Exercise and Depression: It's Complicated

Some ideas seem so nice, so inoffensive and so harmless, that it seems a shame to criticize them.

Take the idea that exercise is a useful treatment for depression. It's got something for everyone.

For doctors, it's attractive because it means they can recommend exercise - which is free, quick, and easy, at least for them - instead of spending the time and money on drugs or therapy. Governments like it for the same reason, and because it's another way of improving the nation's fitness. For people who don't much like psychiatry, exercise offers a lovely alternative to psych drugs - why take those nasty antidepressants if exercise will do just as well? And so on.

But this doesn't mean it's true. And a large observational study from Norway has just cast doubt on it: Physical activity and common mental disorders.

The authors took a large community sample of Norwegian people, the HUNT-2 study, which was done between 1995 and 1997. Over 90,000 people were invited to take part and full data were available from over 40,000.

What they found was that there was an association between taking part in physical exercise as a leisure activity, and lower self-reported symptoms of depression. It didn't matter whether the activity was intense or mild, and it didn't really matter how often you did it: so long as you did it, you got the benefit.

Crucially, however, the same was not true of physical exercise which was part of your job. That didn't help at all, and indeed the most strenuous jobs were associated with more depression (but less anxiety, strangely).

How does this fit with the very popular idea that exercise helps in depression? Well, many randomized trials have indeed shown exercise to be better than not-exercize for depression, but the problem is that these trials are never really placebo controlled. You can usually tell whether or not you're going jogging in the park every morning.

So the direct effects of exercise per se are hard to distinguish from the social and psychological meaning of "exercise". Knowing that you're starting a program of exercise could make you feel better: you're taking positive action to improve your life, you're not helpless in the face of your problems. By contrast, doing heavy work as part of your job, while physiologically beneficial, is unlikely to be so much fun.

This doesn't mean that telling people to get more exercise isn't a good idea, but if the meaning of exercise is more important than the physiology, that has some big implications for how it ought to be used.

It's good news for people who just can't take part in strenuous physical exercise because of physical illness or disability, something which is quite common in mental health. It suggests that these people could still get the benefits attributed to exercise even if they did less demanding forms of meaningful activity.

But it's bad news for doctors tempted to default to "get out and go jogging" whenever they see a potentially depressed person. Because if it's the meaning of exercise that counts, and you recommend exercise in a way which sounds like you're dismissing their problems, the meaning will be anything but helpful.

In clinical trials of exercise, the exercise program has, almost by definition, a positive value: it's the whole point of the trial. And the participants just wouldn't have volunteered for the trial if they didn't, on some level, think it would make them feel better.

But not everyone thinks that way. If you go to your doctor looking to get medication, or psychotherapy, or something like that, and you're told that all you need to do is go and get more exercise, it would be easy to see that as a brush-off, especially if it's done unsympathetically. The point is, if exercise doesn't feel like a positive step, it probably won't be one.

Harvey SB, Hotopf M, Overland S, & Mykletun A (2010). Physical activity and common mental disorders. The British journal of psychiatry : the journal of mental science, 197, 357-64 PMID: 21037212

The Town That Went Mad

Pont St. Esprit is a small town in southern France. In 1951 it became famous as the site of one of the most mysterious medical outbreaks of modern times.

As Dr's Gabbai, Lisbonne and Pourquier wrote to the British Medical Journal, 15 days after the "incident":

The first symptoms appeared after a latent period of 6 to 48 hours. In this first phase, the symptoms were generalized, and consisted in a depressive state with anguish and slight agitation.

After some hours the symptoms became more clearly defined, and most of the patients presented with digestive disturbances... Disturbances of the autonomic nervous system accompanied the digestive disorders-gusts of warmth, followed by the impression of "cold waves", with intense sweating crises. We also noted frequent excessive salivation.

The patients were pale and often showed a regular bradycardia (40 to 50 beats a minute), with weakness of the pulse. The heart sounds were rather muffled; the extremities were cold... Thereafter a constant symptom appeared - insomnia lasting several days... A state of giddiness persisted, accompanied by abundant sweating and a disagreeable odour. The special odour struck the patient and his attendants.

In most patients, these symptoms, including the total insomnia, persisted for several days. In some of the patients, these symptoms progressed to full-blown psychosis:

Logorrhoea [speaking a lot], psychomotor agitation, and absolute insomnia always presaged the appearance of mental disorders. Towards evening visual hallucinations appeared, recalling those of alcoholism. The particular themes were visions of animals and of flames. All these visions were fleeting and variable.

In many of the patients they were followed by dreamy delirium. The delirium seemed to be systematized, with animal hallucinations and self-accusation, and it was sometimes mystical or macabre. In some cases terrifying visions were followed by fugues, and two patients even threw themselves out of windows... Every attempt at restraint increased the agitation.

