The Other Brain

An interesting new book from R. Douglas Fields: The Other Brain.

"Glia" is a catch-all term for every cell in the nervous system that's not a neuron. We have lots and lots of them: on some estimates, 85% of the cells in the brain are glia. But to most neuroscientists at the moment, they're about as interesting as dirt is to archaeologists. They're the boring stuff that gets in the way. The name is Greek for "glue", which says a lot.

It's telling that most neuroscientists (myself included I confess) use the term "brain cells" to mean neurons, even though they're a minority. Hence the book's title: Douglas Fields argues that glia constitute a whole world, another brain - although of course, it's not seperate from the neuronal brain, and neuron-glia interactions are the really interesting thing and the central theme of the book.

Glia have historically been regarded as mere "housekeepers", keeping the brain neat and tidy by cleaning up the byproducts of neural activity. Douglas Fields explains that there's actually a lot more to glia than that, but that even if they were just housekeepers, the housekeeping they do is extremely important.

Astrocytes, one kind of glial cell, are key to the regulation of glutamate levels in the brain. Glutamate is by far the most common neurotransmitter yet it's also the most dangerous: glutamate can kill neurons if they receive too much of it (excitotoxicity). I previously wrote about some bad clams which can cause permanent brain damage if who eat them; the toxin responsible mimics the action of glutamate.

By quickly clearing up glutamate as it's released from neurons, astrocytes perform a vital function which saves the brain from self-destruction. Yet recent evidence has shown that they don't just mop up neurotransmitters, they also respond to them, and even release them. People are nowadays talking about the "tripartite synapse" - presynaptic neuron, postsynaptic neuron, and glia.


Glia even have their own communication network quite seperate from the neuronal one. Whereas neurons use electrical currents to convey signals, and chemicals to talk to other cells, astrocytes are interconnected via direct gap-junctions - literally, little holes bridging the membranes between neighbors.

Waves of calcium can travel through these junctions across long distances. The function of this glial network is almost entirely mysterious at present, but it's surely important, or it wouldn't have evolved. (A few types of human neurons do the same thing; in some animals it's more common.)

The subtitle is overblown, as subtitles often are ("From Dementia to Schizophrenia, How New Discoveries About the Brain are Revolutionizing Medicine and Science"); the book also repeats itself in a number of places, especially when it's castigating neuroscientists for overlooking glia for so long (a fair point, but it gets old.) Overall though it's very readable and it's got some nice anecdotes as well as the science.

The Other Brain makes an excellent case that neuroscience can't remain neuron-science if it hopes to answer the big questions. It's certainly opened my eyes to the importance of glia and given me ideas for my own research. As such it's one of those rare popular science books that will prove interesting to professionals and others too.

Link: Also reviewed here.
Disclaimer: I got a free review copy.

An Astonishingly Brilliant Epic Tour-De-Force

So I was browsing my local bookshop yesterday.

But what to buy? The back covers are not very helpful. Apparently, every novel published nowadays is, at the worse, a breathtaking masterpiece. Most are epoch-making, life-changing works of godlike genius.

OK, but which ones are actually good?

Why is this? Part of it, surely, is that literature is an incestuous world where the same authors who write the books are the first port of call when publishers want blurbs for everyone else's. Clearly you don't want to say anything bad about your peers lest you stop getting invites to dinner parties. Unless you're embroiled in a "bitter literary feud", but no-one has the energy to do that on a regular basis.

Because everyone is constantly complimenting each other in this way, praise inflation sets in and we soon reach the point where "This is a very good book" would be a serious insult.

There's also a theory, which has been around for a good few hundred years and maybe forever, that creative types are a breed apart from everyone else, possessed of divine powers and insight. Not just the really great artists, but any artist as a profession.

When Nietzsche wrote a book comparing himself favourably to Jesus, with chapters called "Why I Am So Clever" and "Why I Am A Destiny", people thought that was a bit much. (It didn't help that he went completely insane the next year.) You can't go on record and say that about yourself, but say it about your friends and get them to say it about you, and it seems to work quite nicely.

The Decline And Fall of Effects In Science

Nature has a piece called Unpublished results hide the decline effect.
This refers to the fact that many scientific findings which seem to indicate something big is happening, end up getting smaller and smaller as more people try to replicate them until they, eventually, may vanish entirely.

The Last Psychiatrist's take is that "The Decline Effect" just represents sloppy thinking, treating different things as if they were all instances of The One True Phenomenon. Someone does a study about something and finds an effect. Then someone else comes along and does a new study, of a related but different topic, and finds a different result. Both are right: there's a difference. Only if you, sloppily, decide that both studies were measuring the same thing does the "Decline Effect" appear.

This is perfectly true and I've touched on it before, but I think it's a bit optimistic. It assumes that the first study was true. Sometimes they are. But because of the way science is published at the moment, a lot of results that get published are flukes. Some even say that the majority are.

