reasons for the rejection of the ACMD's advice. The ACMD is government's official expert body on illicit drugs, remember.

The issue Nutt focusses on is the question of whether cannabis should be a "Class C" or a "Class B" illegal drug, B being "worse", and carrying stricter penalties. It was Class B until 2004, when it was made Class C. In 2007, the Government asked the ACMD to advise on whether it should be re-reclassified back up to Class B. This was in response to concerns about the impact of cannabis on mental health, specifically the possibility that it raises the risk of psychotic illnesses.

The resulting ACMD report is available on the Government's website. They concluded that while cannabis use is certainly not harmless, "the harms caused by cannabis are not considered to be as serious as drugs in class B and therefore it should remain a class C drug."

Despite this, the Government took the decision to reclassify cannabis as Class B. In his lecture Nutt criticizes this decision - slightly. Nutt quotes the Home Secretary as saying, in response to the ACMD's report -

"Where there is a clear and serious problem [i.e. cannabis health problems], but doubt about the potential harm that will be caused, we must err on the side of caution and protect the public. I make no apology for that. I am not prepared to wait and see."

Nutt describes this reasoning as -

"the precautionary principle - if you’re not sure about a drug harm, rank it high... at first sight it might seem the obvious decision – why wouldn’t you take the precautionary principle? We know that drugs are harmful and that you can never evaluate a drug over the lifetime of a whole population, so we can never know whether, at some point in the future, a drug might lead to or cause more harm than it did early in its use."

But he says, there's more to it than this. Firstly, we don't know anything about how classification affects drug use. The whole idea of upgrading cannabis to Class B to protect the public relies on the assumption that it will reduce drug use by deterring people from using it. But there is no empirical evidence as to whether this actually happens. As Nutt points out, stricter classification might equally well increase use by making it seem forbidden, and hence, cooler. (If you think that's implausible, you have forgotten what it is like to be 16.) We just don't know.

Second, he says, the precautionary principle devalues the evidence and is thereby self-defeating because it means that people will not take any warnings about drug harms seriously - "[it] leads to a position where people really don’t know what the evidence is. They see the classification, they hear about evidence and they get mixed messages. There’s quite a lot of anecdotal evidence that public confidence in the scientific probity of government has been undermined in this kind of way." Can anyone really dispute this?

Finally, he raises the MMR vaccine scare as an example of the precautionary principle ironically leading to concrete harms. Concerns were raised about the safety of a vaccine, on the basis of dubious science. As a result, vaccine coverage fell, and the incidence of measles, mumps and rubella in Britain rose for the first time in decades. The vaccine harmed no-one; these diseases do. We just don't know whether cannabis reclassification will have similar unintended consequences.

That's what the Home Secretary described as "lobbying for a change of government policy". I wish all lobbyists were this reasonable.

The Home Secretary's second charge against Nutt - "It is important that the government's messages on drugs are clear..." - is even more specious. Nutt's messages were the ACMD's messages, and as he points out, the only lack of clarity comes from the fact that the government and their own Advisory Council disagree with each other. This is hardly the ACMD's fault, and it's certainly not Nutt's fault for pointing it out.

All of this is doubly ridiculous because of one easily-forgotten fact - cannabis was downgraded from Class B to Class C in 2004 by the present Labour Party government. Nutt's "lobbying" therefore consists of a recommendation that the government do something they themselves previously did. And if the government are worried about the clarity of their message, the fact that they themselves were saying that cannabis was benign enough to be a Class C drug just 5 years ago might be somewhat relevant.

Nutt has said that he was surprised to learn that he had been sacked. I'm sure this surprise was genuine because Nutt is an academic, and in academia, Nutt's "criticisms" would hardly even be considered as such. Here by contrast is an extract from a peer review comment I got a couple of days ago regarding a scientific paper I wrote:

The manuscript falls short of its goals in several respects: The basic phenomenon ... is barely presented... The style and language of the review leave a lot to be desired... The citations and reference list are appalling.

The same reviewer also criticized the basic argument of my article, implicitly branding the whole paper - all 10,000 words of it, which took dozens of hours to write - a complete waste of time.

Ouch. But as an academic, giving, and receiving, this kind of treatment is all part of the job, and that's just as it should be. I'm confident that my argument is sound, so I'm going to take the criticisms on board, rewrite the paper appropriately, and submit it to another journal. What I'm not going to do is bear a grudge against the reviewer. (Well maybe a little: the references weren't that bad.) To be fair, unlike Nutt's, this review was not made in the public domain, but then, I'm not a Government elected by the public.

Nutt's mistake was to think that it's possible to have a serious debate about a serious political issue. In fact, it was probably not such a bad mistake, since the job of the ACMD, as the Government sees it, is a fairly pointless one: their job is to give expert advice and then let it be ignored. As various ACMD members have noted, they work for free, in the public interest. If I were on the Committee, I would resign now, not just out of sympathy for Nutt, but because it's a crap job.

In his dismissal letter, the Home Secretary told Nutt, "It is not the job of the Chair of the Government's advisory Council to initiate a public debate on the policy framework for drugs". I would have thought he was exactly the person who should do this if such a debate was necessary, as it obviously is. Well, now we know better. It wasn't his job. Although, thanks to the government who sacked him, a drug debate is now going on in the British media for the first time in years. In the long run, Nutt's most important action as Chair of the ACMD may well have been getting sacked from it.

[BPSDB]

Nature (2009). A drug-induced low Nature, 462 (7269), 11-12 DOI: 10.1038/462011b

Daniel Cressey (2009). Sacked science adviser speaks out Nature

Real vs Placebo Coffee

2009-11-02T13:41:00.014Z

Coffee contains caffeine, and as everyone knows, caffeine is a stimulant. We all know how a good cup of coffee wakes you up, makes you more alert, and helps you concentrate - thanks to caffeine.

Or does it? Are the benefits of coffee really due to the caffeine, or are there placebo effects at work? Numerous experiments have tried to answer this question, but a paper published today goes into more detail than most. (It caught my eye just as I was taking my first sip this morning, so I had to blog about it.)

The authors took 60 coffee-loving volunteers and gave them either placebo decaffeinated coffee, or coffee containing 280 mg caffeine. That's quite a lot, roughly equivalent to three normal cups. 30 minutes later, they attempted a difficult button-pressing task requiring concentration and sustained effort, plus a task involving mashing buttons as fast as possible for a minute.

The catch was that the experimenters lied to the volunteers. Everyone was told that they were getting real coffee. Half of them were told that the coffee would enhance their performance on the tasks, while the other half were told it would impair it. If the placebo effect was at work, these misleading instructions should have affected how the volunteers felt and acted.

Several interesting things happened. First, the caffeine enhanced performance on the cognitive tasks - it wasn't just a placebo effect. Bear in mind, though, that these people were all regular coffee drinkers who hadn't drunk any caffeine that day. The benefit could have been a reversal of caffeine withdrawl symptoms.

Second, there was a small effect of expectancy on task performance in the placebo group - but it worked in reverse. People who were told that the coffee would make them do worse actually did better than those who expected the coffee to help them. Presumably, this is because they put in extra effort to try to overcome the supposedly negative effects. This paradoxical placebo response reminds us that there's more to "the placebo effect" than meets the eye.

Finally, no-one who got the decaf noticed that it didn't actually contain caffeine, and the volunteer's ratings of their alertness and mood didn't differ between the caffeine and placebo groups. So, this suggests that if you were to secretly replace someone's favorite blend with decaf, they wouldn't notice - although their performance would nevertheless decline. Bear that in mind when considering pranks to play on colleagues or flatmates.

It looks like science has just confirmed another piece of The Wisdom of Seinfeld:

Elaine: Jerry likes Morning Thunder.
George: Jerry drinks Morning Thunder? Morning Thunder has caffeine in it. Jerry doesn't drink caffeine.
Elaine: Jerry doesn't know Morning Thunder has caffeine in it.
George: You don't tell him?
Elaine: No. And you should see him. Man, he gets all hyper, he doesn't even know why! He loves it. He walks around going, "God, I feel great!"
- Seinfeld, "The Dog"

[BPSDB]

Harrell PT, & Juliano LM (2009). Caffeine expectancies influence the subjective and behavioral effects of caffeine. Psychopharmacology PMID: 19760283

A Weighty Issue

2009-11-01T18:30:00.004Z

The BBC asks - "Why are fat people abused? Why is "fattism" seen by many as an acceptable prejudice?"

Psychoanalyst Susie Orbach explains or tries to:

Often the assumption is that overweight people have lost their self-control. That frightens society because there is so much emphasis on being slim, she says.
"Often it's not the larger person's excess weight that is the problem, it's the other people's obsession with being thin. Most people want to be slim, but this perceived physical perfection is difficult to hold on to and they fear losing control of it. Women and men can be on diets their whole lives and it's utterly miserable. They project that fear and unhappiness on to people who are bigger and that often translates into abuse and attacks. It's a way of people disassociating themselves from what they fear the most - getting fat."

But this is pure psychobabble. Like saying that all homophobes are repressed homosexuals, it's satisfying, but not true. (Although...) Most people fear cancer, but we don't "project" this fear onto others by accusing them of having it, or hating people who do have it. Orbach seems to still adhere to the Freudian idea that obvious explanations of human behaviour are usually wrong, and that people's true motives are unconscious, and usually embarrassing.

The truth is more straightforward. For various cultural and historical reasons most of us prefer thinness to fatness. And crucially we see weight as something people have personal control over. Far from fearing that overweight people have lost their self-control, we think they choose not to use it.