In severe cases muscular spasms appeared, recalling those of tetanus, but seeming to be less sustained and less painful... The duration of these periods of delirium was very varied. They lasted several hours in some patients, in others they still persist.

In total, about 150 people suffered some symptoms. About 25 severe cases developed the "delirium". 4 people died "in muscular spasm and in a state of cardiovascular collapse"; three of these were old and in poor health, but one was a healthy 25-year-old man.

At first, the cause was assumed to be ergotism - poisoning caused by chemicals produced by a fungus which can infect grain crops. Contaminated bread was, therefore, thought to be responsible. Ergotism produces symptoms similar to those reported at Pont St. Esprit, including hallucinations, because some of the toxins are chemically related to LSD.

However, there have been other theories. Some (including Albert Hofmann, the inventor of LSD) attribute the poisoning to pesticides containing mercury, or to the flour bleaching agent nitrogen trichloride.

More recently, journalist Hank Albarelli claimed that it was in fact a CIA experiment to test out the effects of LSD as a chemical weapon, though this is disputed. What really happened is, in other words, still a mystery.

Link: The Crazies (2010) is a movie about a remarkably similar outbreak of mass insanity in a small town.

GABBAI, LISBONNE, & POURQUIER (1951). Ergot poisoning at Pont St. Esprit. British medical journal, 2 (4732), 650-1 PMID: 14869677

Massive Magnets Reveal More Sex In the Brain

"Is that a 7 Tesla magnet in your pocket, or are you just pleased to see me?"

German neuroscientists Metzger et al report on the results of a study using the latest, ultra-high-field Magnetic Resonance Imaging to measure brain activity in response to sexually arousing stimuli.

Most fMRI studies are done using MRI scanners with a field strength of either 1.5 Tesla or, most commonly nowadays, 3.0 Tesla. However, a few especially forward-thinking, by which I mean wealthy, research centres have started investing in 7 Tesla scanners.

Stronger magnetic fields mean that the scanner is able to pick up smaller differences in brain activation, with a better temporal and spatial resolution, although it's not all good news because some of the artefacts that can spoil MRI images also get worse with higher fields. 7 Tesla magnets are also so incredibly powerful that you literally have to tread carefully around them: move too fast through the field, and you can suffer dizziness, vertigo, and visual disturbances...

Anyway, Metzger et al's paper is one of the first 7 Tesla fMRI studies and it's pretty cool. They managed to achieve a spatial resolution of 1.7 x 1.7 x 3 mm , or about three times better than most studies, and a temporal resolution of 1 second, twice or three times better than usual.

They showed heterosexual male subjects a range of pictures, some of them pornographic, others "emotional" but non-sexual. They found that anticipating seeing a picture, as opposed to than actually viewing one, activated different areas of the cortex and also of the thalamus (see image above). Sexual arousal was also correlated with activity in a third thalamic area.

This fits with previous work, so it's not too surprising, but it shows the power of 7 Tesla fMRI: as you can see, the thalamus is a small structure, and conventional fMRI struggles to localize activity to particular subdivisions of it. But we know that the thalamus is a hotbed of activity, because almost all the information that goes to and from the rest of brain passes through it. Until now, fMRI researchers have tended to treat the thalamus as a no-man's land but with any luck, 7 Tesla scanners will start to change that. For those who can afford them...

Metzger CD, Eckert U, Steiner J, Sartorius A, Buchmann JE, Stadler J, Tempelmann C, Speck O, Bogerts B, Abler B, & Walter M (2010). High field FMRI reveals thalamocortical integration of segregated cognitive and emotional processing in mediodorsal and intralaminar thalamic nuclei. Frontiers in neuroanatomy, 4 PMID: 21088699

The 9 Circles of Scientific Hell

Dante's Inferno: a classic of world literature, the definitive statement of the mediaeval Christian world-view, the first major work in the Italian language, and the basis for a violent videogame. The poem offers a tour through the nine increasingly horrible levels of Hell, in which sinners are tormented forever.

But Dante lived before the era of modern science. I thought I'd update his scheme to explain what happens to those guilty of various scientific sins, ranging from the commonplace to the shocking.

Bear in mind that Dante's Hell had a place for everyone, and it was only Christ's intervention that saved anyone from it; even "good" people went to Hell because everyone sins. But they are still sins. Likewise, very few scientists (and I'm certainly not one of them) would be able to avoid being condemned to some level of this Inferno... but, that's no excuse.

First Circle: Limbo

"The uppermost circle is not a place of punishment, so much as regret. Those who have committed no scientific sins as such, but who turned a blind eye to it, and encouraged it by their awarding of grants and publications, spend eternity on top of this barren mountain, watching the carnage below and reflecting on how they are partially responsible..."