The problem is that there are so many ways to statistically analyze any given body of data that it's easy to test and retest it until you find a "positive result" - and then publish that, without saying (or only saying in the small print) that your original tests all came out negative. Combine this with selective publication of only the best data, and other scientific sins, and you can pull positive results out the hat of mere random noise.

In the Nature article, Jonathan Schooler discusses this and suggests that an open-access repository of findings (meaning raw data rather than the end product of analyses) would be A Good Thing. I agree. However, he seems to think that if we did this, we might still observe the "Decline Effect", and would be able to find out more about it. He even seems to suggest that some kind of weird quantum effect might mean that scientists are actually changing the laws of reality by observing them

Perhaps, just as the act of observation has been suggested to affect quantum measurements, scientific observation could subtly change some scientific effects. Although the laws of reality are usually understood to be immutable, some physicists, including Paul Davies, director of the BEYOND: Center for Fundamental Concepts in Science at Arizona State University in Tempe, have observed that this should be considered an assumption, not a foregone conclusion.

Hmm. Maybe. But there is really no need to posit such magical mysteries when plain old statistical conjuring tricks seem like a perfectly good explanation. On my view a raw result repository would not explain the decline effect, but just make it disappear.

Schooler doesn't go into detail as to how this repository would be set up, but he does cite the fact that we already have a pretty good one for clinical trials of medicines conducted in the USA. Anyone running a clinical trial is required to register it in advance, saying what they're planning to do and crucially, to spell out which statistics they are going to run on the data when it arrives.

What's really silly is that most scientists already do this when applying for funding: most grant applications include detailed statistical protocols. The problem is that these are not made public so people can ignore them when it comes to publication. Back in 2008 I suggested that scientific journals should require all studies, not just clinical trials, to be publicly pre-registered if they're to be considered for publication. This would be eminently do-able if there was a will to make it happen.

Schooler, J. (2011). Unpublished results hide the decline effect Nature, 470 (7335), 437-437 DOI: 10.1038/470437a

Cell Phones Are Somehow Related To The Brain

The BBC says

Mobile phones 'affect the brain'

The paper's from Nora Volkow and colleagues from NIDA in the USA. Volkow's best known for her work on addiction.

47 people got 18FDG Positron Emission Tomography. This method measures brain glucose use as a proxy for how hard cells are working. They say that this makes it better than other kinds of PET which merely measure regional blood flow. I bet they really wanted to do this study with fMRI, because PET scans cost loads, but of course you can't take a cellphone into an MRI scanner.

There were two conditions: a control in which they had a phone stuck to each ear but they were both off, and an active condition in which the right-ear phone was switched on and receiving a call - but muted so they couldn't hear anything. Each subject was scanned twice, once under each condition, so that's 94 scans.

What happened? In the Results section they say that (my emphasis):

SPM comparisons on the absolute metabolic measures showed significant increases (35.7 vs 33.3 µmol/100 g per minute for the on vs off conditions, respectively; mean difference, 2.4 [95% CI, 0.67-4.2]; P=.004) in a region that included the right orbitofrontal cortex and the lower part of the right superior temporal gyrus. No areas showed decreases.

In other words a highly signficiant finding of increased glucose uptake in the areas of the brain closest to the cell phone. Whoa, that's big. However, it seems that this result was not corrected for multiple comparisons, because in the table of results they give the corrected p value for the activated cluster as p=0.05 - bang on exactly low enough to be considered significant, but no lower.

Their method for correcting for multiple comparisons was also quite unusual and I'm not quite sure what to make of it. It's on the right-hand column of Page 810. Maybe commentators will be able to offer some insight.

There's a few other things to note here. They show a nice big colorful This Is Your Brain On Phone image but it's a "representative" image of one brain, rather than an averaged image from all subjects. This is really not good practice. It's acceptable - but only because there's no alternative - for data which can't be averaged, like microscope pics.

With between-group comparisons of neuroimaging data, the averages are computed as part of the statistical analysis, and should be shown. With single-subject data we're left having to trust the authors to have really picked a "representative" image as opposed to "the best image".

Second, this has nothing to do with cancer. Brain activation happens all the time and very rarely does it have cancerous consequences. In fact this is so unrelated to cancer that I shouldn't even be mentioning cancer in this post. However, I feel the need to because the BBC (and most other outlets) did. Thus we saw curious paragraphs like this (direct quote):

Since the boom in mobile phone use, there has been considerable interest in the effect on the body. The largest study on 420,000 mobile phone users in Denmark, has not shown a link between phone use and cancer. This small study on 47 people...

Why mention cancer, if the only thing you say about it is that there's no link? Presumably because of the following chain of associations: cell phones use radiation...radiation causes cancer...cell phones and cancer!

I have no idea if cell phones cause cancer. Just from basic biology though, if they were going to cause any cancer, it'd probably be skin cancer rather than brain cancer, since a) they're closest to the skin, not the brain and b) brain cancer is incredibly rare because the brain contains no rapidly dividing cells, whereas skin cancer is common because skin is made of exactly that.

