The Prefrontal Cortex Is Holistic

The question of whether the brain is "modular" - whether different parts do different things - has been a neuroscientific talking point since the days of the phrenologists.

They were the guys who believed that, not only were there modules, but that you could tell how big they were by measuring the shape of someone's skull, and so learn about their personality.

Phrenology made modules unfashionable for a while, but today they're back, and most of fMRI consists in trying to find areas of the brain that do different stuff, but in a new paper Wilson et al argue against taking modularism too far: Functional localization within the prefrontal cortex: missing the forest for the trees?

Their focus is the prefrontal cortex (PFC), a large chunk of the front of the brain which is bigger in humans than in any other species. The PFC is routinely subdivided into segments, each with (presumably) a different function. So we have the "emotional" vmPFC, the "memory" dlPFC, the "pleasure" OFC, etc.

Wilson et al don't dispute that there are some variations in function between different bits of the PFC, but they say that in all the excitement over localization, we may have overlooked the role of the PFC as a whole.

They discuss evidence from monkeys with PFC damage (or lesions which disconnect it from the rest of the brain). Damage to the entire PFC, they say, leaves monkeys completely unable to perform tasks which require storing concepts over time. For example, they can't learn that whenever they see, say, a red button, they ought to press it to get food. But if part of the PFC is intact, and it doesn't matter which part, monkeys can do this with only minor problems.

However, the PFC isn't required for all tasks. If the task only involves information which is all presented at once, the lesioned monkeys are OK. So they could learn, given a big panel covered in red buttons, to push the buttons to get food, because the buttons are all there simultaneously.

Hence the data from these tasks are congruent with the notion that [the PFC] is only crucial in memory during tasks requiring the processing of temporally complex events. This can be defined as an event to be learned about, in which information that is crucial to that learning is presented at more than one point in time, or that can only be interpreted with respect to a preceding event.

They say that evidence from human neuroimaging studies supports this view.

A meta-analysis has shown consistent recruitment of the same network of regions in the PFC across a range of cognitive demands. The authors argue that this supports specialization of function within the PFC, but of an unexpected nature, namely ‘a specific frontal-lobe network that is consistently recruited for solution of diverse cognitive problems’. The idea that large and different regions of the PFC are recruited by any task at hand supports our argument that the function of the PFC as a whole exceeds the sum of the functions of its subcomponents.

This all has echoes of Karl Lashley, an early neuroscientist (died 1958) who proposed the theory of "mass action" - that the whole cortex contributes to behaviour, rather than each part doing different things ("modularism").

Jerry Fodor, whose classic book The Modularity of Mind (1983) helped to rehabilitate modularism from its reputation as "phrenological", was also an advocate of this view - within limits.

Fodor argued that some brain systems, like vision, hearing and language, were cortical modules, but that above this, there was a non-modular system which was the basis for thought, intelligence and decision making. If I remember correctly, he didn't explicitly say that the prefrontal cortex was this system, but I'm sure he'd have no objections to Wilson et al's account.

Wilson CR, Gaffan D, Browning PG, & Baxter MG (2010). Functional localization within the prefrontal cortex: missing the forest for the trees? Trends in neurosciences PMID: 20864190

Big Pharma Explain How To Pick Cherries

Here at Neuroskeptic, we see a lot of bad science. Maybe, over the years (all 2 of them) that I've been writing this blog, I've become a bit jaded. Maybe I'm less distressed by it than I used to be. Cynical, even.

But this one really takes the biscuit. And then it takes the tin. And relieves itself in it: A New Population-Enrichment Strategy to Improve Efficiency of Placebo-Controlled Clinical Trials of Antidepressant Drugs.

Don't worry - it's from a big pharmaceutical company (GlaxoSmithKline), so I don't have to worry about hurting feelings.

It's is full to bursting with colourful graphs and pictures, but the basic idea is very simple. As in "simpleton".

Suppose you're testing a new drug against placebo. You decide to do a multicentre trial, i.e. you enlist lots of doctors to give the drug, or placebo, to their patients. Each clinic or hospital which takes part is a "centre". Multicentre trials are popular because they're an easy way of quickly testing a drug on a large number of patients.

Anyway, suppose that the results come in, and it turns out that the drug didn't work any better than placebo, which unfortunately is what happens rather often in modern trials of antidepressants. Oh dear. The drug's crap. That's the end of that chapter.

...or is it?!? say GSK. Maybe not. They have a clever trick. Look at the results from each centre individually. Placebo response rates will probably vary between centres: in some of them, the placebo people don't get better, in others, they get lots better.

Now, suppose that you just chucked out all of the data from centres where the people on placebo got much better, on the grounds that there must be something weird going on in those ones. They reanalyzed the data from 1,837 patients given paroxetine or placebo, across 124 centres. In the dataset as a whole, paroxetine barely outperformed placebo. However, in the centres where people on placebo only improved a little, the drug was much better than placebo!