Second Circle: Overselling
"This circle is reserved for those who exaggerated the importantance of their work in order to get grants or write better papers. Sinners are trapped in a huge pit, neck-deep in horrible sludge. Each sinner is provided with the single rung of a ladder, labelled 'The Way Out - Scientists Crack Problem of Second Circle of Hell"

Third Circle: Post-Hoc Storytelling
"Sinners condemned to this circle must constantly dodge the attacks of demons armed with bows and arrows, firing more or less at random. Every time someone is hit in some part of their body, the demon proceeds to explain at enormous length how they were aiming for that exact spot all along."

Fourth Circle: P-Value Fishing

"Those who tried every statistical test in the book until they got a p value less than 0.05 find themselves here, an enormous lake of murky water. Sinners sit on boats and must fish for their food. Fortunately, they have a huge selection of different fishing rods and nets (brandnames include Bayes, Student, Spearman and many more). Unfortunately, only one in 20 fish are edible, so they are constantly hungry."

Fifth Circle: Creative Use of Outliers
"Those who 'cleaned up' their results by excluding inconvenient data-points are condemned here. Demons pluck out their hairs one by one, every time explaining that they are better off without that hair because there was something wrong with it."

Sixth Circle: Plagiarism

"This circle is entirely empty because as soon as a sinner arrives, a winged demon carries them to another circle and forces them to suffer the punishment meted out to the people there. After their 3 year "post" is up, they are carried to another circle, and so on..."

Seventh Circle: Non-Publication of Data
"Here sinners are chained to burning chairs in front of desks covered with broken typewriters. Only if they can write an article describing their predicament, will they be set free. Each desk has a file-drawer stuffed full of these, but the drawers are locked.

Eighth Circle: Partial Publication of Data
"At any one time exactly half of the sinners here are chased around by demons prodding them with spears. The demons choose who to chase at random after ensuring that the groups are matched for age, gender, height and weight. Howling desert winds blow a constant torrent of articles announcing the success of a new program to enhance participation in physical exercise - but with no mention of the side effects."

Ninth Circle: Inventing Data
"Here Satan himself lies trapped forever in a block of solid ice alongside the worst sinners of all. Frozen in front of their eyes is a paper explaining very convincingly that water cannot freeze in the environmental conditions of this part of Hell. Unfortunately, the data were made up."

Links: This has been kindly translated into Russian here and into Portuguese here.

Autism Gives You Biblical Superpowers

We've all heard about autistic "savants" with amazing mathematical, memory or artistic abilities. But could autism give you the power to kill 1,000 men armed only with a donkey bone?

Samson was the original Chuck Norris. Granted mighty strength by God so long as he didn't cut his hair or shave, Samson's first act of heroism was ripping a lion to shreds with his bare hands. Then he moved onto people. According to the Book of Judges:

"And Samson said, With the jawbone of an ass, heaps upon heaps, with the jaw of an ass have I slain a thousand men." - Judges 15:16

Samson later bested even this achievement. Finding himself trapped in a building with over 3,000 enemies who were about to sacrifice him to their pagan god, Samson single-handedly demolished the building by smashing some pillars, killing everyone including himself.

What does this have to do with autism? Well, according to Indian neurologists Mathew and Pandian in a new paper, it shows that Samson had it. No, really.

One of the earliest incidents recorded from Samson's adult life is the journey to Timnath with his parents where he tears a lion with his bare hands. On his return, he finds a swarm of bees and honey in the carcass of the lion, which he eats, and offers his parents (Judges 14:8-9). Abnormal eating is one of the atypical behaviors noted among children with autism [ref].

Throughout Samson's life, it is seen that he performed extraordinary physical feats... It is possible that Samson was able to perform these feats as he may have been insensitive to pain, which is occasionally seen among autistics [ref]. A study of hospitalized individuals carried out in Sweden had reached the conclusion that individuals with autism or autism spectrum disorders are prone to acts of violence [ref].

Hmm. Fair to say this falls into the "speculative" category. They also diagnose other Biblical characters with various disorders ranging from strokes to acromegaly but Samson's autism is certainly the most "interesting" of the bunch.

Link: This study also blogged at Autism Jabberwocky, an extremely good blog I only found out about yesterday. I've subscribed, you should too.

Mathew SK, & Pandian JD (2010). Newer insights to the neurological diseases among biblical characters of old testament. Annals of Indian Academy of Neurology, 13 (3), 164-166 PMID: 21085524

I Wish I Hadn't Said That

In the past two weeks Britain has seen two men attempt to travel back in time.

First there was Steven Fry, who gave an interview to a gay magazine in which he said:

"I feel sorry for straight men. The only reason women will have sex with them is that sex is the price they are willing to pay for a relationship with a man... Of course, a lot of women will deny this and say, 'Oh no, but I love sex, I love it!' But do they go around having it the way that gay men do?"

amongst other variations on that theme. People got annoyed, although it's not exactly a new idea, and as soon as it all kicked off, Fry twittered

So some fucking paper misquotes a humorous interview I gave, which itself misquoted me and now I'm the Antichrist. I give up. Bye bye.