So even if if this increased brain glucose metabolism somehow was related to cancer of the brain, this would be the least of our worries, because if cell phones somehow caused brain cancer, they'd almost certainly cause many times more cases of skin cancer and the brain cancer would be a footnote.

But the point is, this study has nothing to do with cancer so forget I said that. If you have trouble forgetting, just hold your mobile phone over your temporal lobes until your hippocampus is overloaded and you suffer memory loss.

Link: Also blogged here and here.

Volkow, N., Tomasi, D., Wang, G., Vaska, P., Fowler, J., Telang, F., Alexoff, D., Logan, J., & Wong, C. (2011). Effects of Cell Phone Radiofrequency Signal Exposure on Brain Glucose Metabolism JAMA: The Journal of the American Medical Association, 305 (8), 808-813 DOI: 10.1001/jama.2011.186

The Brain's Sarcasm Centre? Wow, That's Really Useful

A team of Japanese scientists have found the most sarcastic part of the brain known to date. They also found the metaphor centre of the brain and, well, it's kind of like a pair of glasses.

The paper is Distinction between the literal and intended meanings of sentences and it's brought to you by Uchiyama et al. They took 20 people and used fMRI to record neural activity while the volunteers read 4 kinds of statements:

• Literally true
• Nonsensical
• Sarcastic
• Metaphorical

The neat thing was that the statements themselves were the same in each case. The preceding context determined how they were to be interpreted. So for example, the statement "It was bone-breaking" was literally true when it formed part of a story about someone in hospital describing an accident; it was metaphorical in the context of someone describing how hard it was to do something difficult; and it was nonsensical if the context was completely unrelated ("He went to the bar and ordered:...").

Here's what they found. Compared to the literally-true and the nonsensical statements, which were a control condition, metaphorical statements activated the head of the caudate nucleus, the thalamus, and an area of the medial PFC they dub the "arMPFC" but which other people might call the pgACC or something even more exotic; names get a bit vague in the frontal lobe.


The caudate nucleus, as I said, looks like a pair of glasses. Except without the nose bit. The area activated by metaphors was the "lenses". Kind of.

Sarcasm however activated the same mPFC region, but not the caudate:

Sarcasm also activated the amygdala.

*

So what? This is a very nice fMRI study. 20 people is a lot, the task was well-designed and the overlap of the mPFC blobs in the sarcasm-vs-control and the metaphor-vs-control tasks was impressive. There's clearly something going on there in both cases, relative to just reading literal statements. Something's going on in the caudate and thalamus with metaphor but not sarcasm, too.

But what can this kind of study tell us about the brain? They've localized something-about-metaphor to the caudate nucleus, but what is it, and what does the caudate actually do to make that thing happen?

The authors offer a suggestion - the caudate is involved in "searching for the meaning" of the metaphorical statement in order to link it to the context, and work out what the metaphor is getting at. This isn't required for sarcasm because there's only one, literal, meaning - it's just reversed, the speaker actually thinks the exact opposite. Whereas with both sarcasm and metaphor you need to attribute intentions (mentalizing or "Theory of Mind").

That's as plausible an account as any but the problem is that we have no way of knowing, at least not from imaging studies, if it's true or not. As I said this is not the fault of this study but rather an inherent challenge for the whole enterprise. The problem is - switch on your caudate, metaphor coming up - a lot like the challenge facing biology in the aftermath of the Human Genome Project.

The HGP mapped the human genome, and like any map it told us where stuff is, in this case where genes are on chromosomes. You can browse it here. But by itself this didn't tell us anything about biology. We still have to work out what most of these genes actually do; and then we have to work out how they interact; and they we have to work out how those interactions interact with other genes and the environment...

Genomics people call this, broadly speaking, "annotating" the genome, although this is not perhaps an ideal term because it's not merely scribbling notes in the margins, it's the key to understanding. Without annotation, the genome's just a big list.

fMRI is building up a kind of human localization map, a blobome if you will, but by itself this doesn't really tell us much; other tools are required.

Uchiyama HT, Saito DN, Tanabe HC, Harada T, Seki A, Ohno K, Koeda T, & Sadato N (2011). Distinction between the literal and intended meanings of sentences: A functional magnetic resonance imaging study of metaphor and sarcasm. Cortex; a journal devoted to the study of the nervous system and behavior PMID: 21333979

The Web of Morgellons

A fascinating new paper: Morgellons Disease, or Antipsychotic-Responsive Delusional Parasitosis, in an HIV Patient: Beliefs in The Age of the Internet

“Mr. A” was a 43-year-old man...His most pressing medical complaint was worrisome fatigue. He was not depressed...had no formal psychiatric history, no family psychiatric history, and he was a successful businessman.

He was referred to the psychiatry department by his primary-care physician (PCP) because of a 2-year-long complaint of pruritus [itching] accompanied by the belief of being infested with parasites. Numerous visits to the infectious disease clinic and an extensive medical work-up...had not uncovered any medical disorder, to the patient’s great frustration.