Well, of course it was. Imagine that the drug has no effect. Some people just get better and others don't. Let's assume that each person randomly gets between 0 and 25 better, with an equal chance of any outcome. Half are on drug and half are on placebo, but it makes no difference.

Let's further assume that there are 50 centres, with 20 people per centre (1000 people total). I knocked up a "simulation" of this in Excel (it took 10 minutes). Here's what you get:

The blue dots show, for each imaginary centre, drug improvement vs. placebo improvement. There's no correlation (it's random), and, on average, there is no difference: both average out at 12 points. The drug doesn't work.

The red dots show the "Treatment Effect" i.e. [drug improvement - placebo improvement]. The average is 0 - because the drug doesn't work. But there's a strong negative correlation between Treatment Effect and the placebo improvement - in centres where people improved lots on placebo, the drug worked worse.

This is exactly what Glaxo show in Figure 1a (see above). They write:

The analysis of the surface response indicated the predominant role of center specific placebo response as compared with the dose strength in determining the Treatment Effect of paroxetine.

But of course they correlate. You're correlating placebo improvement with itself: the "Treatment Effect" is a function of the placebo improvement. It's classic regression to the mean.

Of course if you chuck out the centres where people on placebo do well (the grey box in my picture), the drug seems to work pretty nicely. But this is cheating. It is cherry-picking. It is completely unscientific. (To give the authors their due, they also eliminated the centres where the placebo response was very low. This could, under some assumptions, make the analysis unbiased, but they don't show that this was their intention, let alone that it would eliminate all of the bias.)

The authors note that this could be a source of bias, but say that it wouldn't be one if it was planned out in advance: "in order to overcome the bias risk, the enrichment strategy should be accounted for and pre-planned in the study protocol." This is like saying that if you announce, before playing chess, that you are going to cheat, it's not cheating.

To be fair to the authors, assuming the drug does work, this method would improve your chances of correctly detecting the effect. Centres with very high placebo responses quite possibly are junk. Assuming the drug works.

But if we're assuming the drug works, why are we bothering to do a trial? The whole point of a trial is to discover something we don't know. The authors justify their approach by suggesting that it would be useful for drug companies who want to do a "proof-of-concept" trial to find out whether an experimental drug might work under the most favourable conditions, i.e. whether they should bother continuing to research it.

They say that such trials "are inherently exploratory in their conception, aimed at signal detection, open to innovation..." - in other words, that they're not meant to be as rigorous as late-stage trials.

Fair enough. But this method is not even suitable for proof-of-concept, because it would (as I have shown above in my 10 minute simulation) increase your chance of finding an "effect" from a drug that doesn't work.

Whatever the truth is, this method will give the same result, so it's not useful evidence. It's like saying "Heads I win, tails you lose". You've set it up so that I lose - the coin toss doesn't tell us anything.

All of the author's results are based on trials in which the drug "should have worked": they do not appear to have simulated what would happen if they used this method on trials where it didn't work, as I just did. So I'm doing Pharma a big favour by writing this post, because if they adopt this approach, they're more likely to waste money on drugs that don't work.

They should be paying me for this stuff.

Merlo-Pich E, Alexander RC, Fava M, & Gomeni R (2010). A New Population-Enrichment Strategy to Improve Efficiency of Placebo-Controlled Clinical Trials of Antidepressant Drugs. Clinical Pharmacology and Therapeutics PMID: 20861834

Sociopathic Dementia

Frontotemporal dementia (FTD) is a tragic, but scientifically fascinating, disease.


FTD only accounts for a small fraction of dementias in total (estimates range from 2% to 10%), but it typically strikes people aged in their 50s or 60s, i.e. much earlier than the average for Alzheimer's disease, the most common cause of dementia. As a result, FTD accounts for a large proportion of early-onset cases.

The symptoms are different to those of Alzheimer's, at least in the early stages. Memory problems and confusion are not prominent. Nor are hallucinations and delusions, which are seen in 20% of Alzheimer's, but only 2% of FTD.

Instead, patients often present with language problems - either forgetting what words mean, starting with uncommon words and progressing to easy ones ("semantic dementia"), or losing the ability to articulate speech ("nonfluent aphasia").

But the most disturbing effects are behavioural and personality changes. These are not seen in all cases, but in some people (the "behavioural variant"), they are the main symptom. Patients may begin to act entirely out of character, including criminal acts.

Aggressive behaviour is also sometimes seen in Alzheimer's, but it's usually associated with confusion or hallucinations: people "don't know what they're doing". In FTD, patients can commit serious crimes even though their cognitive function is pretty much intact: they do know what they're doing.