Fortunately for his 1.9 million followers he came back to Twitter a week later and blogged in his defence.

Now, as noted by Private Eye magazine, Fry never offered any support for his Tweet that he'd been doubly misquoted. Rather he claimed that, although he had indeed said the words in question, he didn't believe them.

the keenest disappointment...is the idea that there are people out there who actually swallow the notion that I am so stupid as to believe that women don’t enjoy sex. That I am dense, dotty and suicidally deluded enough to make a public declaration of such a crazed belief... I entertain no such notion... I can truly report that I [am] quite assured of the fact that women do indeed enjoy sex.

In fact...

I chatted to [the interviewer], we had a pleasant, relaxed and easy conversation. That’s the word, a conversation... At some point we chatted about gay sexuality – well, you would wouldn’t you, for a gay magazine? – and as part of that conversation I repeated the old canard about how men, unlike women, were cursed with their uniquely pressing and annoying libidos.

...I do not believe it as some kind of eternal gender truth, I was simply taking a thought for a walk, I was “playing gracefully with ideas” to repeat Oscar’s great phrase, or at least attempting to do so.

But what does this mean, exactly? Why would he repeat that old canard, if he didn't think there was at least something in it? It's not like the statement is so obviously crazy that that goes without saying that he doesn't believe it: hence why it's an old canard.

It's true that the nuances of speech get flattened out in print. But when he said it, he evidently didn't make it clear that he thought the idea was "stupid ... dense, dotty and suicidally deluded... crazed" - as he later claimed.

Then it happened again. Lord Young (who ironically is 78), a government advisor, said that Britain's economy was strong, that many British people had profited from the "so-called recession" due to low interest rates, and that current government spending cuts were no big deal in the grand scheme of things.

People got annoyed, and he quickly retracted his words saying that his comments were "insensitive and inaccurate", though he still had to resign in the end. Why he'd suddenly revised his analysis of the economic situation, or what was wrong with his earlier statements, he didn't bother to explain...

Fry and Young obviously misjudged how socially acceptable their words would be. They made a faux-pas. We've all done it: you say something and then realize, to your horror, that everyone's jaw just dropped a little. You wish you could un-say that.

But the point is you can't.

Unless, it appears, you're in the media. Fry and Young tried to do just that. But why on earth is that acceptable? Are we so touchy that we'd rather have someone insult our intelligence by trying to convince us that they don't believe something we all heard them say, than have someone believe something we don't agree with?

Autism Following Viral Infection

I just discovered a remarkable case report from 1986 about a Swedish girl who developed all of the major symptoms of autism at the age of 14, following a severe brain infection.

Autism generally becomes noticeable in early childhood. There are plenty of cases in which autistic people don't get diagnosed until much later in life, but the symptoms invariably turn out to go back a long way. Older children, teenagers and adults don't just go autistic overnight. Except in this case, if you believe it.

The patient, "A", was born to healthy parents and developed perfectly normally, though she was described as somewhat shy. Just before her 14th birthday, she became ill with what at first seemed to be nothing more than a fever and mild headache.

However, a week later, she developed a severe headache and had a seizure. After being rushed to hospital, she was unconscious for a few hours and then awoke, tired but fairly lucid. However, her recovery was only temporary:

On day 6 there was a severe aggravation of symptoms and she became confused, part of the time verbally and physically aggressive, at other times tired and apathetic. She kept complaining of the headache.

These complaints would be perhaps the last time she would use language appropriately for the purposes of communication.

From day 10 she became autistic, reacting not to people but to pain. She would avert her gaze when approached. She was still febrile.... From day 12 to day 19 she was sometimes comatose and sometimes awake, "looking through people with her empty staring gaze," in the words of her mother (day 18) according to the medical records. She reacted with a pained facial expression even to rather slight noises (day 19).

She then began to recover some of her faculties, but only some:

On day 33: "lying in bed, accepting food orally for the first time, avoiding gaze contact but looking around her when she is not observed. Obviously sensitive to smells and taste. Empty, autistic like gaze."

Day 40: "still quite 'fenced-off' but manipulated small objects with great skill. She echoed what nurses and mother said to her. Wrote simple words. Laughed in odd situations and raged with anger without obvious cause."

Day 45: "autistic, not responding to social interactions, but echoing long phrases and sometimes chatting away in a cocktail party fashion."

Autism is defined by a 'triad' of symptoms: difficulties with social interaction; difficulties with communication; and insistence on sameness, or repetitive interests and behaviours.

Of these, it's perhaps not surprising that brain damage could cause the first two. We socialize and communicate with our brains, so of course damage could cause difficulties. What makes this case remarkable is that the patient also developed the third element of triad, repetitive behaviours.

From day 70 bilateral flapping stereotypies of the hands were observed. She had also had bouts when she would laugh intensively and jump up and down, surreptitiously... She would carry with her small plastic objects and protest if these were removed. She would scream for hours if daily routines were changed in any way.

