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.

ResearchBlogging.orgHarvey 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.

ResearchBlogging.orgGABBAI, 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...

ResearchBlogging.orgMetzger 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

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 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?

ResearchBlogging.orgRigoni 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

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.

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