This is why it's "OK" to not like fat people; just as it's OK to not like criminals, selfish people, racists, etc. It's "their fault". Whereas it's not OK to make fun of people with one leg, deaf people, people with genetic disorders and so on. They "can't help it".

But there are grey areas, and this is where it gets interesting. People with cancer deserve sympathy... unless perhaps it's "their fault" for getting it, e.g. lung cancer from heavy smoking. Paedophiles deserve severe punishment... unless perhaps it's not their fault. How could it not be? How about if they developed a compulsive urge to view child porn due to the medication they were taking for Parkinson's disease? Or if they started abusing their daughter because of a brain tumour?

This is why one Kathryn Szrodecki, who campaigns on behalf of overweight people, is quoted by the BBC as saying

"We're simply not all built to be slim, our genetic make-ups are all different."

In other words: actually it's not our fault. Likewise, conservatives say homosexuality is a choice; liberals say it's something you're born being. Both sides implicitly agree that if something's not a choice, it's wrong to treat people badly for it. In an attempt to destigmatize clinical depression, a billboard famously proclaimed that "Depression is a flaw in chemistry not character" - it's not your fault.

The trend at the moment is towards things being no-one's fault. It's happened to everything from drug and alcohol addiction to antisocial and criminal behaviour (as ADHD, Conduct Disorder, Personality Disorders, etc.) By contrast, I can't think of anything which has moved in the other direction. Of course, not everyone accepts that, say, addiction is a disease. Many people still think it's a moral issue. But they're on the back foot. The wind is blowing in the other direction.

We can expect even more of this in the future, as neuroscience and genetics find biological causes and correlates of ever more behaviours. Brain scans in particular have a seductive allure when it comes to making things seem to be outside the sphere of choice. As for how valid any of this is, well, that's another story. But if the fat acceptance movement wants to advance their cause, finding a few fMRI scans might be the best way to do it.

More Antidepressant Debates

2009-10-29T20:00:00.002Z

Six months ago, I asked What's The Best Antidepressant?, and I discussed a paper by Andrea Cipriani et al. The paper claimed that of the modern antidepressants, escitalopram (Lexapro) and sertraline (Zoloft) offer the best combination of effectiveness and mild side effects, and that sertraline has the advantage of being much cheaper.

The Cipriani paper was a meta-analysis of trials comparing one drug against another. With a total of over 25,000 patients, it boasted an impressively large dataset, but I advised caution. Their method of crunching the numbers (indirect comparisons) was complex, and rested on a lot of assumptions.

I wasn't the only skeptic. Cipriani et al has attracted plenty of comments in the medical literature, and they make for some fascinating reading. Indeed, they amount to crash-course in the controversies surrounding antidepressants today - a whole debate in microcosm. So here's the microcosm, in a nutshell:

In The Lancet, the original paper was accompanied by glowing praise by one Sagar Parikh:

Free of any potential funding bias... Now, the clinician can identify the four best treatments... A new gold standard of reliable information has been compiled for patients to review.

But critical comments swiftly appeared in the Lancet's letters pages. While not accusing Cipriani and colleagues themselves of bias or conflicts-of-interest, Tom Jefferson noted that way back in 2003, David Healy drew attention to:

documents that a communications agency acting on behalf of the makers of sertraline were forced to make available by a US court. Among them was a register of completed sertraline studies awaiting to be assigned to authors. This practice (rent-a-key-opinion-leader) is of unknown prevalence but it undermines any attempt at reviewing the evidence in a meaningful way.

This is what's known as medical ghostwriting, and it is indeed a scandal. However, by itself, ghostwriting doesn't distort evidence as such. It's what's published - or not published - that counts. Almost all antidepressant trials are run and funded by drug companies. All too often, they just don't publish data showing their products in an unfavourable light. The fearsome John Ioannidis - known for writing papers with titles like Why most published research findings are false - pulled no punches in reminding readers of this, in his letter:

Among placebo controlled antidepressant trials registered with the US FDA, most negative results are unpublished or published as positive. Take sertraline, which Cipriani and colleagues recommend as the best ... of five FDA-registered trials, the only positive trial was published, one negative trial was published as positive, and three negative trials were unpublished. Head-to-head comparisons can suffer worse bias, since regulatory registration is uncommon. Meta-analysis of published plus industry-furnished data could spuriously suggest that the best drugs are those with the most shamelessly biased data ...

Ioannidis also noted that Cipriani did not include placebo-controlled trials in their analysis. He helpfully provided a table showing that if you do include these trials, the ranking of antidepressants is very different:

Of course, Ioannidis was not saying that the drug-vs-placebo data is better than the drug-vs-drug trials. After all, he had just declared it to be biased. But neither is it necessarily worse, and there's no good reason not to consider it.

Cipriani et al's response to their critics was a little light on detail. In response to concerns of industrial publication bias, they said that:

we contacted the original authors and pharmaceutical companies to obtain further data or to confirm reported figures.

But of course the pharmaceutical companies were under no obligation to play ball. They could just have chosen not to reveal embarrassing data. Rather more reassuring is the fact that the original paper did look for correlations between the drug company running each trial, and the results of the trial; they didn't find any. Rather cheekily, Cipriani et al then went on to suggest that they were the ones who were sticking it to Big Pharma:

The standard thinking has become that most antidepressants are of similar average efficacy and tolerability ... In some ways, this is a comfortable position for industry and its hired academic opinion leaders—it sets a low threshold for the introduction of new agents which can initially be marketed on the basis of small differences in specific adverse effects rather than on clear advantages in terms of overall average efficacy and acceptability.

They certainly have a point here. If aspiring antidepressants had to be proven better than existing ones in order to be sold, instead of just as good, there would probably have been no new antidepressants since Prozac in 1990. (And Prozac is only "better" than the drugs available in 1960 in that it's safer and has fewer side effects; it's no more effective.)

But this is not really relevant to whether the Cipriani analysis is valid. And in The Lancet letters, the authors did not address some of the criticisms, such as Ioannidis's point about including placebo-controlled trials, at all. They do point out that their raw data is available online for anyone to play around with.

The debate continued in the pages of Evidence Based Mental Health. In 2008, Gerald Gartlehner and Bradley Gaynes conducted a rather similar meta-analysis, but they reached very different conclusions. They declared that all post-1990 antidepressants are equally effective (or ineffective).

In their comments on the Cipriani paper, Gartlehner and Gaynes say that they were just more cautious in interpreting the results of a complex and problematic statistical process:

Ranking sertraline and escitalopram higher than other drugs conveys a precision
and existence of clinically important differences that is not reflected in the body of evidence. ...for sertraline and escitalopram the range of probabilities actually extends from the first to the eighth rank for both efficacy and acceptability... the validity of results of indirect comparisons depends on various assumptions, some of which are unverifiable ... We simply took underlying uncertainties into greater consideration and interpreted findings more cautiously than Cipriani and colleagues.

They also accuse Cipriani et al of various technical shortcomings - and in a meta-analysis, such 'technicalities' can often greatly the skew the results:

they included studies with very different populations such as frail elderly, patients with accompanying anxiety and inpatients as well as outpatients ... the effect measure of choice was odds ratios rather than relative risks. Odds ratios have mathematical advantages that statisticians value. Practitioners, however, frequently overestimate their clinical importance...

Cipriani et al respond to some of these technical criticisms, while admitting that their analysis has limitations. But, they say, even an imperfect ranking of antidepressants is better than none at all:

We have a choice. We may either make the best use of the available randomised evidence or we essentially ignore it. We believe that it is better to have a set of criteria based on the available evidence than to have no criteria at all... We believe that, despite the likely biases of the included trials, and the limitations of our approach, our analysis makes the best use of the randomised evidence, providing clinicians with evidence based criteria that can be used to guide treatment choices.

What are we to make of all this? Here's my two cents. It's implausible that all antidepressants are truly equally effective. They affect the brain in different ways. The pharmacological differences between SSRIs such as Prozac, Zoloft and Lexapro are minimal at best but mirtazapine and reboxetine, say, target entirely different systems. They work differently, so it would be odd if they all worked equally well.

The search phrase that most often leads people to this blog is "best antidepressant". People really want to know which antidepressant is most likely to help them. In truth, everyone responds differently to every drug, so there is no one best treatment. But Cipriani et al are quite right that even a roughly correct ranking could help improve the treatment of people with depression, even if the differences are tiny. If Drug X helps 1% more people than Drug Y on average, that's a lot of people when 30 million Americans take antidepressants every year.

So, what is the best antidepressant, on average? I don't know. But maybe it's escitalopram or sertraline. Stranger things have happened.

Ioannidis JP (2009). Ranking antidepressants. Lancet, 373 (9677) PMID: 19465221

Gartlehner, G., & Gaynes, B. (2009). Are all antidepressants equal? Evidence-Based Mental Health, 12 (4), 98-100 DOI: 10.1136/ebmh.12.4.98

Barack Obama Boosts Testosterone

2009-10-26T19:09:00.011Z

But only if you voted for him, and only if you're a man. That's according to a PLoS One paper called Dominance, Politics, and Physiology.

It's already known that in males, winning competitions - achieving "dominance" - causes a rapid rise in testosterone release, whilst losing does the opposite. That's true in humans, as well as in other mammals. The authors wondered whether the same thing happens when men "win" vicariously - i.e. when someone we identify with triumphs.

What better way of testing this than the U.S. Presidential Election? The authors took 163 American voters, and got them to provide saliva samples before, during and after the results came in on the night of the 4th November. Here's what happened -

In Obama supporters (the blue line, natch), salivary testosterone levels stayed flat throughout the crucial hours. But supporters of John McCain or Libertarian candidate Bob Barr, suffered a testosterone crash after Obama's victory became apparent. That was only true in men, though; in women, there was no change.