Mario F. Mendez discusses this in a new paper, The Unique Predisposition to Criminal Violations in Frontotemporal Dementia, and asks whether people who commit crimes while suffering from FTD should be considered legally responsible for their apparantly "sociopathic" actions. He presents 4 case histories.

Patient 1: A left-handed male in his sixties began stalking and attempting to molest children for the first time in his life. He followed children home from school and tried to touch them... On another occasion, he stood at the foot of a pool and stared at the children for a prolonged time.

When he exposed himself to his neighbor’s children, he was arrested. The patient did not deny his actions, could describe them in detail, and endorsed them as wrong and harmful. Despite this, he stated that he did not feel that he was causing harm at the time of his acts.

The patient’s personality had deteriorated over the prior four years, with decreased concern for others, disinhibition, and compulsive hoarding. He had caused disturbances at work, such as intruding into others’ conversations and walking into others’ offices... constantly pilfering... hiding money.... In addition, he ate indiscriminately, even going through waste containers and eating garbage. He stopped showering and wore the same clothes every day.

Neuropsychological testing and brain scans suggested early FTD, and his mother had reportedly suffered unspecified dementia; FTD is often genetic. He was not prosecuted. This case has a lot in common with the man who became a pedophile after surgery for a brain tumour: not just the pedophilia, but other symptoms like compulsive hoarding, over-eating, etc.

Patient 4: A right-handed man in his early fifties had a hit-and-run accident and left the scene without concern. He had struck a van with passengers but kept driving. The police stopped him a short distance away from the scene, and he did not deny his action.

Leaving the scene of an accident was not characteristic of his premorbid personality, yet he had had several recent traffic violations... He could recall and describe the accident, knew that it was wrong to leave the scene, but did not feel the need to stop at the time.

Over the prior two years, the patient’s pervasive behavior had significantly changed. He had become disengaged and emotionally detached; for example, he did not react to the death of his mother...

He was no longer embarrassed over passing gas or belching in public or appearing partially clothed in front of others. The patient had a tendency toward hyperorality, especially for peanuts, and had a decline in personal hygiene. Other aspects of the history included dysarthria and a recent tendency to choke on liquids.

This patient showed clear signs of motor neuron disease, which occurs in up to 15% of FTD cases. He died, as a result of the progression of the motor neuron disease, one year later, after developing other symptoms of FTD. His death meant he could not be tried for the hit-and-run.

Mendez notes that legally, these patients would probably not qualify for the "insanity defence". Under the British M'Naghten Rules, also adopted by the USA, the defendant is only eligible if they were

labouring under such a defect of reason, from disease of the mind, as not to know the nature and quality of the act he was doing; or, if he did know it, that he did not know he was doing what was wrong.

These patients do not fit that bill.

Finally, why does FTD cause sociopathic behaviour? Mendez says that it is because it involves degeneration of the vmPFC, linking FTD patients to the classic case of Phineas Gage whose vmPFC was destroyed by a flying iron rod. But Gage, while he did show personality changes, actually managed to function fairly well in society.

So temporal lobe degeneration probably also contributes to the FTD behavioural syndrome, especially since many of the symptoms (like compulsive eating) are seen in monkeys with temporal lobe lesions.

Mendez MF (2010). The unique predisposition to criminal violations in frontotemporal dementia. The journal of the American Academy of Psychiatry and the Law, 38 (3), 318-23 PMID: 20852216

The Rise of the Mouse

Everyone knows that scientists experiment on rats, and guinea-pigs. That's why we have "lab rats" and why, if you're trying out something new, you're a "human guinea-pig".

But this is all out of date. Nowadays, mice are the most popular lab animals. Here's a graph showing the number of scientific papers published each year, mentioning each kind of critter (data gathered with this script):

Rats were on top until about 10 years ago, when mice overtook them. Why? No-one wants to study mice if they can help it: they are horrible to work with compared to rats, and rats are more similar to humans physiologically. This is why rats were more popular for a long time. (Contrary to popular belief, guinea pigs were never used all that much, and they've become even less popular with the rise of mice.)

Non-scientists tend to think of rats as just big mice. They're not: mice are less intelligent, harder to handle (they bite... a lot), and they smell bad. The fact that they're smaller makes surgery, and even simple stuff like taking blood samples, much harder. On the plus side, you can fit more of them in any given space, making them cheaper, but that's about it.

So why did mice suddenly claim the crown? One word - knockout. Mice are the only mammal in which it's easy to perform genetic knockout, i.e. eliminating the function of a single gene. It's extremely difficult in rats, because, for reasons no-one really understands, it is harder to get rat stem cells to grow in vitro.

Knockout mice were "invented" in 1989, and the inexorable rise in the number of mouse papers began a few years later. Recently, there have been reports that knockout rats may now be easy; whether this will lead to a rat renaissance remains to be seen.