10 years later, when the case report was written, her condition had changed only slightly.

At the age of 22 years she moved to a small group home for mentally retarded persons... The most severe problem nowadays is her insistence on sameness. She absolutely refuses to go to the bathroom and screams for a quarter of an hour every morning before she finally accepts... Then she refuses to leave the bathroom and screams for another quarter of an hour. This pattern is followed every day without fail and intrudes on almost all activities of daily life.

What happened to her? She suffered from herpes simplex encephalitis, a viral infection of the brain. X-rays at the age of 22 showed serious damage to the temporal lobes of the brain, extending to parts of the parietal lobes. (No pictures were provided, however.)

Can her case really be described as a "typical autistic syndrome"? Certainly, there are striking similarities, from the obsessive routines, to the echolalia (repeating what other people say), to the avoidance of eye contact, all classic symptoms of severe autism.

Of course it's always possible that the case report was written to accentuate these similarities, in order to make a nice publication. There have been a handful of other similar cases, though the same caveats apply. Still, if we do accept that these patients are indeed autistic, the implications for understanding the neurobiology of "normal" autism are obvious.

Link: "The Man With Half A Brain" who developed a rather different pattern of symptoms after herpes encephalitis.

Gillberg, C. (1986). Brief report: Onset at age 14 of a typical autistic syndrome. A case report of a girl with herpes simplex encephalitis Journal of Autism and Developmental Disorders, 16 (3), 369-375 DOI: 10.1007/BF01531665

England Rules the (Brain) Waves

Yes, England has finally won something. After a poor showing in the 2010 World Cup, the Eurovision Song Contest, and the global economic crisis, we're officially #1 in neuroscience. Which clearly is the most important measure of a nation's success.

According to data collated by ScienceWatch.com and released recently, each English neuroscience paper from the past 10 years has been cited, on average, 24.53 times, making us the most cited country in the world relative to the total number of papers published (source here). We're second only to the USA in terms of overall citations.

(In this table, "Rank" refers to total number of citations).

Why is this? I suspect it owes a lot to the fact that England has produced many of the technical papers which everyone refers to (although few people have ever read). Take the paper Dynamic Causal Modelling by Karl Friston et al from London. It's been cited 649 times since 2003, because it's the standard reference for the increasingly popular fMRI technique of the same name.

Or take Ashburner and Friston's Voxel-Based Morphometry—The Methods, cited over 2000 times in the past 10 years, which introduced a method for measuring the size of different brain regions. Or take...most of Karl Friston's papers, actually. He's the single biggest contributor to the way in which modern neuroimaging is done.

The Limits of Neuroplasticity

Neuroplasticity is in.


Books tell us about The Brain That Changes Itself or advise us on how to Train Your Mind, Change Your Brain.

Now there's no doubt that the brain is plastic, able to rewire itself in response to damage or training, and that it's more so than was generally believed, say, 20 years ago. It's clearly an important and interesting field, but a little caution is warranted. Neuroplasticity can't fix everything.

If the brain were infinitely plastic, brain damage would be no big deal. You'd get over it pretty quickly, so long as some of your brain was intact and able to rewire itself to compensate. Unfortunately, that's rarely what happens. Well, unfortunately unless you're a neurologist; they'd be out of a job if it were otherwise...

Swiss neurologists Bindschaedler et al have provided a nice example of the limits of neuroplasticity in a new paper: Growing up with bilateral hippocampal atrophy: From childhood to teenage.

Patient "VJ" was diagnosed with bilateral atrophy of the hippocampus at age 8. The damage almost certainly dated back a few hours after his birth which followed a normal pregnancy and delivery:

VJ had convulsions, then an episode of apnoea, which required treatment by phenobarbital and mask-assisted ventilation respectively. Hypertonia and hyperreactivity were followed by a period of hypotonia and somnolence during the 8 following days.

He seemed to make a full recovery, and never suffered another seizure. However, as he grew up, his parents noticed that he was forgetful and had difficulty concentrating. At the age of 8, he was referred for an MRI scan, which revealed severe atrophy of the hippocampus, and the related structures the fornix and the mammilary bodies, on both sides of the brain.

The diagnosis was hypoxic-ischaemic encephalopathy: a lack of oxygen. For some reason, the hippocampus is especially vulnerable to this; selective hippocampal damage is also common after carbon monoxide poisoning.

VJ is a bit like a childhood version of the famous adult patient HM, however, there are important differences. Apart from occurring much earlier, obviously, VJ's damage was less severe. Unlike HM he did not lack the nearby entorhinal cortex or parahippocampal cortex.

The authors followed him up to age 17, and did lots of tests of his cognitive function. The pattern that emerged is that VJ showed a selective impairment of memory for personal events (episodic memory). He learned to read normally, and he scored well on tests of general knowledge. So he had preserved semantic memory, memory for facts. His IQ was normal.