Although no parasites were ever trapped, Mr. A caused skin damage by probing for them and by applying topical solutions such as hydrogen peroxide to “bring them to the surface.” After reading about Morgellons disease on the Internet, he “recalled” extruding particles from his skin, including “dirt” and “fuzz.”

During the initial consultation visit with the psychiatrist, Mr. A was apprehensive but cautiously optimistic that a medication could help. The psychiatrist had been forewarned by the PCP that the patient had discovered a website describing Morgellons and “latched onto” this diagnosis.

However, it was notable that the patient allowed the possibility (“30%”) that he was suffering from delusions (and not Morgellons), mostly because he trusted his PCP, “who has taken very good care of me for many years.”

The patient agreed to a risperidone [an antipsychotic] trial of up to 2 mg per day. [i.e. a lowish dose]. Within weeks, his preoccupation with being infested lessened significantly... Although not 100% convinced that he might not have Morgellons disease, he is no longer pruritic and is no longer damaging his skin or trying to trap insects. He remains greatly improved 1 year later.

(Mr A. had also been HIV+ for 20 years, but he still had good immune function and the HIV may have had nothing to do with the case.)

"Morgellons" is, according to people who say they suffer from it, a mysterious disease characterised by the feeling of parasites or insects moving underneath the skin, accompanied by skin lesions out of which emerge strange, brightly-coloured fibres or threads. Other symptoms include fatigue, aches and pains, and difficulty concentrating.

According to almost all doctors, there are no parasites, the lesions are caused by the patient's own scratching or attempts to dig out the non-existent critters, and the fibres come from clothes, carpets, or other textiles which the patient has somehow inserted into their own skin. It may seem unbelievable that someone could do this "unconsciously", but stranger things have happened.

As the authors of this paper, Freudenreich et al, say, Morgellons is a disease of the internet age. It was "discovered" in 2002 by a Mary Leitao, with Patient Zero being her own 2 year old son. Since then its fame, and the reported number of cases, has grown steadily - especially in California.

Delusional parasitosis is the opposite of Morgellons: doctors believe in it, but the people who have it, don't. It's seen in some mental disorders and is also quite common in abusers of certain drugs like methamphetamine. It feels like there are bugs beneath your skin. There aren't, but the belief that there are is very powerful.

This then is the raw material in most cases; what the concept of "Morgellons" adds is a theory, a social context and a set of expectations that helps make sense of the otherwise baffling symptoms. And as we know expectations, whether positive or negative, tend to be become experiences. The diagnosis doesn't create the symptoms out of nowhere but rather takes them and reshapes them into a coherent pattern.

As Freudenreich et al note, doctors may be tempted to argue with the patient - you don't have Morgellons, there's no such thing, it's absurd - but the whole point is that mainstream medicine couldn't explain the symptoms, which is why the patient turned to less orthodox ideas.

Remember the extensive tests that came up negative "to the patient’s great frustration." And remember that "delusional parasitosis" is not an explanation, just a description, of the symptoms. To diagnose someone with that is saying "We've no idea why but you've imagined this". True, maybe, but not very palatable.

Rather, they say, doctors should just suggest that maybe there's something else going on, and should prescribe a treatment on that basis. Not rejecting the patient's beliefs but saying, maybe you're right, but in my experience this treatment makes people with your condition feel better, and that's why you're here, right?

Whether the pills worked purely as a placebo or whether there was a direct pharmacological effect, we'll never know. Probably it was a bit of both. It's not clear that it's important, really. The patient improved, and it's unlikely that it would have worked as well if they'd been given in a negative atmosphere of coercion or rejection - if indeed he'd agreed to take them at all.

Morgellons is a classic case of a disease that consists of an underlying experience filtered through the lens of a socially-transmitted interpretation. But every disease is that, to a degree. Even the most rigorously "medical" conditions like cancer also come with a set of expectations and a social meaning; psychiatric disorders certainly do.

I guess Morgellons is too new to be a textbook case yet - but it should be. Everyone with an interest in the mind, everyone who treats diseases, and everyone who's ever been ill - everyone really - ought to be familiar with it because while it's an extreme case, it's not unique. "All life is here" in those tangled little fibres.

Freudenreich O, Kontos N, Tranulis C, & Cather C (2010). Morgellons disease, or antipsychotic-responsive delusional parasitosis, in an hiv patient: beliefs in the age of the internet. Psychosomatics, 51 (6), 453-7 PMID: 21051675

WMDs vs MDD

Weapons of Mass Destruction. Nuclear, chemical and biological weapons. They're really nasty, right?

Well, some of them are. Nuclear weapons are Very Destructive Indeed. Even a tiny one, detonated in the middle of a major city, would probably kill hundreds of thousands. A medium-sized nuke could kill millions. The biggest would wipe a small country off the map in one go.

Chemical and biological weapons, on the other hand, while hardly nice, are just not on the same scale.