Heh. Of course, we hardly needed biology to tell us that people often identify strongly with their preferred political parties, and the fact that social events cause hormonal changes shouldn't surprise anyone - the brain controls the secretion of most hormones.

The gender difference is interesting, though. Does this mean that men identify closer with politicians? Or maybe only with male ones - what would have happened if Hilary had won... or Palin? It could be that the testosterone surge accompanying success is strictly a man thing, although it's been shown to occur in women in some studies, but not consistently.

Finally, I should mention that this paper contains some excellent quotes, such as "...Robert Barr, who arguably did not have a chance of winning...", "In retrospective reports of their affective state upon the announcement of Obama as the president-elect, McCain and Barr voters felt significantly more unhappy" and my favourite, "men who voted for John McCain or Bob Barr (losers)". That last one may be taken slightly out of context.

Stanton, S., Beehner, J., Saini, E., Kuhn, C., & LaBar, K. (2009). Dominance, Politics, and Physiology: Voters' Testosterone Changes on the Night of the 2008 United States Presidential Election PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007543

Deep Brain Stimulation for Depressed Rats

2009-10-23T21:40:00.002+01:00

Deep-brain stimulation (DBS) is probably the most exciting emerging treatment in psychiatry. DBS is the use of high-frequency electrical current to alter the function of specific areas of the brain. Originally developed for Parkinson's disease, over the past five years DBS has been used experimentally in severe clinical depression, OCD, Tourette's syndrome, alcoholism, and more.

Reports of the effects have frequently been remarkable, but there have been few scientifically rigorous studies, and the number of psychiatric patients treated to date is just dozens. So the true usefulness of the technique is unclear. How DBS works is also a mystery. Even the most basic questions - such as whether high-frequency stimulation switches the brain "on" or "off" - are still being debated.

Recent data from rodents sheds some important light on the issue: Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. The authors took rats, and implanted DBS electrodes in the infralimbic cortex. This area is part of the vmPFC. It's believed to be the rat equivalent of the human region BA25, the subgenual cingulate cortex, which is the most common target for DBS in depression. The current settings (100 microA, 130 Hz, 90 microsec) were chosen to be similar to the ones used in humans.

In a standard rat model of depression, the forced-swim test, infralimbic DBS exerted antidepressant-like effects. DBS was equally as effective as imipramine, a potent antidepressant, in terms of reducing "depression-like" behaviours, namely immobility.

This is not all that surprising. Almost everything which treats depression in humans also reduces immobility in this test (along with few things which don't treat it). Much more interesting is what did and did not block the effects of DBS in these rats.

First off, DBS worked even when the rat's infralimbic cortex had been destroyed by the toxin ibotenic acid. This strongly suggests that DBS does not work simply by activating the infralimbic cortex, even though this is where the electrodes were implanted.

Crucially, infralimbic lesions did not have an antidepressant effect per se, which also rules out the theory that DBS works by inactivating this region. (Infralimbic lesions produced by other methods did have a mild antidepressant effect, but it was smaller than the effect of DBS. This may still be important, however.)

What did block the effects of DBS was the depletion of serotonin (5HT). Serotonin is known to its friends as the brain's "happy chemical", although it's a bit more complicated than that. Most antidepressants target serotonin. And rats whose serotonin systems had been lesioned got no benefit from DBS in this study.

So this suggests that DBS might work by affecting serotonin, and indeed, DBS turned out to greatly increase serotonin release, even in a distant part of the brain (the hippocampus). Interestingly this lasted for nearly two hours after the electrodes were switched off.

Depletion of another neurotransmitter, noradrenaline, did not alter the effects of DBS.

Overall, it seems that infralimbic DBS works by increasing serotonin release, but that this is not because it activates or inactivates the infralimbic cortex itself. Rather, nearby structures must be involved. The most likely explanation is that DBS affects nearby white-matter tracts carrying signals between other areas of the brain; the infralimbic cortex might just happen to be "by the roadside". Many researchers believe that this is how DBS works in humans, but this is the first hard evidence for this.

Of course, evidence from rats is never all that hard when it comes to human mental illness. We need to know whether the same thing is true in people. As luck would have it, you can temporarily reduce human serotonin levels with a technique called acute tryptophan depletion This reverses the effects of antidepressants in many people. If this rat data is right, it should also temporarily reverse the benefits of DBS. Someone should do this experiment as soon as possible - I'd like to do it myself, but I'm British, and all the DBS research happens in America. Bah, humbug, old bean.

There's a couple of others things to note here. In other behavioural tests, infralimbic DBS also had antidepressant-like effects: it seemed to reduce anxiety, and it made rats more resistant to the stress of having electrical shocks (although only slightly.) Finally, DBS in another region, the striatum, had no antidepressant effect at all. That's a bit odd because DBS of the striatum does seem to treat depression in humans - but the part of the striatum targeted here, the caudate-putamen, is quite separate to the one targeted in human depression, the nucleus accumbens.

Hamani, C., Diwan, M., Macedo, C., Brandão, M., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A., Fletcher, P., & Nobrega, J. (2009). Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats Biological Psychiatry DOI: 10.1016/j.biopsych.2009.08.025

On Sexed-Up Statistics

2009-10-21T23:55:00.003+01:00

In yesterday's Guardian, Nick Davies, author of seemingly every British blogger's favourite book, Flat Earth News, delivered a pair of remarkable articles that confirmed him as one of the country's most important journalists.

In the first, Davies reported that a recent nationwide police initiative, Operation Pentameter, did not convict anyone of the crime of forcing women into prostitution after illegally trafficking them into the country.

This is rather surprising because, as he explains in a companion comment piece, forced sex trafficking has been widely reported as rife in Britain. The government has been telling Parliament and the nation that there are no less than 25,000 victims across the country. Anti-prostitution groups and charities agreed. Davies goes on to describe how this startling statistic was constructed through a process of exaggeration, misunderstanding, and plain invention.

In 1998, two academics identified a total of 71 trafficked women in the UK, and this did not refer specifically to forced or coerced trafficking. They suggested that the true figure could be anywhere between 142 and 1,420, but admitted that this was speculation, based on the assumption that for every confirmed case, there might be 2 to 20 in reality. A Christian charity quoted this as "an estimated 1,420 women", and others quoted them. The snowball had begun.

A second study estimated 4,000 victims of trafficking, but the researchers noted that this figure was "subject to a very large margin of error", "should be treated with great caution" and "should be regarded as an upper bound", as it was based on many assumptions. Heedless, another major charity quoted this as "4,000 trafficked women ... this figure is believed to be a massive underestimation of the problem". The government started repeating 4,000 as a fact.

Not to be outdone, a tabloid headline then reported no less than 25,000 sex slaves on the streets of Britain! Politicians started quoting this as a fact, although the newspaper provided no evidence for this figure at all. Asked why they believed it, a government minister said he used to work for the tabloid in question, and he trusted them to be accurate.

I have no idea how common forced sex trafficking is. I'd imagine it's not an easy thing to detect, let alone prove in court, so it could be going on behind closed doors and never make it into the statistics. It does happen, and obviously, every case is one too many.

But what certainly is true is that statistics have been greatly exaggerated, and then repeated, by the government and by various campaigning organizations. For more informed commentary on the issue by workers in the field, see Dr Petra Boynton's remarks here and the ongoing discussion here featuring Boynton and Belinda Brooks-Gordon.

Politician Dennis McShane MP "responded" to the criticisms of the 25,000 figure in an almost unwatchable TV interview and unconvincing article in which, amongst other things, he claims that 25,000 came from Amnesty International statistics. This is an outright lie. In fact, the tabloid did quote someone from Amnesty who commented on trafficking in general, but they didn't mention about numbers at all.

Attentive Neuroskeptic readers may well be experiencing a sense of déjà vu at this point. I have often written about the statistic - ubiquitous in Britain and elsewhere - that "1 in 4 people suffer mental illness". That number is made up, rather like the inflated statistics on forced sex trafficking.

Why are such statistics made up, and why are the made-up numbers usually shockingly high ones? It's no coincidence. This is what happens when the only people with an interest in talking about a statistic also have an interest in making it seem as high as possible. This is not to say that anyone deliberately fiddles the numbers, but rather, people naturally focus on the ones that suit them best.

In the case of mental illness, those who research mental illness know that their funding depends on the idea that it's a widespread problem. The more common people think it is, the more important studying it seems. Meanwhile, charities representing the interests of the mentally ill like high statistics because they make mental illness seem more "normal", thus destigmatizing it. It can't hurt their donation rates either.

With sex slavery, the inflated statistics were produced and repeated by organisations opposed to prostitution on moral grounds (including Christian charities and feminist groups), and by the government. The government's interest in the matter seems to be that they are currently trying to pass a law further restricting prostitution and the sex industry. The 25,000 supposed sex slaves must have helped convince Parliament about the importance of this move...

There must be many other examples of inflated statistics out there. It's inevitable, because in order to be taken seriously and to attract money, media attention and political support, campaigning organisations need to make their cause sound important. We can hardly blame charities for doing this, and as for politicians, we know not to trust them about anything. To expect an activist group or a political party to deal with evidence in a neutral and objective way is just naive.

What we'll always need, therefore, is people to scrutinize claims about social problems to keep the campaigners and the politicians honest. This is, or should be, the job of the media, but as Davies points out, the British media completely failed to do this for years. There will always be sexed-up statistics. What we need is more journalists like Davies to sex them back down again.