Even his episodic memory impairment was selective, however. He was severely impaired on tests of memory recall, i.e. "What did you do yesterday?". But on tests of recognition - "Have you ever seen this picture before?" - he did perfectly well.

This fits with lots of previous studies showing that the hippocampus is required for recall while the nearby cortex is more important for recognition. When asked to describe events in his past, he was essentially unable to do so, unless he was provided with "clues" or "reminders" to trigger recognition.

So VJ's brain couldn't rewire itself to compensate for the lack of a hippocampus, despite the fact that the damage occurred at birth, and the brain is considered to be at its most plastic during childhood.

This is not all that surprising really. The hippocampus is a unique region, containing specialized circuitry which is just not found anywhere else in the brain. Most of the evidence for large-scale neuroplasticity concerns the cerebral cortex. When part of the cortex is damaged, other cortical areas can sometimes compensate for the loss: but the cortex can't turn itself a substitute hippocampus.

Bindschaedler, C., Peter-Favre, C., Maeder, P., Hirsbrunner, T., & Clarke, S. (2010). Growing up with bilateral hippocampal atrophy: From childhood to teenage Cortex DOI: 10.1016/j.cortex.2010.09.005

The Tree of Science

How do you know whether a scientific idea is a good one or not?


The only sure way is to study it in detail and know all the technical ins and outs. But good ideas and bad ideas behave differently over time, and this can provide clues as to which ones are solid; useful if you're a non-expert trying to evaluate a field, or a junior researcher looking for a career.

Today's ideas are the basis for tomorrow's experiments. A good idea will lead to experiments which provide interesting results, generating new ideas, which will lead to more experiments, and so on.

Before long, it will be taken as granted that it's true, because so many successful studies assumed it was. The mark of a really good idea is not that it's always being tested and found to be true; it's that it's an unstated assumption of studies which could only work if it were true. Good ideas grow onwards and upwards, in an expanding tree, with each exciting new discovery becoming the boring background of the next generation.

Astronomers don't go around testing whether light travels at a finite speed as opposed to an infinite one; rather, if it were infinite, their whole set-up would fail.

Bad ideas generate experiments too, but they don't work out. The assumptions are wrong. You try to explain why something happens, and you find that it doesn't happen at all. Or you come up with an "explanation", but next time, someone comes along and finds evidence suggesting the "true" explanation is the exact opposite.

Unfortunately, some bad ideas stick around, for political or historical reasons or just because people are lazy. What tends to happen is that these ideas are, ironically, more "productive" than good ideas: they are always giving rise to new hypotheses. It's just that these lines of research peter out eventually, meaning that new ones have to take their place.

As an example of a bad idea, take the theory that "vaccines cause autism". This hypothesis is, in itself, impossible to test: it's too vague. Which vaccines? How do they cause autism? What kind of autism? In which people? How often?

The basic idea that some vaccines, somewhere, somehow, cause some autism, has been very productive. It's given rise to a great many, testable, ideas. But every one which has been tested has proven false.

First there was the idea that the MMR vaccine causes autism, linked to a "leaky gut" or "autistic enterocolitis". It doesn't, and it's not linked to that. Then along came the idea that actually it's mercury preservatives in vaccines that cause autism. It doesn't. No problem - maybe it's aluminium? Or maybe it's just the Hep B vaccine? And so on.

At every turn, it's back to square one after a few years, and a new idea is proposed. "We know this is true; now we just need to work out why and how...". Except that turns out to be tricky. Hmm. Maybe, if you keep ending up back at square one, you ought to find a new square to start from.

Genes To Brains To Minds To... Murder?

A group of Italian psychiatrists claim to explain How Neuroscience and Behavioral Genetics Improve Psychiatric Assessment: Report on a Violent Murder Case.

The paper presents the horrific case of a 24 year old woman from Switzerland who smothered her newborn son to death immediately after giving birth in her boyfriend's apartment. After her arrest, she claimed to have no memory of the event. She had a history of multiple drug abuse, including heroin, from the age of 13.

Forensic psychiatrists were asked to assess her case and try to answer the question of whether "there was substantial evidence that the defendant had an irresistible impulse to commit the crime." The paper doesn't discuss the outcome of the trial, but the authors say that in their opinion she exhibits a pattern of "pathologically impulsivity, antisocial tendencies, lack of planning...causally linked to the crime, thus providing the basis for an insanity defense."

But that's not all. In the paper, the authors bring neuroscience and genetics into the case in an attempt to provide

a more “objective description” of the defendant’s mental disease by providing evidence that the disease has “hard” biological bases. This is particularly important given that psychiatric symptoms may be easily faked as they are mostly based on the defendant’s verbal report.

So they scanned her brain, and did DNA tests for 5 genes which have been previously linked to mental illness, impulsivity, or violent behaviour. What happened? Apparently her brain has "reduced gray matter volume in the left prefrontal cortex" - but that was compared to just 6 healthy control women. You really can't do this kind of analysis on a single subject, anyway.