Sure, there are nightmare scenarios - a genetically engineered supervirus that kills a billion people - but they're hypothetical. If someone does design such a virus, then we can worry. As it is, biological weapons have never proven very useful. The 2001 US anthrax letters killed 5 people. Jared Loughner killed 6 with a gun he bought from a chain store.

Chemical weapons are little better. They were used heavily in WW1 and the Iran-Iraq War against military targets and killed many but never achieved a decisive victory, and the vast majority of deaths in these wars were caused by plain old bullets and bombs. Iraq's use of chemical weapons against Kurds in Halabja killed perhaps 5,000 - but this was a full-scale assault by an advanced air force, lasting several hours, on a defenceless population.

When a state-of-the-art nerve agent was used in the Tokyo subway attack, after much preparation by the cult responsible, who had professional chemists and advanced labs, 13 people died. In London on the 7th July 2005, terrorists killed 52 people with explosives made from haircare products.

Nuclear weapons aside, the best way to cause mass destruction is just to make an explosion, the bigger the better; yet conventional explosives, no matter how big, are not "WMDs", while chemical and biological weapons are.

So it seems to me that the term and the concept of "WMDs" is fundamentally unhelpful. It lumps together the apocalyptically powerful with the much less destructive. If you have to discuss everything except guns and explosives in one category, terms like "Unconventional weapons" are better as they avoid the misleading implication that all of these weapons are very, and equivalently, deadly; but grouping them together at all is risky.

That's WMDs. But there are plenty of other unhelpful concepts out there, some of which I've discussed previously. Take the concept of "major depressive disorder", for example. At least as the term is currently used, it lumps together extremely serious cases requiring hospitalization with mild "symptoms" which 40% of people experience by age 32.

Boy Without A Cerebellum...Has No Cerebellum

A reader pointed me to this piece:

Boy Without a Cerebellum Baffles Doctors

Argh. This is going to be a bit awkward. So I'll just say at the outset that I have nothing against kids struggling with serious illnesses and I wish them all the best.


The article's about Chase Britton, a boy who apparantly lacks two important parts of the brain: the cerebellum and the pons. Despite this, the article says, Chase is a lovely kid and is determined to be as active as possible.

As I said, I am all in favor of this. However the article runs into trouble is where it starts to argue that "doctors are baffled" by this:

When he was 1 year old, doctors did an MRI, expecting to find he had a mild case of cerebral palsy. Instead, they discovered he was completely missing his cerebellum -- the part of the brain that controls motor skills, balance and emotions.

"That's when the doctor called and didn't know what to say to us," Britton said in a telephone interview. "No one had ever seen it before. And then we'd go to the neurologists and they'd say, 'That's impossible.' 'He has the MRI of a vegetable,' one of the doctors said to us."

Chase is not a vegetable, leaving doctors bewildered and experts rethinking what they thought they knew about the human brain.

They don't say which doctor made the "vegetable" comment but whoever it was deserves to be hit over the head with a large marrow because it's just not true. The cerebellum is more or less a kind of sidekick for the rest of the brain. Although it actually contains more brain cells than the rest of the brain put together (they're really small ones), it's not required for any of our basic functions such as sensation or movement.

Without it, you can still move, because movement commands are initiated in the motor cortex. Such movement is clumsy and awkward (ataxia), because the cerebellum helps to coordinate things like posture and gait, getting the timing exactly right to allow you to move smoothly. Like how your mouse makes it easy and intuitive to move the cursor around the screen.

Imagine if you had no mouse and had to move the cursor with a pair of big rusty iron levers to go left and right, up and down. It would be annoying, but eventually, maybe, you could learn to compensate.

From the footage of Chase alongside the article it's clear that he has problems with coordination, albeit he's gradually learning to be able to move despite them.

Lacking a pons is another kettle of fish however. The pons is part of your brainstem and it controls, amongst other things, breathing. In fact you (or rather your body) can survive perfectly well if the whole of your brain above the pons is removed; only the brainstem is required for vital functions.

So it seems very unlikely that Chase actually lacks a pons. The article claims that scans show that "There is only fluid where the cerebellum and pons should be" but as Steven Novella points out in his post on the case, the pons might be so shrunken that it's not easily visible - at least not in the place it normally is - yet functional remnants could remain.

As for the idea that the case is bafflingly unique, it's not really. There are no less than 6 known types of pontocerebellar hypoplasia caused by different genes; Novella points to a case series of children whose cerebellums seemed to develop normally in the womb, but then degenerated when they were born prematurely, which Chase was.

The article has had well over a thousand comments and has attracted lots of links from religious websites amongst others. The case seems, if you believe the article, to mean that the brain isn't all that important, almost as if there was some kind of immaterial soul at work instead... or at the very least suggesting that the brain is much more "plastic" and changeable than neuroscientists suppose.

Unfortunately, the heroic efforts that Chase has been required to make to cope with his disability suggest otherwise and as I've written before, while neuroplasticity is certainly real it has its limits.

The Mystery of Stiff Person Syndrome

"Stiff Person Syndrome" (SPS) is a rare neurological disease with a silly name but serious symptoms.