[BPSDB]

Antidepressant Sales Rise as Depression Falls

2009-10-19T17:10:00.002+01:00

Antidepressant sales are rising in most Western countries, and they have been for at least a decade. Recently, we learned that the proportion of Americans taking antidepressants in any given year nearly doubled from 1996 to 2005.

The situation has been thought to be similar in the UK. But a hot-off-the-press paper in the British Medical Journal reveals some surprising facts about the issue: Explaining the rise in antidepressant prescribing.

The authors examined medical records from 1.7 million British patients in primary care (General Practice, i.e. family doctors.) They found that antidepressant sales rose strongly between 1993 and 2005, not because more people are taking these drugs, but entirely because of an increase in the duration of treatment amongst the antidepressant users. It's not that more people are taking them, it's that people are taking them for longer.

In fact, the number of people being diagnosed with depression and prescribed antidepressants has actually fallen over time. The rate of diagnosed depression remained steady from 1993 to about 2001, and then fell markedly, by about a third, up to 2005. This trend was seen in both men and women, but there were age differences. In 18-30 year olds, there was a gradual increase in diagnoses before the decrease. (Note that these graphs show the number of people getting their first ever diagnosis of depression in each year.)
The likelihood of being given antidepressants for a diagnosis of depression stayed roughly constant, at about 75-80% across the years. However, the average duration of treatment increased over time -

The change doesn't look like much, but remember that even a small change in the number of long-term users translates into a large effect on the total number of sales, because each long-term user takes a lot of pills. The authors conclude

Antidepressant prescribing nearly doubled during the study period—the average number of prescriptions issued per patient increased from 2.8 in 1993 to 5.6 in 2004. ... the rise in antidepressant prescribing is mainly explained by small changes in the proportion of patients receiving long term treatment.

Wow. I didn't see that coming, I'll admit. A lot of people, myself included, had assumed that rising antidepressant use was caused by people becoming more willing to seek treatment for depression. Or maybe that doctors were becoming more eager to prescribe drugs. Others believed that rates of clinical depression were rising.

There's no evidence for either of these theories in this British data-set. The recent fall in clinical depression diagnoses, following an increase in young people over the course of the 1990s, is especially surprising. This conflicts with the only British population survey of mental health, the APMS. The APMS found that rates of depression and mixed anxiety/depression increased between 1993 and 2000 in most age groups but least of all in the young, and little change 2000 to 2007. I trust this new data more, because population surveys almost certainly overestimate mental illness.

How does this result compare to elsewhere? In the USA, the average number of antidepressant prescriptions per patient per year rose from "5.60 in 1996 to 6.93 in 2005" according to a recent estimate. In this study yearly "prescriptions issued per patient increased from 2.8 in 1993 to 5.6 in 2004." So there's a major trans-Atlantic difference. In Britain, the length of use increased greatly, while in the US it only rose slightly, but from a higher baseline.

Finally, why has this happened? We can only speculate. Maybe doctors have become more keen on long-term treatment to prevent depressive relapse. Or maybe users have become more willing to take antidepressants long-term. Modern drugs generally have milder side effects than older ones, so this makes sense, although some people would say that this is just further proof that modern antidepressants are "addictive"...

Moore M, Yuen HM, Dunn N, Mullee MA, Maskell J, & Kendrick T (2009). Explaining the rise in antidepressant prescribing: a descriptive study using the general practice research database. BMJ (Clinical research ed.), 339 PMID: 19833707

Deconstructing the Placebo

2009-10-17T11:30:00.003+01:00

Last month Wired, announced that Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why.

The article's a good read, and the basic story is true, at least in the case of psychiatric drugs. In clinical trials, people taking placebos do seem to get better more often now than in the past (paper). This is a big problem for Big Pharma, because it means that experimental new drugs often fail to perform better than placebo, i.e. they don't work. Wired have just noticed this, but it's been being discussed in the academic literature for several years.

Why is this? No-one knows. There have been many suggestions - maybe people "believe in" the benefits of drugs more nowadays, so the placebo effect is greater; maybe clinical trials are recruiting people with milder illnesses that respond better to placebo, or just get better on their own. But we really don't have any clear idea.

What if the confusion is because of the very concept of the "placebo"? Earlier this year, the BMJ ran a short opinion piece called It’s time to put the placebo out of our misery. Robin Nunn wants us to "stop thinking in terms of placebo...The placebo construct conceals more than it clarifies."

His central argument is an analogy. If we knew nothing about humour and observed a comedian telling jokes to an audience, we might decide there was a mysterious "audience effect" at work, and busy ourselves studying it...

Imagine that you are a visitor from another world. You observe a human audience for the first time. You notice a man making vocal sounds. He is watched by an audience. Suddenly they burst into smiles and laughter. Then they’re quiet. This cycle of quietness then laughter then quietness happens several times.

What is this strange audience effect? Not all of the man’s sounds generate an audience effect, and not every audience member reacts. You deem some members of the audience to be “audience responders,” those who are particularly influenced by the audience effect. What makes them react? A theory of the audience effect could be spun into an entire literature analogous to the literature on the placebo effect.

But what we should be doing is examining the details of jokes and of laughter -

We could learn more about what makes audiences laugh by returning to fundamentals. What is laughter? Why is “fart” funnier than “flatulence”? Why are some people just not funny no matter how many jokes they try?

And this is what we should be doing with the "placebo effect" as well -

Suppose there is no such unicorn as a placebo. Then what? Just replace the thought of placebo with something more fundamental. For those who use placebo as treatment, ask what is going on. Are you using the trappings of expertise, the white coat and diploma? Are you making your patients believe because they believe in you?

Nunn's piece is a polemic and he seems to be conclude by calling for a "post-placebo era" in which there will be no more placebo-controlled trials (although it's not clear what he means by this). This is going too far. But his analogy with humour is an important one because it forces us to analyse the placebo in detail.

"The placebo effect" has become a vague catch-all term for anything that seems to happen to people when you give them a sugar pill. Of course, lots of things could happen. They could feel better just because of the passage of time. Or they could realize that they're supposed to feel better and say they feel better, even if they don't.

The "true" placebo effect refers to improvement (or worsening) of symptoms driven purely by the psychological expectation of such. But even this is something of a catch-all term. Many things could drive this improvement. Suppose you give someone a placebo pill that you claim will make them more intelligent, and they believe it.

Believing themselves to be smarter, they start doing smart things like crosswords, math puzzles, reading hard books (or even reading Neuroskeptic), etc. But the placebo itself was just a nudge in the right direction. Anything which provided that nudge would also have worked - and the nudge itself can't take all the credit.

The strongest meaning of the "placebo effect" is a direct effect of belief upon symptoms. You give someone a sugar pill or injection, and they immediately feel less pain, or whatever. But even this effect encompasses two kinds of things. It's one thing if the original symptoms have a "real" medical cause, like a broken leg. But it's another thing if the original symptoms are themselves partially or wholly driven by psychological factors, i.e. if they are "psychosomatic".

If a placebo treats a "psychosomatic" disease, then that's not because the placebo has some mysterious, mind-over-matter "placebo effect". All the mystery, rather, lies with the psychosomatic disease. But this is a crucial distinction.

People seem more willing to accept the mind-over-matter powers of "the placebo" than they are to accept the existence of psychosomatic illness. As if only doctors with sugar pills possess the power of suggestion. If a simple pill can convince someone that they are cured, surely the modern world in all its complexity could convince people that they're ill.

[BPSDB]

Nunn, R. (2009). It's time to put the placebo out of our misery BMJ, 338 (apr20 2) DOI: 10.1136/bmj.b1568

Who's the Greatest Sportsperson?

2009-10-14T19:00:00.001+01:00

Who's the greatest sports person of all time?

Clearly, whoever it is has to also be the best in the history of their particular sport. But there are lots of sports, and equally many best players. Who's better - the greatest footballer, or the greatest golfer, or...?

You could just pick your personal favourite. If you like soccer, then Pelé is probably the greatest sportsman. Those who prefer baseball would most likely plump for Ty Cobb. But is there a way of objectively deciding who's the greatest of the great?

Yes, and the answer is Australian cricketer Sir Don Bradman (1908-2001). Why? It's all down to σ, the standard deviation - a fantastically useful, yet often misunderstood, mathematical technique. Time for a quick stats lesson.

For any collection of numbers, it's easy to calculate the mean - the sum of the numbers divided by how many there are. For example, the mean of 10, 20 and 30 is 20 : 10+20+30=60 / 3. This is what's commonly called the "average", although statisticians don't like that word.

The mean of 19,20, 21 is 20 as well. But there's obviously an important difference between these two sets of values. The first is more variable, or "spread out", than the second. How can we measure the "spread" of a set of numbers?

A convenient way would be to calculate the mean difference from the mean of the numbers. For 10,20, and 30, the differences from the mean are 10, 0, and 10, and the mean of the differences is 6.66 : 10+10=20 / 3. For 19,20,21, the differences are 1,0 and 1, and the mean difference is 0.66. The numbers are evil, but the principle is straightforward.

The standard deviation (aka the "s.d." or σ, "sigma") is similar to the mean difference, but it's calculated using a slightly more complicated method. First, work out the differences from the mean, then square them all, and calculate the mean of the squared values. This is called the variance. The square root of the variance is the standard deviation, σ.

For 10,20,30, the deviations are 10,0,10. Squared, that's 100,0,100, and the mean is 66.6, which is the variance. The square root of 66.6 = 8.16, so that's the standard deviation, σ. This is higher than the mean difference, but in most cases it's fairly close to it. σ turns out to be more useful in many ways, so it's generally what we use.

σ allows us to compare very different kinds of numbers in terms of how "unusually high" or "unusually low" they are. Imagine that the height of men has a mean of 180 cm, with a σ of 10 cm. In that case, a man who stands 200 cm tall would be 2 σ above the mean.

