The Mystery of Trephination

Why did ancient peoples cut holes in their heads?

The Woman of Pritschoena died around 4,500 years ago in what's now Saxony-Anhalt, Germany. Her skeleton was discovered in 1913 by a local archaeologist. Thanks to being buried in a gravel pit, her remains are exceptionally well preserved.

The Woman's skull is a fine example of trephination - the practice of deliberately cutting holes in the skull. She was trephined not once but twice, as you can see in the images above taken from a paper just out. In both cases, the skull around the hole shows clear evidence of healing, which shows that the Woman must have survived the procedures.

Trephination is a historical mystery. Stone-age peoples around the world were fond of doing it - trephinations have been found on skulls from Europe, the Americas and Asia. The authors of this paper say that there are records of at least 800 trephined skulls.

In some parts of Europe, it seems that the survival rate for the operation was over 90%. It was a delicate procedure, with stone tools used to carefully scrape away and remove the bone without damaging the tissue underneath. But no-one knows why they did it. Some argue that it may have been used as a treatment for epilepsy or mental illness, but it's impossible to really know what it was meant to achieve.

Alfieri, A., Strauss, C., Meller, H., Stoll-Tucker, B., Tacik, P., and Brandt, S. (2012). The Woman of Pritschoena: An Example of the German Neolithic Neurosurgery in Saxony-Anhalt Journal of the History of the Neurosciences, 21 (2), 139-146 DOI: 10.1080/0964704X.2011.575117

Take Your Placebos, Or Die

People who take their medication as directed are less likely to die - even when that "medication" is just a sugar pill.

This is the surprising finding of a paper just published, Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST). 

BEST was a clinical trial of beta blockers, drugs used in certain kinds of heart disease. The patients were aged about 60 and they all suffered from heart failure. Everyone was randomly assigned to get a beta blocker or placebo, then followed up for 3 years to see how they did.

Here's the big finding: in the placebo group of 1174 patients, the people who took all of their placebo pills on time (the good adherers), were significantly less likely to die than the patients who missed lots of doses. People who took over 75% as directed were 40% less likely to die than those with less than 75% adherence:

That's pretty interesting. The pills were placebos - they can't have had any benefit. So what's going on?

It gets even better. You might be tempted to write off these results as obvious: "Clearly, people who follow the study instructions are just 'healthy' people in other ways - maybe they take more exercise, eat better, etc. and that's what protects them."

Certainly, that's what I'd have said.

But what's remarkable is that when the authors corrected the statistics for all the confounding variables they measured - including things like age, gender, ethnicity, smoking, body mass index and blood pressure - it barely changed the effect. Some of the factors did correlate with adherence, but not in a way that it could explain the adherence effect on mortality.

This isn't the first study to find this effect. The authors themselves have already reported it, as have other researchers going back decades (many of which also tried, and failed, to explain it through confounding factors.) They say that it's unlikely to be a case of publication bias.

So what we have is a large effect, which cannot be causal, yet which can't be explained by any obvious confounds. Logically then, it must be the result of a confound (or more than one) that aren't obvious.

This is an important lesson. It's common for someone to do a study and find an interesting / scary / controversial correlation between two things. Often one is some kind of lifestyle factor, diet, environmental exposure, or whatever, and the other is some nasty disease. "And it wasn't explained by confounds!", such studies often conclude.

What the placebo adherence effect demonstrates is that there may be confounds no-one has thought of. They might even be impossible to measure. And if these mystery confounds can literally kill you, they can probably cause all kinds of other effects too.

In other words this illustrates the truism that correlation is not causation - not even when you're really sure it is...

Pressman, A., Avins, A., Neuhaus, J., Ackerson, L., and Rudd, P. (2012). Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST) Contemporary Clinical Trials DOI: 10.1016/j.cct.2011.12.003

Does MRI Make You Happy?

A startling new paper from Tehran claims Antidepressant effects of magnetic resonance imaging-based stimulation on major depressive disorder.

Yes, this study says that having an MRI scan has a powerful antidepressant effect.

They took 51 depressed patients, and gave them all either an MRI scan or a placebo sham scan. The sham was a "scan" in a decommissioned scanner. The magnet was off but they played recorded scannerish sounds to make it believable. Patients were blinded to group.