Knockouts have revolutionized biology, because they make it easy to investigate what each gene does. Just knock it out, and see what's wrong with your mouse. This is why there are mouse models of so many genetic diseases, while rat and monkey models are only available for a few disorders.

The Refrigerator Mother

Autism is biological: that's the one thing everyone agrees about it. Scientific orthodoxy is that it's a neurodevelopmental condition caused by genetics, in most cases, and by environmental insult, such fetal exposure to anticonvulsants, in rare cases. Jenny McCarthy orthodoxy is that "toxins" - usually in vaccines - are to blame, not genes, and that the underlying damage might be in the gut not the brain: but they agree that it's biological.

However, it hasn't always been this way. From the 1950s to about the 1980s, there was a widespread view that autism was a purely psychological condition. Bruno Bettelheim is the name most often linked to this view. Bettelheim spent most of his career at the University of Chicago's Orthogenic School, an institution for "disturbed" children, including autistics as well as "schizophrenic" and others.

His magnum opus was his book The Empty Fortress: Infantile Autism and the Birth of the Self, in which he outlined his theory of autism illustrated by three long case histories. His ideas are now referred to as the "refrigerator mother" theory.

For Bettelheim, autism was a reaction to severe neglect. Not of physical needs, which would be fatal, but of emotional relations. In his view, the most common underlying cause of this neglect was when the mother (and to a lesser extent, the father) did not want the child to exist. They cared for him, but they did so in a mechanical fashion, treating the baby as a mouth to feed and a nappy to change, rather than as a human being.

Hence the "refrigerator" - it provides food, but it's cold.

The result was that the child never learned to interact with the mother on anything other than a mechanical level; and for Bettelheim, as for most psychoanalysts, our relationships with our parents were the model on which all our other relationships were based.

The mechanical mother thus left the autistic child unable to relate to anyone, indeed, unable to conceive of the existence of other human beings, and thus lacking a sense of "self" as opposed to "others".


The repetitive behaviours and obsessive interests characteristic of autism were seen as an active, even heroic, coping strategy. They were the child's way of asserting what little self they had, by doing something for themselves, albeit something "pointless". But they also had symbolic meanings: "Joey's" interest in fans, propellers and other rotating objects was interpreted as a representation of the "vicious circle" of his life. And so on.

*

Bettelheim's ideas are now generally derided as dangerously wrong; his reputation suffered a hit when, after his suicide in 1990, stories emerged from former colleagues and patients painting him in a nasty light. But psychiatry's wider turn away from Freud and towards biology probably made his downfall inevitable.

Today the "refrigerator mother theory" is routinely cited as a cautionary tale of how deeply one can misunderstand autism. Ironically, Bettelheim's only reference to that term in The Empty Fortress is a quotation, from none other than Leo Kanner, the man who coined the term 'childhood autism' in 1944. Kanner referred to the "emotional refrigeration" he observed in the families of autistic children, although it's not clear that he thought of it as causing the autism.

There is no doubt that Bettelheim's approach was unscientific. He repeatedly claimed that the fact that many children improved after three or four years at the Orthogenic School proved that their autism was psychological, because if it were biological it would be permanent.

Yet there is no reason to assume that children with a neurodevelopmental disorder would never change as they grew up. There was no control group, let alone a placebo group, to show that the children wouldn't have "grown out of" some symptoms anyway. (Edit: In fact, Kanner himself had written about improvement with age way back in 1943, in the first ever paper about autistic children! So there was simply no excuse for Bettelheim's flawed argument.)

Bettelheim's attributing the cause of autism to family dynamics was post hoc: for each autistic child, he looked back into their family history (i.e. what the parents reported) and found that they "consciously or unconsciously" didn't want the child to exist.

Yet all this proves is that it is possible to interpret a parent's behaviour in that way, in retrospect, if you want to. The "or unconsciously" caveat creates endless scope for over-interpretation.

But even if we now see autism as a neurodevelopmental disorder, there is something attractive about Bettelheim's book: it seems to be a serious attempt to understand the autistic experience "from the inside", and to appreciate the autistic child as a person rather than a disease. This is something that we rarely see nowadays.

Bettelheim's problem was that he tried to understand autistic behaviour from the assumption that the autistic child was, deep down, entirely "normal". Hence his interpretation of, say, Joey's fascination with rotating objects as symbolic of his life situation (and also as reflecting the fact that his father was often flying away in propeller-driven aircraft, which he was).

Yet couldn't it be that Joey was just fascinated by spinning fans per se? There's nothing interesting about rotating objects. They must have a hidden meaning. Otherwise it makes no sense - to someone who isn't autistic. But all that means is that trying to understand the autistic child is rather difficult if you don't bear in mind that they are autistic.