Now imagine that this man has an IQ of 145. IQ has a mean of 100 and a σ of 15, so this man's IQ is 3 σ above the mean. He is both tall and smart, but in an important way, he's smarter than he is tall, even though it obviously makes no sense to compare a height to an IQ score directly.

This brings us back to sports and Don Bradman. If you calculate the mean and the σ for some measure of sporting achievement, you can work out how many σ above (or below) the mean any given player is. In soccer, you might pick goals scored per match. In baseball, you might go with the batting average.

It turns out that if you do this, Don Bradman is the greatest sportsman of all time: his batting average was 4.4 σ above the mean for professional cricketers. Pelé comes second, as his goals-per-game was 3.7 σ above average, while Ty Cobb's batting average was 3.6 σ high. Bradman was the best cricketer ever, and Pelé was the best footballer ever, but Bradman was the best by a much larger margin than Pelé was.

Of course, we probably shouldn't take this too seriously. There are lots of assumptions here - it assumes that goals-per-match is the ultimate measure of a footballer's ability, which rules out defenders entirely, for example. And the statistician responsible for this work, Charles Davis, only looked at cricket, soccer, baseball, golf and basketball. And he was Australian, like Bradman, which may not be coincidence.

But still, it's an interesting result, and a good illustration of the power of σ. In science, σ has manifold uses. Whenever you see a picture of "brain activation" measured with fMRI, for example, those colourful patches actually represent areas where neural activation is unusually highly correlated with something.

For example, if you show people a picture, and activation in a certain area increases whenever you do, this is unusually highly correlated (relative to the rest of the brain where activation is random). The "hotter" colours correspond to higher σ values, specifically z scores. When you see "blobs on the brain", 9 times out of 10, you're literally looking at statistics.

Placebos Have Side Effects Too

2009-10-12T17:30:00.001+01:00

The placebo is the most talked-about treatment in medicine.

Everyone's heard of the "placebo effect", by which pills containing no drugs at all, just chalk and sugar, often seem to make people feel better. But if the mere expectation of improvement can produce improvement, then the expectation of unpleasant consequences, such as side effects, should make people feel worse. This is sometimes called the "nocebo" effect.

Two recently published papers tried to measure it. They looked at people who took part in randomized controlled trials of various drugs, and who were given placebos. Because different drugs have different known side effects, if the nocebo effect is real, the side effects reported by the placebo group should depend on the drug they think they might be taking. As the authors of one of the papers put it:

In a typical clinical trial, the subjects know they can receive either the active medication or the placebo and, accordingly, they are informed about the possible adverse events they may experience during the trial. ... Therefore, informing subjects about the possible adverse events they may experience, may have a significant impact on their expectations and experiences of negative effects.

Accordingly, Rief et al compared the side effects reported in the placebo groups of a large number of antidepressant drug trials. At the same time a separate group of researchers, Amanzio et al, did the same thing for trials of migraine drugs, which is a nice coincidence.

Both papers found that reported side effects do indeed depend on the drug being studied. In the antidepressant paper, people who believed they might be on tricyclic antidepressants (TCAs) reported many more "side effects" than those in trials of SSRIs. These included dry mouth, drowsiness, constipation, and sexual problems. This makes sense, because TCAs do have worse side effects than SSRIs.

Likewise, for the migraine trials, the placebo groups in trials of anticonvulsants reported more symptoms associated with those drugs, such as dizziness and sleepiness. Placebo groups in trials of NSAIDs (like aspirin) were more likely to report upset stomachs and so forth. Finally, in trials of triptans, which have very mild side effects, the placebo group reported few problems.

It's also interesting to compare the two papers. None of the migraine trial placebo patients reported experiencing sexual problems, while many of the antidepressant placebo patients did. Some antidepressants can cause sexual problems, while migraine drugs generally don't.

So, was the "nocebo effect" really making people feel worse? It could well have been, although there are other interpretations. People might just be more willing to report symptoms that they believe are drug side effects. Researchers might be more likely to write them down. And different kinds of people end up in trials of different drugs: some people might be more likely to report certain symptoms. Just as with placebos, we shouldn't rush to ascribe incredible mind-over-matter powers to the "force of suggestion" when there are more prosaic explanations.

Nevertheless, there's an important lesson here. Anecdotal evidence about drug's side effects shouldn't be accepted at face value, any more than anecdotes about their benefits. Drugs do, of course, cause adverse effects. But some drugs have worse reputations than they deserve in this regard. In such cases, nocebo effects might account for some of the reported problems...

Rief W, Nestoriuc Y, von Lilienfeld-Toal A, Dogan I, Schreiber F, Hofmann SG, Barsky AJ, & Avorn J (2009). Differences in Adverse Effect Reporting in Placebo Groups in SSRI and Tricyclic Antidepressant Trials: A Systematic Review and Meta-Analysis. Drug safety : an international journal of medical toxicology and drug experience, 32 (11), 1041-56 PMID: 19810776

Amanzio M, Corazzini LL, Vase L, & Benedetti F (2009). A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain PMID: 19781854

Statistically

2009-10-11T11:40:00.003+01:00

"Statistically, airplane travel is safer than driving..." "Statistically, you're more likely to be struck by lightning than to..." "Statistically, the benefits outweigh the risks..."

What does statistically mean in sentences like this? Strictly speaking, nothing at all. If airplane travel is safer than driving, then that's just a fact. (It is true on an hour-by-hour basis). There's no statistically about it. A fact can't be somehow statistically true, but not really true. Indeed, if anything, it's the opposite: if there are statistics proving something, it's more likely to be true than if there aren't any.

But we often treat the word statistically as a qualifier, something than makes a statement less than really true. This is because psychologically, statistical truth is often different to, and less real than, other kinds of truth. As everyone knows, Joseph Stalin said that one death is a tragedy, but a million deaths is a statistic. Actually, Stalin didn't say that, but it's true. And if someone has a fear of flying, then all the statistics in the world probably won't change that. Emotions are innumerate.

Another reason why statistics feel less than real is that, by their very nature, they sometimes seem to conflict with everyday life. Statistics show that regular smoking, for example, greatly raises your risk of suffering from lung cancer, emphysema, heart disease and other serious illnesses. But it doesn't guarantee that you will get any of them, the risk is not 100%, so there will always be people who smoke a pack a day for fifty years and suffer no ill effects.

In fact, this is exactly what the statistics predict, but you still hear people referring to their grandfather who smoked like a chimney and lived to 95, as if this somehow cast doubt on the statistics. Statistically, global temperatures are rising, which predicts that some places will be unusually cold (although more will be unusually warm), but people still think that the fact that it's a bit chilly this year casts doubt on the fact of global warming.

Some people admit that they "don't believe in statistics". And even if we don't go that far, we're often a little skeptical. There are lies, damn lies, and statistics, we say. Someone wrote a book called How To Lie With Statistics. Few of us have read it, but we've all heard of it.

Sometimes, this is no more than an excuse to ignore evidence we don't like. It's not about all statistics, just the inconvenient ones. But there's also, I think, a genuine distrust of statistics per se. Partially, this reflects distrust towards the government and "officialdom", because most statistics nowadays come from official sources. But it's also because psychologically, statistical truth is just less real than other kinds of truth, as mentioned above.

I hope it's clear that I do believe in statistics, and so should you, all of them, all the time, unless there is a good reason to doubt a particular one. I've previously written about my doubts concerning mental health statistics, because there are specific reasons to think that these are flawed.

But in general, statistics are the best way we have of knowing important stuff. It is indeed possible to lie with statistics, but it's much easier to lie without them: there are more people in France than in China. Most people live to be at least 110 years old. Africa is richer than Europe. Those are not true. But statistics are how we know that.

[BPSDB]

A Vaccine For White Line Fever?

2009-10-08T20:15:00.001+01:00

A study claims that it's possible to immunize against cocaine: Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained Patients. But does it work? And will it be useful?
The idea of an anti-drug vaccine is not new; as DrugMonkey explains in his post on this paper, monkeys were being given experimental anti-morphine vaccines as long ago as the 1970s. This one has been under development for years, but this is the first randomized controlled trial to investigate whether it helps addicts to use less of the drug.

Martell et al, a Yale-based group, recruited 115 patients. They all used both cocaine and opiates, and were given methadone treatment to try to reduce their opiate use. The reason why the authors chose to focus on these patients is that the methadone keeps people coming back for more and makes them less likely to drop out of the study, or as they put it, "retention in methadone maintenance programs is substantially better than in primary cocaine treatment programs. We also offered subjects $15 per week to enhance retention."

The vaccine consists of a bacterial protein (cholera toxin B-subunit) chemically linked to a cocaine-like molecule, succinylnorcocaine. Like all vaccines, it works by provoking an immune response. The bacterial protein triggers the production of antibodies, proteins which recognize and bind to specific targets.

In this case, the antibodies bind cocaine (anti-cocaine IgG) because of the succinylnorcocaine in the vaccine. Once a molecule of cocaine is bound to the antibody, it's effectively out of commission, as it cannot enter the brain. So, the vaccine should reduce or abolish the effects of the drug. The control group were given a dummy placebo vaccine.