Not in fact a disorder caused by an overdose of Viagra, the defining feature of SPS is uncontrollable muscle rigidity, which comes and goes in bouts, but generally gets worse over time. However, other symptoms are seen including depression, anxiety, and other neurological features such as cerebellar ataxia.

What causes SPS? Well, it's been known for over 20 years that most SPS patients have antibodies against the enzyme GAD65, which is required for the production of GABA, the main inhibitory neurotransmitter in the brain. The body shouldn't be producing antibodies against its own proteins, but unfortunately this does happen quite often, for various reasons, and the result is autoimmune diseases.

So this all seems to make sense. We know that GABA causes muscle relaxation by reducing the brain's input to the muscles. This is why GABA drugs like Valium are muscle-relaxants, and it's part of the reason why drunk people tend to stagger around.

This also explains the anxiety symptoms, because Valium and beer make you less anxious, while drugs that block GABA cause panic attacks. Anti-GAD65 antibodies block GAD, so less GABA gets made. So SPS is autoimmunity against GAD65. Mystery solved?

Not quite. Anti-GAD65 antibodies are also seen in most people with Type I diabetes, but the vast majority of diabetics luckily don't suffer SPS. Mystery remains.

Two studies just out investigated exactly what the antibodies produced by SPS patients do. Geis et al purified the antibodies from a 53 year old woman with SPS and serious anxiety, and injected them into the brains of some rats.

The rats became very anxious. Here's what the cowardly critters did in a standard rodent anxiety test: they avoided the open spaces, which are naturally scary to rodents, who prefer dark, enclosed places:

This was associated with reduced GABA production.

Meanwhile Manto et al found that anti-GAD65 antibodies from another patient with SPS caused very different effects in rat brains compared to the antibodies derived from a patient with autoimmune cerebellar ataxia, but no SPS symptoms. They also found that two kinds of off-the-shelf anti-GAD65 antibodies commonly used in research had different effects as well.

Taken together this all suggests that SPS is caused by anti-GAD65 antibodies, but they have to be a particular type. Different antibodies cause different symptoms even though they all bind to GAD65.

Presumably this is because it's a big protein, and antibodies could bind to any part of it. Only ones that block the "business end" - the part which actually catalyzes the formation of GABA - will cause problems. A bit like how if you get shot in the heart, that's the end of you, but get shot in the foot and it probably won't be.


Geis, C., et al. (2011). Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats PLoS ONE, 6 (2) DOI: 10.1371/journal.pone.0016775

Manto MU, Hampe CS, Rogemond V, & Honnorat J (2011). Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet journal of rare diseases, 6 (1) PMID: 21294897

The Short 2000 Decade

Historian Eric Hobsbaum famously talked about "the Short 20th Century": 1914 to 1989. The idea being that 1900-1914 was pretty much like the 19th century, but everything really changed with the outbreak of World War 1. Only the fall of the Berlin Wall brought that era, broadly speaking an era defined by wars or the threat of wars in Europe, to an end.

I'm going to make a rash prediction now and say that the first decade of this century started on 9/11/2001, and it ended yesterday, 2/11/2011.

That it started on 9/11 is fairly obvious. Saying that the 9/11 era ended yesterday is why this is a possibly rash prediction, but I think it's fair to say that the game has just changed completely.

For the past decade the main story in world politics has been Islamic extremism. Of course Islamic extremism has not suddenly disappeared overnight; but the way in which the rest of the world deals with it will from now on have to be very different.

For the past 10 years, the people of Muslim countries have had very little say in the matter. Their governments - with just a couple of exceptions - were not democratic. More importantly, they were apparently safe and secure in being non-democratic.

Someone could overthrow them and install new governments from outside, but they had efficient internal security and there was no prospect of them being overthrown from within. So to all intents and purposes, our relationship with "the Islamic world" was our relationship with their governments. Get the governments on our side, or not, and the rest will follow, or not. We thought.

That worked, or seemed to, for 10 years. Never again. For better or worse, the people of Muslim countries are now an issue.

Antidepressants Don't Work...In Fish

Here at Neuroskeptic fMRI scanning and antidepressants are both big topics.


As I discussed lask week, fish - specifically salmon - are the next big thing in fMRI and the number of salmon brains being scanned is growing at a remarkable rate. But fish haven't made much of an entrance into the world of antidepressants...until now.

Swedish scientists Holmberg et al have just published a paper asking: Does waterborne citalopram affect the aggressive and sexual behaviour of rainbow trout and guppy?

SSRI antidepressants, of which citalopram is one, are very popular. So popular, in fact, that non-trivial levels of SSRIs have been found in sewage and there's a concern that they might make their way into lakes and rivers and thereby affect the behaviour of the animals living there.

Holmberg et al set out to see what citalopram did to some fish in an attempt to find out whether this is likely to be a major problem. So they put some citalopram in the fish's water supplies and then tested their aggressiveness and also their sex drives. It turns out that one of the main ways of measure fish aggression is to put a mirror in their tank and see if they try to fight their own reflection. Fish are not very bright, really.