They found that people in the scanner group improved much more than those in the sham group over two weeks. Actually there were two different kinds of scans, T1 structural MRI and EPI functional MRI, but they were the same:

Now, if this is true, it's huge. Obviously. For one thing, it would undermine the whole premise of functional MRI, which is that it's a method of recording brain activity. If it's also stimulating the brain in some way at the same time, then it would make it hard to interpret those activations. In particular it would cast all the studies using fMRI in depression into doubt.

So is it true? I can't see any obvious flaws in the design. Assuming that the authors are right when they say that "patients could not distinguish the difference between the actual and sham MRI scan", i.e. assuming that the blind was truly blind, then the methodology was sound.

But let's look at the statistics. The paper is full of very impressive p values less than 0.001 but those turn out to all be referring to the changes within each group, and those changes are fairly meaningless. What matters is the differences in the groups and

Changes in BDI scores (between baseline and day 14) were significantly different among the three studied groups (F=5.48, p=0.007 overall) using ANOVA, and between the DWI group vs. Sham and T1 vs. Sham (p<0.05) using post hoc tests. Changes in HAMD24 scores (between baseline and day 14) were also compared among the 3 groups using ANOVA but the level of significance was slightly above the significance threshold (F=2.89, p=0.06).

Which is rather less convincing. There was a close-to-significant group difference in the HAMD24, and a significant but only just effect on the BDI. Remember that there were only 17 people in each group.

I'm inclined to think that this is one of the 5% of experiments which will produce a nominally significant result even assuming everything goes to plan and there are no confounds. My suspicion is that everyone in the trial got better (they were all on antidepressants, plus there's the placebo effect and the effect of time) - except a small number of people who didn't improve. And by chance they were all in the sham group.

The reason I'm skeptical is that I just can't see a plausible mechanism. The authors suggest that MRI scans might stimulate the brain in a similar way to TMS and that this could have antidepressant effects.

But there's a lot of problems with this: 1) the evidence is questionable whether TMS even works for depression 2) the magnetic stimulation of the brain generated during MRI is much weaker than in the case of TMS and 3) if MRI really stimulated the brain like TMS, then, like TMS, it would have a risk of triggering seizures in people with epilepsy. But it doesn't.

Vaziri-Bozorg SM, et al (2011). Antidepressant effects of magnetic resonance imaging-based stimulation on major depressive disorder: a double-blind randomized clinical trial. Brain imaging and behavior PMID: 22069111

Susan Greenfield's Dopamine Disaster

It's Susan Greenfield again.

Continuing her campaign warning of the dangers of modern technology in terms of their effects on the vulnerable brains of the young, the British neuroscientist and Baroness has written another article. This is the latest of many. None of them have been in peer reviewed academic journals.

This one's behind the Great Times Paywall so I can't link to it, but it's called Are video games taking away our identities?

The first part of the article is hard to argue against. Either you'll agree with it or you won't. Personally, videogames as Greenfield describes them bear little resemblance to any games that I've played recently. Similarly for her account of the Internet. But maybe this rings true for some:

Screen images do not depend for their impact on seeing one thing in terms of anything else. Their premium lies invariably in their raw sensory content... we are perhaps heading towards a much weaker sense of identity by engaging in a world where we are the passive recipient of senses and where there is no fixed narrative of past and future but an atomised thrill of the moment. One could even suggest that the constant self-centred readout on Twitter belies a more childlike insecurity, an existential crisis.

Greenfield then moves into discussing the brain, and this is where the science comes in. This is her "home turf" - she's Professor of physiology at Oxford. Yet it's a shambles.

There is one alarm bell ringing, which suggests that increasing 2D screen existence may be having undesirable effects: it is the threefold increase over the past decade in prescriptions for drugs for attention deficit hyperactivity disorder.

While this could be due to changes in doctors’ prescribing procedures, or indeed to a greater recognition and medicalisation of attentional problems, a third possibility could indeed be that if the young brain is exposed from the outset to a world of fast action-reaction, of instant new screen images flashing up with each press of a key, then such rapid interchange might lead to a shorter attention span.

The human condition can be basically divided into two alternating modes, first described by Euripedes... the rational “bread force”, characterised by a strong cognitive take on the world — a personalised past, present and future, in turn related to an active prefrontal cortex and lower levels of the brain chemical dopamine; and the “wine force”, more the state of young children or those adults indulging in “letting themselves go”, in situations perhaps involving wine, women and song, where a strong sensory environment demands less reflection, more passive reaction.