As for her genes, well, she had genes. On the famous and much-debated 5HTTLPR polymorphism, for example, her genotype was long/short; while it's true that short is generally considered the "bad" genotype, something like 40% of white people, and an even higher proportion of East Asians, carry it. The situation was similar for the other four genes (STin2 (SCL6A4), rs4680 (COMT), MAOA-uVNTR, DRD4-2/11, for gene geeks).

I've previously posted about cases in which a well-defined disorder of the brain led to criminal behaviour. There was the man who became obsessed with child pornography following surgical removal of a tumour in his right temporal lobe. There are the people who show "sociopathic" behaviour following fronto-temporal degeneration.

However this woman's brain was basically "normal" at least as far as a basic MRI scan could determine. All the pieces were there. Her genotypes was also normal in that lots of normal people carry the same genes; it's not (as far as we know) that she has a rare genetic mutation like Brunner syndrome in which an important gene is entirely missing. So I don't think neurobiology has much to add to this sad story.

*

We're willing to excuse perpetrators when there's a straightforward "biological cause" for their criminal behaviour: it's not their fault, they're ill. In all other cases, we assign blame: biology is a valid excuse, but nothing else is.

There seems to be a basic difference between the way in which we think about "biological" as opposed to "environmental" causes of behaviour. This is related, I think, to the Seductive Allure of Neuroscience Explanations and our fascination with brain scans that "prove that something is in the brain". But when you start to think about it, it becomes less and less clear that this distinction works.

A person's family, social and economic background is the strongest known predictor of criminality. Guys from stable, affluent families rarely mug people; some men from poor, single-parent backgrounds do. But muggers don't choose to be born into that life any more than the child-porn addict chose to have brain cancer.

Indeed, the mugger's situation is a more direct cause of his behaviour than a brain tumour. It's not hard to see how a mugger becomes, specifically, a mugger: because they've grown up with role-models who do that; because their friends do it or at least condone it; because it's the easiest way for them to make money.

But it's less obvious how brain damage by itself could cause someone to seek child porn. There's no child porn nucleus in the brain. Presumably, what it does is to remove the person's capacity for self-control, so they can't stop themselves from doing it.

This fits with the fact that people who show criminal behaviour after brain lesions often start to eat and have (non-criminal) sex uncontrollably as well. But that raises the question of why they want to do it in the first place. Were they, in some sense, a pedophile all along? If so, can we blame them for that?

Rigoni D, Pellegrini S, Mariotti V, Cozza A, Mechelli A, Ferrara SD, Pietrini P, & Sartori G (2010). How neuroscience and behavioral genetics improve psychiatric assessment: report on a violent murder case. Frontiers in behavioral neuroscience, 4 PMID: 21031162

Bionic Eye Lets Blind See

No, really. Read all about it in a remarkable (if awkwardly named) new paper from German team Zrenner et al, Subretinal electronic chips allow blind patients to read letters and combine them to words.

The device acts as an artificial retina. It's a tiny 3 x 3.1 mm panel (about ■ that size) containing an array of 1,500 individual light-sensitive microphotodiodes (38 x 40).

Each sensor converts incoming light into an electrical current - the brighter, the stronger - and outputs it through a tiny electrode. These currents stimulate nerve cells in the retina, in the same way that the eye's own photoreceptor cells normally do.

Of course, for this to be useful, you need to have a retina with functioning nerve cells, an intact optic nerve to convey the information to the brain, and working visual brain areas. This means that the technology is only useful for certain kinds of blindness caused by damage to photoreceptor cells. However, such blindness is quite common; retinitis pigmentosa, a genetic disorder, is one such.

Did it work? Yes. The chip was implanted in three patients, all of whom had been born sighted but had become almost completely blind due to retinal degeneration. In all three patients, the chip restored some degree of vision.

However, the benefits were most dramatic in Patient 2. He gained the ability to recognise everyday objects like spoons, bananas, and apples; he could read a clock to tell the time; and he could read letters (albeit special, extremely large letters about 8 cm high). "YouTube or it didn't happen?" Here you go...

The subretinal implant is not the only bionic eye idea in town, however. There have been various attempts to provide the blind with surrogate vision, like the camera attached to the tongue. Other researchers have been working on using - effectively - an external ("epiretinal") camera, which then interfaces with the optic nerve to transmit information to the brain.

However, Zrenner et al say that their method is better. Well, they would, but they make a good case. With an epiretinal device, you need to process the information into a form which the brain can recognise, but even after doing so, it takes some "getting used to".

Patients in this study were immediately able to make sense of what they saw, because the implant works much like a healthy retina. Also, epiretinal approaches have so far only provided up to 60 pixels.