Anyway, the good news for fish everywhere was that seven days of citalopram exposure had no effect at all, even at doses much higher than those reported as a pollutant (the maximum dose was 0.1 mg/l). And the authors had no conflicts of interest: Big Pharma had nothing to do with this research, although Big Fish Farmer did because they bought the fish from one.

However, this may not be the end of the story, because it turned out that citalopram was very poorly absorbed into the fish's bloodstreams. But other antidepressants have been reported to accumulate in fish. Clearly, the only way to find out for sure what's going on would be to use fMRI...

Holmberg A, Fogel J, Albertsson E, Fick J, Brown JN, Paxéus N, Förlin L, Johnsson JI, & Larsson DG (2011). Does waterborne citalopram affect the aggressive and sexual behaviour of rainbow trout and guppy? Journal of hazardous materials PMID: 21300431

The Social Network and Anorexia

Could social networks be more important than the media in the spread of eating disorders?

There's a story about eating disorders roughly like this: eating disorders (ED) are about wanting to be thin. The idea that thinness is desireable is something that's spread by Western media, especially visual media i.e. TV and magazines. Therefore, Western media exposure causes eating disorders.

It's a nice simple theory. And it seems to fit with the fact that eating disorders, hitherto very rare, start to appear in a certain country in conjunction with the spread of Westernized media. A number of studies have shown this. However, a new paper suggests that there may be rather more to it: Social network media exposure and adolescent eating pathology in Fiji.

Fiji is a former British colony, a tropical island nation of less than a million. Just over half the population are ethnic native Fijian people. Until recently, these Fijians were relatively untouched by Western culture, but this is starting to change.

The authors of this study surveyed 523 Fijian high school girls. Interviews took place in 2007. They asked them various questions relating to, one the one hand, eating disorder symptoms, and on the other hand, their exposure to various forms of media.

They looked at both individual exposure - hours of TV watched, electronic entertainment in the home - and "indirect" or "social network" exposure, such as TV watched by the parents, and the amount of electronic entertainment their friends owned. On top of this they measured Westernization/"globalization", such as the amount of overseas travel by the girls or their parents.

So what happened? Basically, social network media exposure, urbanization, and Westernization correlated with ED symptoms, but when you controlled for those variables, personal media exposure didn't correlate. Here's the data; the column I've highlighted is the data where each variable is controlled for the others. The correlations are pretty small (0 is none, 1.0 would be perfect) but significant.


They conclude that:

Although consistent with the prevailing sociocultural model for the relation between media exposure and disordered eating... our finding, that indirect exposure to media content may be even more influential than direct exposure in this particular social context, is novel.

The idea that eating disorders are simply a product of a culture which values thinness as attractive has always seemed a bit shaky to me because people with anorexia frequently starve themselves far past the point of being attractive even by the unrealistic standards of magazines and movies.

In fact, if eating disorders were just an attempt to "look good", they wouldn't be nearly so dangerous as they are, because no matter how thin-obsessed our culture may be, no-one thinks this is attractive, or normal, or sane. But this, or worse, is what a lot of anorexics end up as.

On the other hand, eating disorders are associated with modern Western culture. There must be a link, but maybe it's more complicated than just "thin = good" causes anorexia. What if you also need the idea of "eating disorders"?

This was the argument put forward by Ethan Watters in Crazy Like Us (my review)... in his account of the rise of anorexia in Hong Kong. Essentially, he said, anorexia was vanishingly rare in Hong Kong until after the much-publicized death of a 14 year old girl, Charlene Chi-Ying, in the street. As he put it:

In trying to explain what happened to Charlene, local reporters often simply copied out of American diagnostic manuals. The mental-health experts quoted in the Hong Kong papers and magazines confidently reported that anorexia in Hong Kong was the same disorder that appeared in the United States and Europe...

As the general public and the region's mental-health professionals came to understand the American diagnosis of anorexia, the presentation of the illness in [Hong Kong psychiatrist] Lee's patient population appeared to transform into the more virulent American standard. Lee once saw two or three anorexic patients a year; by the end of the 1990s he was seeing that many new cases each month.

Now it's important not to see this as trivializing the condition or as a way of blaming the victim; "they're just following a trend!". You only have to look at someone with anorexia to see that there is nothing trivial about it. However, that doesn't mean it's not a social phenomenon.

It's a long way from the data in this study to Watters' conclusions, but maybe not an impossible leap. Part of Westernization, after all, is exposure to Western ideas about what is healthy eating and what's an eating disorder...

Becker, A., Fay, K., Agnew-Blais, J., Khan, A., Striegel-Moore, R., & Gilman, S. (2011). Social network media exposure and adolescent eating pathology in Fiji The British Journal of Psychiatry, 198 (1), 43-50 DOI: 10.1192/bjp.bp.110.078675

Did My Genes Make Me Do It?