...An increase in physiological arousal can be linked to excessive release of dopamine. Could the screen experience be tilting this ancient balance in favour of the more infantile, senses-driven brain state?

Greenfield says that high dopamine and low prefrontal cortex activity is associated with irrationality and a deficit in attention. Video games are causing a flood of dopamine and causing ADHD. That would make sense, if ADHD was caused by too much dopamine, and if drugs for ADHD reduced dopamine release.

The problem is that it's the exact opposite. Drugs for ADHD increase dopamine release and ADHD is widely believed (although it's controversial) to be caused by a dopamine deficit.

Greenfield then says "We know too that dopamine suppresses the activity of neurons in the prefrontal cortex", but this is a serious oversimplification. Dopamine has complex effects on target neurons. It can inhibit firing, but it can also excite it. It all depends on the conditions. Here's what the authors of an influential scientific review said in 2004: "It is agreed by most researchers is that dopamine is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter"

Some say that dopamine helps to "tune" the prefrontal by increasing the signal to noise ratio - more signal, less noise. Here's one of the most cited papers about dopamine and the PFC: Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey.

Remember that drugs for ADHD like Ritalin, which are sometimes used illicitly by students without that disorder to help them focus and concentrate, cause dopamine release. If Greenfield were right, it would be the exact opposite.

...[other] people characterised by an underactive prefrontal cortex are those with schizophrenia, this time not due to physical damage but rather a chemical imbalance, in particular an excessive amount of the transmitter dopamine. In schizophrenia, like children, the patient is easily distracted, cannot interpret proverbs, is not strong on metaphor but takes the world literally; it is a vibrant world that can implode on, and overwhelm, the fragile firewall of the schizophrenic mindset.

This again is a serious simplification. Actually, you don't need to be a neuroscientist to work that out. Just recall the earlier bit: Greenfield has said that ADHD is caused by too much dopamine leading to an underactive prefrontal cortex. Now she says that schizophrenia is the same. So why are the symptoms of ADHD completely different from schizophrenia?

Why is it, in fact, that Ritalin and similar dopamine releasing drugs help with ADHD, but can make schizophrenia worse?

As a neuroscientist, I can tell you that we don't really know what's going on with dopamine in ADHD or schizophrenia. There's decent evidence that dopamine is involved in schizophrenia, but not in any straightforward sense. Schizophrenia is now believed to be linked to reduced dopamine in the prefrontal cortex, and too much in other areas.

As for ADHD, remember: the leading theory is that it's about too little dopamine. Not too much.

The only disease that we know certainly is associated with too little dopamine is Parkinson's. Contrary to Greenfield's theory, people with Parkinson's often have cognitive and mood problems as well as the better known difficulties with movements. They're not super intelligent, prefrontal-cortex-wielding geniuses.

I appreciate that an opinion piece in the Times is never going to be a rigorously argued scientific paper, but the fact that Greenfield's article contains several claims which are the exact opposite of the truth (or at least of current scientific thinking) calls her credibility into serious question.

The Limits of (Neuro)science

Will science ever understand the brain?

To start off with, it must be admitted that science has done a pretty good job of explaining pretty much everything else in the universe, so just going on past experience, it probably will.

But some say that, sure, the scientific method is fine for things like chemistry, but not for others. The human brain (or some aspect of it: consciousness, the mind, love, belief, or whatever) is the most popular exception. Science just won't work on it, we're told. It's too complex.

Maybe, but I find this view rather blinkered. It relies on taking our current state of knowledge as an eternal truth.

To see humanity as a mystery surrounded by a world of unmysterious things is a very new idea. It would have seemed bizarre just 300 years ago. Back then, nature was pretty much inscrutable. At best human life was no more mysterious. In many ways, less so. There were no end of philosophical, psychological and religious theories, many of them so plausible that they're still around today.

The notion that humans are complex and hard, while nature is easy, is an illusion created (ironically) by the successes of reductionist science. Some of the biggest questions facing mankind for eons have answered so well, that we don't even see them as questions. Why do people get sick? Bacteria and viruses. Why does the sun shine? Nuclear fusion. Easy.

But only easy now. Think of the billions of people who lived and died before say 1800 - they saw the sun every day and they had no idea why it shone, and they knew no-one else did. You may not understand nuclear fusion, but you know that physicists do, you know it's no mystery. 300 years ago, it would have been very tempting to think that no-one would ever know, that the answers were known only by God.