Still, the chip has limitations. The image is greyscale, much less detailed than normal vision (38x40 pixels - an iPhone has 960x640), and being tiny, it only covers a small fraction of the normal visual field - although given that all detailed vision takes place in a tiny part of the retina called the fovea, this is not as much of a limitation as it first appears so long as you implant the chip where the fovea used to be; notably, this is what they did for Patient 2.

The chip also requires an external power supply, meaning that patients need to carry a battery pack around, and of course, they have a fairly hefty wire coming out of the side of their head. But really, that's not that important because this is a frickin' bionic eye, and it actually works.

Eberhart Zrenner, et al. (2010). Subretinal electronic chips allow blind patients to read letters and combine them to words Proc. R. Soc. B : 10.1098/rspb.2010.1747

Blue Morning

Recently, I wrote about diurnal mood variation: the way in which depression often waxes and wanes over the course of the day. Mornings are generally the worst.

A related phenomenon is late insomnia, or "early morning waking".

But this phrase is rather an understatement. Everyone's woken up early. Maybe you had a flight to catch. Or you were drunk and threw up. Or you just needed a pee. That's early morning waking, but not the depressive kind. When you're depressed, the waking up is the least of your problems.

Suddenly, you are awake, more awake than you've ever been. And you know something terrible has happened, or is about to happen, or that you've done something terribly wrong. It feels like a Eureka moment. You can be a level-headed person, not given to jumping to conclusions, but you will be convinced of this.

In a panic attack, you think you're going to die. Your heart is beating too fast, your breathing's too deep: your body is exploding, you can feel it too closely. With this, With this, you think you should die or even, in some sense, already have. It feels cold: you can no longer feel the warmth of your own body.

The moment passes; the terrible truth that you were so certain of five minutes ago becomes a little doubtful. Maybe it's not quite so bad. At this point, the wakefulness goes too, and you become, well, as tired as you ought to be at 3 am. You try to go back to sleep. If you're lucky, you succeed. If not, you lie awake until morning in a state of miserable contemplation.

While it's happening, you think that you're going to feel this way forever; bizarrely, you think you always have felt this way. In fact, this is the darkest hour.

*

Why does this happen? There has been almost no research on early morning waking. Presumably, because it's so hard to study. To observe it, you would have to get your depressed patients to spend all night in your brain scanner (or, if you prefer, on your analyst's couch), and even then, it doesn't happen every night.

But here's my theory: the key is the biology of sleep. There are many stages of sleep; at a very rough approximation there's dreaming REM, and dreamless slow-wave. Now, REM sleep tends to happen during the second half of the night - the early morning.

During REM sleep, the brain is, in many respects, awake. This is presumably what allows us to have concious dreams. Whereas in slow wave sleep, the brain really is offline; slow waves are also seen in the brain of people in comas, or under deep anaesthesia.

When we're awake, the brain is awash with modulatory neurotransmitters, such as serotonin, norepinephrine, and acetylcholine. During REM, acetylcholine is present, while in slow-wave sleep it's not; indeed acetylcholine may well be what stops slow waves and "wakes up" the cortex.

But unlike during waking, serotonin and norepinephrine neurons are entirely inactive during REM sleep - and only during REM sleep. This fact is surprisingly little-known, but it seems to me that it explains an awful lot.

For one thing, it explains why drugs which increase serotonin levels, such as SSRI antidepressants, inhibit REM sleep. Indeed, high doses of MAOi antidepressants prevent REM entirely (without any noticeable ill-effects, suggesting REM is dispensable). SSRIs only partially suppress it.

Ironically, SSRIs can make dreams more vivid and colourful. I've been told by sleep scientists that this is because they delay the onset of REM so the dreams are "shifted" later into the night making you more likely to remember them when you wake up. But there could be more to it than that.

The fact that REM is a serotonin-free zone also explains wet dreams. Serotonin is well known to suppresses ejaculation; that's why SSRIs delay orgasm, one of their least popular side effects, although it's useful to treat premature ejaculation: every cloud has a silver lining.

So, having said all that: could this also explain the terror of early-morning waking? Suppose that, for whatever reason, you woke up during REM sleep, but your serotonin cells didn't wake up quick enough, leaving you awake, but with no serotonin (a situation which never normally occurs, remember). How would that feel?

Using a technique called acute tryptophan depletion (ATD), you can lower someone's serotonin levels. In most people, this doesn't do very much, but in some people with a history of depression, it causes them to relapse. Here's what happened to one patient after ATD:

[her] previous episodes of clinical depression were associated with the loss of important friendships had, while depressed, been preoccupied with fears that she would never be able to sustain a relationship. She had not had such fears since then.

She had been fully recovered and had not taken any medication for over a year. About 2 h after drinking the tryptophan-free mixture she experienced a sudden onset of sadness, despair, and uncontrollable crying. She feared that a current important relationship would end.

We don't know why tryptophan depletion does this to some people, or why it doesn't affect everyone the same way, and it's pure speculation that early morning waking has anything to do with this. But having said that, the pieces do seem to fit.