The results? Biologically speaking, the vaccine worked, but in some people more than others. Out of the 55 subjects who were given the active vaccine, all but one produced anti-cocaine IgG. However, the amount of antibodies produced varied widely. Also, the response was short-lived. The vaccine was given 5 times over the first 12 weeks, but antibody levels did not peak until week 16, after which they fell rapidly.
And the key question - did it reduce cocaine use? Well, sort of. The authors measured drug use in terms of the proportion of urine samples which were cocaine-free. In the active vaccine group, the proportion of drug-free urine samples was higher over weeks 9 to 16, when the antibody levels were high, and this was statistically significant (treatment x time interaction: Z=2.4, P=.01). As expected, the benefit was greater in the people who made lots of antibodies (43 μg/mL) (treatment x time interaction: Z=4.8, P less than .001). But the effect was pretty small:

The bottom line was about 10% more urine samples testing negative, and even that was only true in the minority (38%) of people who responded well to the vaccine! Not very impressive, but on the other hand, the number of drug-free urine tests is a very crude measure of cocaine use. It doesn't tell us how much coke the patients used at a time, or how many times they used it per day.

Also, bear in mind that if it works, this vaccine might increase cocaine use in some people, at least at first. By binding and inactivating some of the cocaine in the bloodstream, the vaccine would mean you'd need to take more of the drug in order to feel the effects. It's curious that the authors relied on just one crude outcome measure and didn't ask the patients to describe the effects in more detail.

So, these are some interesting results, but the vaccine clearly needs a lot of work before it becomes clinically useful, as the authors admit - "Attaining high (43 μg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters." Quite an admission given that this study was partially funded by Celtic Pharmaceuticals, who make the vaccine.

It's also questionable whether any vaccine will be truly beneficial in treating cocaine addiction. Such a vaccine would be a way of reducing the temptation to use cocaine. In this sense, it would be just like naltrexone for heroin addicts, which blocks the effects of the drug. Or disulifram (Antabuse) for alcoholics, which makes drinking alcohol cause horrible side effects. Essentially, these treatments are ways of artificially boosting your "self-control", and they work.

But we've had naltrexone and disulifram for many years. They're cheap and safe. But we still have heroin addicts and alcoholics. This is not to say that they're never helpful - some people find them very useful. But they haven't eradicated addiction because addiction is not something that can be cured with a pill or an injection.

Addiction is a pattern of behaviour, and medications might help people to break free of it, but the causes of addiction are social, economic and psychological as well as biological. People turn to drugs and alcohol when there's nowhere else to turn, and unfortunately, there's no vaccine against that.

Martell BA, Orson FM, Poling J, Mitchell E, Rossen RD, Gardner T, & Kosten TR (2009). Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Archives of general psychiatry, 66 (10), 1116-23 PMID: 19805702

Is Freud Back in Fashion? No.

2009-10-05T22:25:00.008+01:00

Freudian psychoanalysis is the key to treating depression, especially the post-natal kind (depression after childbirth). That's according to a Guardian article by popular British psychologist and author Oliver James. He says that recent research has proven Freud right about the mind, and that psychoanalysis works better than other treatments, like cognitive-behavioural therapy (CBT).

Neuroskeptic readers have encountered James before. He's the person who thinks that Britain is the most mentally-ill country in Europe. I disagree, but that's at least a debatable point. This time around, James's claims are just plain wrong.

So, some corrections. We've got a lot to cover, so I'll keep it brief:

"10% [of new mothers] develop a full-blown depression...which therapy should you opt for? [antidepressants] rule out breastfeeding" - No, they don't. Breast-feeding mothers are able to use antidepressants when necessary, according to the British medical guidelines and others:

Limited data on effects of SSRI exposure via breast milk on weight gain and infant development are encouraging. If a woman has been successfully treated with a SSRI in pregnancy and needs to continue therapy after delivery, there is no need to change the drug, provided the infant is full term, healthy and can be adequately monitored...

James's statement is a dangerous mistake, which could lead to new mothers worrying unduly, or even stopping their medication.

"People given chalk pills but told they are antidepressants are almost as likely to claim to feel better as people given the real thing." - This is true in many cases, although it's a little bit more complicated than that, but this refers to trials on general adult clinical depression, not post-natal depression, which might be completely different.

There's actually only one trial comparing an antidepressant to chalk placebo pills in post-natal depression. The antidepressant, Prozac, worked remarkably well, much better than in most general adult trials. This was a small study, and we really need more research, but it's encouraging.

"Regarding the talking therapies, in one study depressed new mothers were randomly assigned to eight sessions of CBT, counselling, or to psychodynamic psychotherapy. Eighteen weeks later, the ones given dynamic therapy were most likely to have recovered (71%, versus 57% for CBT, 54% counselling)."

This is cherry-picking. In the trial in question the dynamic (psychoanalytic) therapy was slightly better than the other two when depression was assessed in one way, which is what James quotes. The difference was not statistically significant. And using another depression measurement scale, it was no better at all. Take a look, it's hardly impressive:

Plus, after 18 weeks, none of the three psychotherapies was any better to the control, which consisted of doing precisely nothing at all.

"Studies done in the last 15 years have largely confirmed Freud's basic theories. Dreams have been proven to contain meaning." - Nope. Freud believed that dreams exist to fulfil our fantasies, often although not always sexual ones. We dream about what we'd like to do. Except we don't actually dream about it, because we'd find much of it shameful, so our minds hide the true meaning behind layers of metaphor and so forth. "Steep inclines, ladders and stairs, and going up or down them, are symbolic representations of the sexual act..."

If you believe that, good for you, and some people still do, but there has been no research over the past 15 years supporting this (although this is quite interesting). There was never any research really, just anecdotes

"Early childhood experience has been shown to be a major determinant of adult character." Nope. The big story over the past decade is that contra Freud, "shared environment", i.e. family life and child rearing make almost no contribution to adult personality, which is determined by a combination of genes and "individual environment" unrelated to family background. One could argue about the merits of this research but to say that modern psychology is moving towards a Freudian view is absurd. The opposite is true.

"And it is now accepted by almost all psychologists that we do have an unconscious and that it can contain material that has been repressed because it is unacceptable to the conscious mind." Nope. Some psychologists do still believe in "repressed memory" theory, but it's highly controversial. Many consider it a dangerous myth associated with "recovered memory therapy" which has led to false accusations of sexual abuse, Satanic rituals, etc. Again, they may be wrong, but to assert that "almost all" psychologists accept it is bizarre.

"Although slow to be tested, the clinical technique [of Freudian psychoanalysis] has now also been demonstrated to work. The strongest evidence for its superiority over cognitive, short-term treatments was published last year..."

First off, the trial referred to was not about post-natal depression, and it didn't test cognitive therapy at all. It compared long-term psychodynamic therapy, vs. short-term psychodynamic therapy, vs. "solution-focused therapy" in the treatment of various chronic emotional problems. No CBT was harmed in the making of this study.

After 1 year, long-term dynamic therapy was the worst of the three. At 2 years, they were the same. At 3 years, long-term dynamic therapy was the best. Although all these differences were small. Short-term dynamic therapy was no better than solution-focused therapy, which is rather a point against psychoanalysis since solution-focused therapy is firmly non-Freudian. And amusingly, the "short-term" dynamic therapy was actually twice as long as the dynamic therapy in the first study discussed above, which James praised! (20 weekly sessions vs 10). (Edit 23.10.09)

James ends by slagging off CBT and its practitioners, and suggesting that we need a "Campaign for Real Therapy", i.e. not CBT, something he has suggested before. This is the key to understanding why James wrote his muddled piece.

The British government is currently pouring hundreds of millions into the IAPT campaign which aims to "implement National Institute for Health and Clinical Excellence (NICE) guidelines for people suffering from depression and anxiety disorders". NICE guidelines essentially only recommend CBT, so this is effectively a campaign to massively expand CBT services. CBT is widely seen as the only psychotherapy which has been proven to work, in Britain and increasingly elsewhere too.

Oliver James, like quite a lot of people, doesn't like this. And in that, he has a point. There are serious debates to be had over whether CBT is really better than other therapies, and whether we really need lots more of it. There are also serious debates to be had over whether antidepressants are really effective and whether they are over-used. But these are all extremely complex questions. There are no easy answers, no short cuts, no panaceas, and James's brand of sectarian polemic is exactly what we don't need.

[BPSDB]

How Brain Cells Avoid Getting All Tied Up

2009-10-02T19:05:00.004+01:00

During the development of the brain, young neurones need to form connections with other cells. But equally important, they need to avoid making connections with themselves.

Unfortunately, the chance of this happening is rather high. As a neurone grows and branches out in all directions, many of the branches will inevitably come into contact with others from the same cell. They're right next to each other.

So, how do brains achieve self-avoidance? The answer, according to a new Nature paper building on previous work, is a clever mechanism involving a single protein, Dscam1. The DNA code which produces it contains three sections (exons), which can each vary in several ways. There are 12 variants of exon 4, 48 of exon 6, and 33 of exon 9.

That means that Dscam1 can end up in 12 x 48 x 33 = 19,008 different configurations (isoforms). It's as if whenever the protein is formed, it rolls a 12 sided dice, a 48 sided dice, and a 33 sided dice, and then ends up signalling the result. The diagram illustrates this nicely. The clever part is that each developing neurone expresses only a few isoforms, entirely at random.

If a growing neuronal branch encounters another branch with the same Dscam1 isoform, the two identical proteins interact and the branches repel each other. Because every part of any given cell expresses the same "fingerprint", this produces self-avoidance. But the chance that another neighbouring cell will have the same protein is very small. There are billions of neurones in the brain, so many will share the same protein, but the chance of a cell encountering another nearby with the identical fingerprint is tiny.

In this paper, the authors genetically engineered fruit flies (Drosophila) so that they had fewer than the normal 19,008 Dscam1 variants. (Previous work suggests that the system is similar in mammals.) Flies with 4,752 variants developed normally, but with only 1,152, problems arose: neurones got repelled from other nearby neurones because they shared the same protein. With 576, 24, or 12 isoforms, the problem became progressively worse, as the chance of two cells having the same isoform rose.