So, to confidently claim that explaining the human mind will just be too hard is presumptuous. It may or may not be, I don't know. Historically, though, the theory that things are inexplicable has a bad track record.

Then there's the idea that humanity is not so much hard, as different. Philosophers have spent many pages coming up with new ways of phrasing that point. Nature is material, but we're spiritual. Nature is in-itself, but we're for-itself. And so on. If we can understand the mind at all, it certainly won't be through reductionistic, mechanistic, rationalist, objectivist (phew) science, they say.

Again, this seems perfectly plausible... to us, now. But people used to say the same thing about living things in general. That was vitalism, the idea that physics and chemistry were fine for inert matter, but anything alive was radically different.

At a certain point in history, when biology was almost completely seperate from (and primitive compared to) the other sciences, that seemed fine. But it turned out to be wrong. With the benefit of hindsight. Nowadays, no-one sees a radically difference between nature and bacteria, plants or animals... well, except humans.

Maybe the mind will never be understood within the framework of the rest of science. I don't know, but I don't think anyone else does right now, either.

Le Pack It In

Earlier this year, a large group of autism experts signed a consensus statement condemning "Le Packing", a certain procedure used in children with autism.

They said:

This alleged therapy consists of wrapping the patient (wearing only underclothes or naked in the case of young children) several times a week during weeks or months in towels soaked in cold water (10°C to 15°C). The individual is wrapped with blankets to help the body warm up in a process lasting 45 minutes, during which time the child or adolescent is accompanied by two to four staff...

The alleged goal of this technique is to “allow the child to rid him- or herself progressively of its pathological defense mechanisms against archaic anxieties,” by achieving “a greater perception and integration of the body, and a growing sense of containment..."

We have reached the consensus that practitioners and families around the world should consider this approach unethical.

 Le Packing is almost unheard of outside France, where it was invented some years ago by M. A. Woodbury, an American psychiatrist. It's controversial even there.

Now Pierre Delion, a French packer who's previously defended the approach, and even wrote the book on it, has penned an article which discusses the towel-based treatment: Towards a dialogue between psychoanalysis and neuroscience: Connections that are both possible and necessary

The piece (part of a special issue on psychoanalysis and neuroscience) starts out with some general scholarly remarks about previous authors who have discussed Freud and the brain, but it moves on to autism, with some, well, puzzling remarks:

During the first months of life, an infant will actively practice his or her archaic reflexes. Of these, the grasping, which will progressively disappear as voluntary prehension emerges around the age of 4–5 months, is of great interest. The facilitation and/or anaclitic relationships between this reflex and adhesive identification are even more interesting to study together because, for instance, in an autistic child, the first model will integrate under the form of pathological adhesive identification.

In such an example, a strategy for thinking about these two phenomena and making them compatible is using a third term (e.g., Peircean logic, in which adhesive identification is an icon of grasping). If we refer to this important principle from this great American semiotician, the icon is part of the logical representation scheme from the most elementary, the icon, to the most evolved, the symbol, passing by the intermediate, the index...

The relationships between neurological wiring and pre-wiring enable the effective installation of the theory of mind and the phenomenon of projective identification described by Melanie Klein and her students...

Hmm.

On Le Packing itself we get a curious paragraph which seems to be saying that the therapy itself works via a neurophysiological mechanism, but that Freudian theory can explain why the child and their caregivers are anxious. What the anxiety in question is about is not clear. About the packing? That seems the most natural reading:

Another example taken from Pierre Delion’s practice as a therapist for children with autistic disorder is the ‘‘packing’’ technique (Goeb et al., 2008). This is the use of humid wrapping to prevent self-mutilation by using these two different levels [i.e. neuroscience and psychoanalysis] that are nonetheless joint during treatment. This technique uses a neurophysiological hypothesis to try to explain the therapeutic effects, but, at the same time, the psychopathological hypothesis that is given by psychoanalysis helps to format the anxieties that are experienced by the children and invariably shared by their caretakers.

Clinical research regarding this topic is currently being undertaken in Pierre Delion’s child psychiatry department following a hospital program for clinical research (PHRC, NoEudra CT: 2007-A01376-47) entitled ‘‘Demonstration of the efficiency of packing treatments in children affected by autistic disorders with severe behavioral disorders’’.

Delion P (2011). Towards a dialogue between psychoanalysis and neuroscience: Connections that are both possible and necessary. Journal of physiology, Paris PMID: 21963531