A curious legal case from New York raises some interesting issues:

Court Rejects Judge’s Assertion of a Child Pornography Gene

According to the NYT:

A federal appeals court in Manhattan overturned a 6.5 year sentence in a child pornography case on Friday, saying the judge who imposed it improperly found that the defendant would return to viewing child pornography "because of an as-of-yet undiscovered gene."

The judge, Gary L. Sharpe, was quoted as saying, "It is a gene you were born with. And it’s not a gene you can get rid of," before he sentenced the defendant...

A three-judge panel of the United States Court of Appeals for the Second Circuit said in ruling on the defendant’s appeal, "It would be impermissible for the court to base its decision of recidivism on its unsupported theory of genetics."

Now I think we can all agree that judges shouldn't be handing down sentences on the basis of entirely hypothetical genes. However, things becomes a bit less clear if we imagine that the defendant did have a verified genetic abnormality. What then?

As chance would have it, this has just happened in Britain. On Thursday, former delivery driver Alan Potsbury, or as he was known to his colleagues, "Al The Paedo", was convicted of... well, the obvious.

Anyway, Potsbury has Klinefelter's Syndrome, aka XXY syndrome. Normally, women have two X chromosomes, while men have an X and a Y chromosome. People with Klinefelter's have three sex chromosomes, two X and a Y. They're male, but can experience various symptoms as a result of their extra X, although these are often pretty subtle, and the condition often goes undiagnosed.

Now I have no idea whether Potsbury's responsibility for his crime is lessened by the fact that he had a genetic disorder. And I certainly don't want to suggest that Klinefelter's "makes people into paedophiles", not least because in the vast majority of cases, it doesn't.

However, let's assume just for the sake of argument, that in this particular case he wouldn't have done what he did if it weren't for his extra chromosome. Or let's consider any hypothetical case where someone committed a crime "because of" a certain gene. Does this mean, as Judge Sharpe was suggesting, that it means their behaviour will be unlikely to change, and hence that heavy sentences are justified since rehabilitation won't work?

No. The fact that someone's past behaviour was associated with a gene doesn't tell us anything about how easy it would be to change it.

Being a Christian as opposed to a Muslim is, as far as we know, nothing to do with genetics; it's purely a matter of how you were brought up. Yet it's incredibly difficult to change. Many Christians and many Muslims spend their lives trying to make the heathens adopt the true faith and yet the number of successful conversions either way is tiny.

Hair colour, on the other hand, is entirely genetic. Yet it's easy to change. Just buy some bleach and some dye and you can have whatever hair you like. Or if you don't want hair at all, shave it off. You can't change your hair-colour genes, but you can make them irrelevant.

Back to Potsbury, even if we did accept that his paedophilia was in some way a result of his Klinefelter's, that wouldn't mean he was doomed to reoffend. Some behaviours are harder to change than others. Some are more genetic than others. But we can't assume that the one implies the other.

Pharma: Tamed But Still A Big Beast

Everyone knows that Big Pharma go around lying, concealing data and distorting science in an effort to sell their pills. Right?

Actually, not so much. They used to, but most of the really scandalous stuff happened many years ago. The late 80's through to about the turn of the century were the Golden Age of pharmaceutical company deception.

This is when we had drugs that don't work getting approved, with the trials showing that they don't work buried, and only now being uncovered. Data on drug-induced suicides seemingly fudged to make them seem less scary. Textbooks "written by" leading psychiatrists that were, allegedly, in fact ghost-written on behalf of drug companies. Ghost-writing programs with chuckle-some names like CASPPER. And so on.

But today, we have to give credit where credit's due: things have improved. Credit is due not to the companies but to the authorities who put a stop to this nonsense through rules. Mandatory clinical trial registration to ensure all the data is available and stop outcoming cherrypicking. Anti-ghostwriting rules (albeit they're not universal yet.) etc.

What's shocking is how long it took to get these simple rules in place. The next generation of scientists and doctors will look back on the 1990s with disbelief: they let them do what? But at least we woke up eventually.

Still, there's more left to do. At the moment, the main problem, as I see it, is that different jurisdictions have different rules, with the best ideas being confined to one particular place. For instance, the USA has by far the most sensible system of clinical trial registration and reporting. Europe needs to catch up (we are, but slowly.)

Yet the USA is also one of the only countries (with New Zealand) to permit direct-to-consumer (DTC) advertising for prescription drugs. To the rest of the world, this is really weird. We all have a right to free speech. But drug companies pushing drugs directly to patients just isn't a free speech issue, in Europe. Corporations don't speak, they advertise.

By encouraging self-diagnosis and self-treatment, DTC replaces medical judgement with marketing, undermining the doctor-patient relationship. The patient is meant to present his symptoms and the doctor is meant to make a diagnosis and prescribe a treatment. DTC encourages self-diagnosis and self-prescription: the fact that a doctor is still, technically, in charge and has to sign that prescription, means little in practice.

So there's a lot to be happy about, but there's also a lot still to do.