So, in order to avoid tying themselves in knots, brains need somewhere between about one thousand and five thousand Dscam1 variants. It's an elegant solution to the problem of neurite self-avoidance, and a lovely example of evolution at work.

Hattori D, Chen Y, Matthews BJ, Salwinski L, Sabatti C, Grueber WB, & Zipursky SL (2009). Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms. Nature, 461 (7264), 644-8 PMID: 19794492

MAOis For Dummies (And British Pundits)

2009-09-30T10:30:00.005+01:00

Allegedly, British Prime Minister Gordon Brown takes a monoamine oxidase inhibitor (MAOi) antidepressant.

That's the rumor, based on the rumored fact that he is unable to eat certain things, notably cheese and Chianti wine. These are foods rich in tyramine, a chemical that's normally harmless, but can be toxic in people taking MAOis. So, if Brown is indeed on a Chianti-and-cheeseless regime, he almost certainly is taking one of the several MAOis on the market today.

The original source for this idea is this blogger, who claims to have heard it from an unnamed Brown aide. Is he to be believed? A glance over his website shows he is hardly an impartial commentator, and he goes on to demonstrate his psychological insight with statements like

"Obsessive Compulsive Disorder (OCD) is relatively common. Most of us display some obsessive features in everyday life, but under stress a minority of people become borderline or actual OCD in their behaviour, and need medication to control both this and the depression which almost always presents soon afterwards. ... Gordon Brown's symptoms are obvious when viewed in this light: the constant repetition of phrases, and an almost embarrassing (for his Party) need to spray every Parliamentary answer with statistics... they - and the constant speech repetition - represent Brown's unconscious means of controlling the severe anxiety that accompanies depression with OCD."

So one might think that his credibility is somewhat questionable. This hasn't stopped certain corners of the British blogosphere from getting very excited, however, and even respected political journalist Andrew Marr yesterday quizzed Brown about the issue.

Unfortunately, while many are eager to write about Brown and his possible pills, few of them seem to know anything about psychiatry or antidepressants, which has led to some embarrassing errors. So, for the benefit of British pundits, here are some helpful facts.

MAOis -

are not "powerful", "heavy duty" antidepressants. In terms of effectiveness, they are no better, on average, than Prozac. In fact, no antidepressant is much better than any other one. They differ in terms of side effects, but not "strength". For what it's worth, current opinion is that if there is a best antidepressant, it is escitalopram, a modern Prozac-like SSRI with very mild side effects, which is just about as unlike a MAOi as you can imagine.
do not "impair" or "affect judgment". Antidepressants don't. Except that they treat depression, and someone who's happy might make different judgments to someone who's depressed. But these drugs do not affect judgment in the way that intoxicants like alcohol or cocaine do. You don't get high on them. This is why they have no street value. Most drugs which impair judgment get used recreationally, because having your judgment impaired can be fun. Antidepressants aren't.
are not exclusively used in "severe depression". They are usually reserved for when a patient has not responded to other drugs. This is because of their troublesome side effects, including high blood pressure, and the fact that you can't eat cheese. But "treatment-resistant" depression is not the same as "severe" depression. In fact, the more severe the depression, the more likely it is to respond to treatment with conventional drugs. If Brown is on MAOis, he has probably tried at least two or three other drugs, but this is by no means uncommon because antidepressants just don't work especially well. According to the largest trial in a real-world setting, the STAR*D project, only 30% of people fully recover on their first antidepressant and only 30% of the rest respond to the second one.
are not especially effective in OCD, as the source of the rumor claimed - "this older class of drugs has one huge advantage: for severe depression and obsessive compulsive disorder it remains very effective", emphasis in the original. This is just flat-out wrong. Other antidepressants are more useful in OCD. Here's a recent review of drug therapy for OCD. MAOis get a mention... right at the end, after (deep breath) SSRIs, clomipramine, atypical antipsychotics, SNRIs, pregabalin, tricyclic antidepressants, and benzodiazepines. Here's the only published trial comparing a monoamine oxidase inhibitor to another drug, Prozac, for OCD. The MAOi didn't work, Prozac did.
were the first class of antidepressants to be discovered; the very first, iproniazid, was discovered in 1952. Others followed, such as tranylcypromine, phenelzine, and selegiline. Today, there are a handful of MAOis on the market. These include some newer drugs such as moclobemide (which has milder side effects) and the selegiline transdermal patch (which carries fewer dietary restrictions). MAOis are primarily used to treat depression, but are also used in Parkinson's disease.

So, even if Brown is taking MAOis, this has no implications regarding his mental state or competence to govern. What about the possibility that he is depressed? This could be relevant, but considering that the most popular British leader of all time famously suffered from severe depressive episodes throughout his life, including his time in office, the historical precedents are not unfavourable.

Realistically, none of this is going to change people's minds. No-one is really concerned about the possibility that Gordon Brown is using MAOis, or even the possibility that he's depressed. Rather, a lot of people just really don't like him, and this rumor is the latest stick with which to beat him. Blogger Guido Fawkes has been asking "Is Brown Bonkers?" for months. As one journalist put it, "Whether literally the case or not, however, this rumor carries the kind of psychological truth that tends to be more damaging than fact." Which didn't stop him from repeating the rumor uncritically.

[BPSDB]

Encephalon #76

2009-09-28T09:00:00.001+01:00

Welcome to #76 in the fortnightly Encephalon blog carnival series.

Sandra Kiume's Channel N points us to a fascinating and inspiring talk on blindness, vision science and the brain, from MIT Prof. Pawan Sinha. It's an hour long, but well worth your attention.
The tale of a Polish violin prodigy whose career was tragically cut short is recounted over at Providentia. Josef Hassid was originally thought to have been suffering from schizophrenia, but was eventually diagnosed with a brain tumour.
The Neurocritic hits us with a pair of posts about some rather drastic neurological treatments for addiction (one, two), and also reviews a study arguing that neuroscience teaches us that torture doesn't work.
Sharpbrains discusses a pioneering initiative to encourage awareness of dementia in San Francisco.
Neurophilosophy features a pair of typically lucid posts about associative learning in coma patients and an fMRI study showing that hippocampal activity predicts unconscious memory.
Zoe Wool over at Neuroanthropology writes about the life of a solider injured in Iraq and the difficulty in separating the "physical" from the "psychological" in such cases.
Crime and Consequences blogger Steve Erikson alerts us to a provocative new paper of his discussing and criticizing the "neurolaw" movement. Sure to be food for thought.
Brain-inspired "neuromorphic" software may soon be able to recognise text better than current methods, writes Brain Stimulant.
Neurones may be more energy-efficient than previously believed, according to a paper featured at AK's Rambling Thoughts. He also points out the dangers of taking scientific terminology too seriously.
Finally, The Mouse Trap discusses the moodiness of entrepreneurs and the near-chaotic nature of the brain.

That's it for this time. We're still looking for a host for the next edition, so if you're a neuro/psychology blogger and you'd like to be the next Encephalon editor, please email encephalon dot host at gmail dot com.

Panic! In the fMRI Scanner

2009-09-26T15:30:00.000+01:00

Continuing the theme of interesting single case reports, I was pleased to see a paper about brain activity in someone who suffered a panic attack in the middle of an fMRI brain scan experiment.

The unfortunate volunteer, a 46 year old woman, was taking part in an experiment looking at restless-leg syndrome. The scan lasted 40 minutes, and everything was going smoothly until quite near the end, when out of the blue, she had a panic attack.

Obviously, the scan had to be abandoned, but the researchers, not wanting the data they had got to go to waste, decided to see what happened in the woman's brain just as the panic started.

The top graph here shows her heart rate. It starts increasing a bit and then spikes, which shows exactly when the attack occurred. What about the brain? Well, amygdala and left insula activity sort of increase around this time. A bit. If you stare at the lines hard enough.

If you believe they did, it makes sense because the amygdala is known to be involved in anxiety (amongst other things) while the insula is responsible for the perception of the body's internal state, which is rather out of whack during a panic attack.

What doesn't make sense is the middle temporal gyrus bit, which was statistically the only part of the brain where activity was significantly correlated with heart rate (in whole-brain analysis). That region is not believed to have anything to do with panic, and to be honest, it's probably just a fluke.

This is only the second published report about panic during fMRI. There was one previous paper from 2006 about an attack in someone with a history of panic, which also found amygdala activation. But there are sure to be others out there which haven't made it into print - anxiety and panic during scans is not unheard of (the scanner is rather claustrophobic). It would be interesting to get more data on this, because it's obviously rather hard to research real-life panic attacks, on account of them being unpredictable.

Spiegelhalder, K., Hornyak, M., Kyle, S., Paul, D., Blechert, J., Seifritz, E., Hennig, J., Tebartz van Elst, L., Riemann, D., & Feige, B. (2009). Cerebral correlates of heart rate variations during a spontaneous panic attack in the fMRI scanner Neurocase, 1-8 DOI: 10.1080/13554790903066909

Spot The Difference

2009-09-24T09:44:00.005+01:00

As part of my extensive research into the famous dead fish brain scanning study, I decided to read a little bit about the Atlantic salmon (Salmo salar), the fish which started it all.

It turns out, at least according to Wikipedia, that there are various interesting things about this species, for example, it's "much more aggressive than other salmon". Who knew?

However, by far the most interesting thing is that developing salmon embryos are about the cutest things in the world, and look exactly like smiley faces, or maybe Pacman. Those dark spots really are the eyes.

Endless forms most beautiful, indeed.

The Man With Half A Brain

2009-09-22T18:51:00.011+01:00

A lovely new paper reports in fascinating detail on a man who lost a uniquely large portion of his brain: Bilateral limbic system destruction in man.

The authors, Feinstein et al from Iowa City, have studied the patient, "Roger", for 14 years. Roger was born in 1952, and lived a fairly uneventful life until he contracted herpes simplex encephalitis (HSE) at the age of 28.

HSE is an extremely rare condition in which the herpes virus infects the central nervous system. Untreated, it is fatal in 70% of people. Survivors suffer varying degrees of neurological damage. Roger suffered more than most - his is the worst case of herpes encephalitis damage among patients currently alive, and there are only three recorded cases of similarly extensive lesions. Roger lost almost his entire "limbic system":

The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral.

"Limbic system" is an old, vague, but still popular term for a collection of brain structures located deep in the centre of the brain (but not to be confused with the basal ganglia). It's often thought of as the "primitive", "emotional" part of the brain, and there is some truth to this. Roger's limbic system was profoundly damaged on both sides; on the right side, the lesion included the whole temporal lobe and most of the ventral prefrontal cortex as well.

What happened to Roger's mind when his brain suffered such injury? In many ways, remarkably little. His only major impairment is profound anterograde amnesia: he is unable to remember anything that has happened since the infection, which was 28 years ago.

For Roger, not much has changed over the past 28 years. He has virtually no episodic memories for any events that have transpired over the past three decades. For example, he has no recollection of 9/11, and when shown pictures of the planes crashing into the World Trade Center he often responds with bewilderment, speculating that Russia must be attacking America.

This is, obviously, a disabling deficit: Roger cannot lead a normal life. But in other areas of mental functioning, he is quite normal. His IQ is above average; his speech and language abilities are excellent; his vision and hearing are normal, although he has no sense of taste or smell. His short term (working) memory, attention, and reasoning abilities are unimpaired. His motor abilities are fine - he is reportedly an excellent bowler - and he is able to improve motor skills through practice. And his recall of things which happened before the infection is largely preserved, although the few years just before the infection are partially lost.

Fascinatingly, Roger's personality and emotional life seems to have been changed by the infection as well, but in a rather fortunate way -

Roger appears remarkably unconcerned by his condition. He hardly ever complains and, in general, shows little worry for anything in life. Both of his parents and his sister fervently claim that “Roger is always happy,” an observation that is consistent with our own impression. Moreover, based on his family’s report, Roger is paradoxically happier now than he was before his brain damage. ... His premorbid disposition of being somewhat reserved and introverted has shifted to being outgoing and extroverted...

Most conversations with Roger involve animated speech that is replete with prosody, gesture, and, often times, laughing. He readily displays signs of positive emotion including happiness, amusement, interest, and excitement. As previously noted, Roger’s positive mood has remained essentially unchanged over nearly three decades.

His only other reported quirks are an insatiable appetite, and a habit of collecting and holding onto everyday items.

What does all this mean? Neuroscientists will find little about the case surprising. No textbooks are going to have to be rewritten. Roger's inability to form new memories, combined with preserved memory of events up to the few years before the damage, is similar to that seen in other cases of bilateral hippocampus damage. The most famous being the sadly recently deceased patient "H. M.", but there have been plenty of others. The hippocampus seems to be necessarily for forming new long term memories, but the memories themselves are stored elsewhere.

Roger's happy-go-lucky disposition is also not too unexpected, given that he suffered bilateral damage to the ventromedial prefrontal cortex (vmPFC). Last year I wrote about a study from the same Iowa team finding that damage to this area seems to protect against depression. And this is the same region which was targeted by the infamous prefrontal lobotomies of the 40s and 50s - which, for all their ethical shortcomings, sometimes did seem to relieve people of mental anguish.

For me, Roger provides two main lessons, both rather satisfying ones. Firstly, even after losing large parts of the brain, life goes on. The brain is modular, and we can live without many of the modules. And secondly, if our emotional circuitry is damaged, we generally feel better, rather than worse. To put it another way, perhaps, happiness is our default state, and emotions just have a habit of getting in the way.

Feinstein, J., Rudrauf, D., Khalsa, S., Cassell, M., Bruss, J., Grabowski, T., & Tranel, D. (2009). Bilateral limbic system destruction in man Journal of Clinical and Experimental Neuropsychology, 1-19 DOI: 10.1080/13803390903066873

Encephalon #76 - Call for Submissions

2009-09-21T20:30:00.004+01:00

Neuroskeptic will be hosting the 76th instalment of ENCEPHALON, the regular neuroscience and psychology carnival. So get writing, or get submitting things you've already written, about the brain, the mind, and all that kind of thing.

As ever, please e-mail submissions (up to 3 posts) to encephalon dot host at gmail dot com, by the end of this Sunday 27th September!

Why Do We Sleep?

2009-09-19T20:37:00.006+01:00

Why do we sleep? Because otherwise, we'd always be doing stuff.

This is the theory advanced by UCLA sleep researcher Jerome Siegel (website) in a new paper, Sleep viewed as a state of adaptive inactivity (free pdf). It's part of a Nature Reviews Neuroscience special issue on the evolution of the nervous system. Siegel proposes that the evolutionary function of sleep is simply to ensure that animals are only active when the benefits of movement (mostly access to food, and mates) outweigh the costs (activity burns calories, and puts you at risk of predation or accidents).

Sleep, in other words, is our equivalent of the inactive states into which most living things, even plants, periodically enter when it suits them. Even (deciduous) trees spend the cold, dark half of the year doing not very much. In Siegel's view, this is their equivalent of sleep.

This theory stands in contrast to the idea that sleep has a restorative function - that animals need to sleep, because some kind of important biological process can only occur while we're sleeping. This idea is intuitively appealing - it feels like we benefit from sleep, and at least in humans sleep deprivation has many well-documented negative effects.

But, as Siegel points out, we're far from any kind of a consensus on what the biological function of sleep is. It's generally assumed that there is one, and a great many have been proposed - he lists some, ranging from that sleep is important for the formation of new neural connections, to the idea that sleep is needed to reverse cellular damage caused by oxidative stress (interestingly, Siegel himself contributed to one of the papers he gives as a reference for that idea).

If a vital restorative function of sleep were to be conclusively identified, Siegel's theory would obviously be disproven. On the other hand, if Siegel is right, several things should be true. Firstly, the proportion of time that an animal spends asleep should be directly proportional to the amount of time that it is useful for it to be active.

Siegel argues that this is what we find. The big brown bat for example is the doziest of all mammals, sleeping for 20 hours per day. But it wouldn't benefit from being awake any more, because the insects it feeds on are only active for a few hours at dusk. If it were flying around during the day, it would just be wasting energy (and risking becoming lunch for a bird.)

By contrast, he says, some marine mammals (cetaceans, dolphins and whales) never sleep at all. In land mammals, sleep consists of distinct periods of neural activity such as REM and slow wave sleep. Neither, however, occurs in cetaceans. They do show a kind of neural activity called Unihemispheric Slow Waves (USWs). But these are confined to one half of the brain at a time. It's often said that this is "half the brain going to sleep". However, the animals remain moving normally, and are able to avoid obstacles, during USWs. It's not as if only half their body remains awake. As such, Siegel says, the USW state is not sleep.

If it's true that there are animals which never sleep, this is strong evidence for Siegel's theory, and against the idea that sleep plays a vital role. But not everyone agrees with his claim that dolphins and whales don't sleep. See, for example, this 2008 open-access paper, Is Sleep Essential?, which calls Siegel's theory of sleep the "null hypothesis" and then proceeds to criticize it.

In particular, the authors claim that dolphins do sleep, albeit with only one half of their brain at a time, and they make the interesting point that "the very fact that dolphins have developed the remarkable specialization that is unihemispheric sleep, rather than merely getting rid of sleep altogether, should count as evidence that sleep must serve some essential function and cannot be eliminated."

At this point the debate becomes highly technical. The sleep behaviour and neural activity of marine mammals is hardly easy to research, and it looks as though more evidence is needed before we can know for sure whether they sleep or not. This is one of those seemingly trivial questions which could end up deciding between two theories with enormous implications. There are quite a lot of them in science. We don't yet know why we sleep. But the answer may lie with the dolphins.

Siegel, J. (2009). Sleep viewed as a state of adaptive inactivity Nature Reviews Neuroscience, 10 (10), 747-753 DOI: 10.1038/nrn2697

Puff the Illusionary Dragon

2009-09-18T10:46:00.005+01:00

There's a lot of interest in visual illusions at the moment thanks to an excellent article over at Seed, This Picture Is Not Moving.

A while back I wrote about the Hollow Face Illusion in which a hollow (concave) mask of a face appears to be a solid (convex) face and I posted a seriously freaky video featuring Charlie Chaplin. But reader "Jake" just pointed out an even better example of the same illusion, the Paper Dragon.

See the video above. If you like what you see, you can make your own paper dragon by printing out this .pdf here. It only takes 10 minutes, scissors and a bit of sticky tape. I highly recommend it, the effect is astonishing - it really looks as though the dragon's head is moving. You may need to close one eye to get the full experience. (The dragon was designed by ThinkFun).

The dragon, like the Charlie Chaplin mask, is an example of the "depth inversion" effect. Our visual system assumes that objects are convex, rather than concave, especially when those objects are familiar things like faces.

In my opinion the most interesting thing about the phenomena, and indeed with all illusions, is that concious belief cannot override the effect. I know that the dragon's head is concave, I folded it up and stuck it together myself. Yet I still see it as convex. This is strong evidence for the modularity of mind. But that's another story.