Personality Without Genes?

According to a paper just published (but available online since 2010), we haven't found any genes for personality.

The study was a big meta-analysis of a total of 20,000 people of European descent. In a nutshell, they found no single nucleotide polymorphisms (SNPs) associated with any of the "Big 5" personality traits of Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness. There were a couple of very tenuous hits, but they didn't replicate.

Obviously, this is bad news for people interested in the genetics of personality. But I wonder if the implications are even wider -

We know that there are SNPs associated with physical traits like height, weight, hair colour, eye colour, and the risk of various diseases. If none of those SNPs are associated with personality, then none of those traits are causally associated with personality.

"Short man syndrome"? A myth. Rod Stewart was wrong about blondes. There's no such thing as a "fat personality". And so on. Maybe that's not surprising, but more generally, the implication would be that the genes we inherit have no direct or even indirect influence on our personality, which is a pretty radical conclusion when you think through it.

I'm making some assumptions here. Maybe some genes are correlated with personality, but the currently popular "Big 5" approach is just a poor way of measuring of personality. It could also be that there are so many interacting genetic and environmental effects on personality that any given effect is tiny by itself, and even bigger sample sizes, or multivariate data analysis, would be needed to detect such effects.

de Moor, M., et al. (2010). Meta-analysis of genome-wide association studies for personality Molecular Psychiatry, 17 (3), 337-349 DOI: 10.1038/mp.2010.128

The Blinking Brain - A Problem For fMRI?

Every time we blink, a wave of activity sweeps through our brain - and this could be a serious problem for some fMRI researchers.

French neuroscientists Hupé et al report on A BOLD signature of eyeblinks in the visual cortex. They found that spontaneous blinks are associated with a neural activation pattern over the occipital cortex areas responsible for processing vision.

In many ways this is not surprising - when you blink, everything goes dark, and then lights up again, all within a fraction of second, which means that blinks are a kind of very dramatic visual stimulus, equivalent to a big black object suddenly appearing and then vanishing again. However, it's long been believed that blink suppression mechanisms in the eye and brain somehow block out the responses that would otherwise happen during a blink.

Don't be so sure, say Hupé et al. In an elegant experiment, they showed volunteers a standard set of visual stimuli during fMRI scanning, while recording blinks using an eye tracking camera. Then they simply treated the blinks as events, and used standard analysis methods to find neural activation associated with them.

Blinks caused a significant BOLD response over a number of "visual" areas.

Compared to the "real" visual stimuli in the task, the blink signal was less extensive, but no less strong.

So what? The great majority of fMRI experiments don't use eyetracking to measure blinks, so this study raises the scary possibility that blinks could lie behind some of the "stimulus-related" activations that we all know and love. It would be a problem if subject blinks were correlated with the stimuli or tasks, which they might be, because blink rate may vary with our psychological state.

I don't think we should be too worried yet. The blink blobs were essentially confined to parts of the visual cortex. So any study that's not focussed on vision is probably in the clear (although that's just the average response: in some individual subjects, the activations were a lot wider.)

However, as the authors point out, there is a risk that alterations in blink rate, caused, perhaps, by emotional or cognitive stress, might be wrongly "found" to be causing visual cortex activation, which might call into question claims of "top-down" influences on early visual cortex... oh dear.

Hupé, J., Bordier, C., and Dojat, M. (2012). A BOLD signature of eyeblinks in the visual cortex NeuroImage DOI: 10.1016/j.neuroimage.2012.03.001

The Age of ADHD

Diagnosed rates of ADHD in American children have skyrocketed in the past 20 years, and use of medication such as Ritalin and Adderall has increased by an even greater amount.

So says a report just out in Clinical Pediatrics, using data from the major US National Ambulatory Medical Care Survey (NAMCS). The rate of office based visits (i.e. visits when a doctor saw or treated a patient, outside of a hospital) was the main outcome measure. The authors looked at the number of visits reporting a diagnosis of ADHD, and also the number of ADHD visits also involving psychostimulant medication, for kids aged 5 to 18.

See above - that's a big increase, and a lot of visits (remember the Y axis is visits per 1000 children per year.) One thing to remember is that the increase might not mean that there are more patients with ADHD -  it could reflect more visits per patient, but that seems unlikely to account for all of it.

A few thoughts -

The rise of ADHD parallels the recent increase in autism diagnoses. Yet people don't seem to be talking about it to the same extent. We're always hearing about "the autism epidemic", the "Age of Autism". Why aren't we equally concerned about the ADHD 'epidemic'? Why don't we have minor celebs railing about vaccine-damaged ADHD children?

Next - like autism - it seems likely that much or all of the increase is due to changes in awareness and willingness to diagnose the disorder. If so, logically, ADHD must either be being seriously overdiagnosed now, or was being seriously underdiagnosed previously. Or both.

This is especially true of boys. Rates in girls rose pretty much steadily for 15 years but in boys, there have been swings up and down, although the overall trend is still upward. It's always possible that this is a quirk of the NAMCS dataset, but if not, it suggests that ADHD diagnosis in boys is especially prone to changes in diagnostic fashion.

It's tempting, actually, to see the recent fall in boys with ADHD as a consequence of the rise of autism diagnoses over the same period. Autism is predominantly diagnosed in boys and the two disorders are often comorbid.

Maybe, boys are now getting autism diagnoses which are then felt to explain their behaviour, meaning that they don't "need" an ADHD diagnosis, which previously they would have got. But that's just my speculation, and it's probably reading too much into the data, because there was also a peak in 1994 which I can't see any explanation for.

Sclar DA, Robison LM, Bowen KA, Schmidt JM, Castillo LV, and Oganov AM (2012). Attention-Deficit/Hyperactivity Disorder Among Children and Adolescents in the United States: Trend in Diagnosis and Use of Pharmacotherapy by Gender. Clinical pediatrics PMID: 22399571

The Case of the Phantom Phantom Finger

A "phantom limb" is the sensation that an amputated limb (or other body part) is still present.

They can be distressing, especially when they're accompanied by pain in the "limb" which is not uncommon. The leading theory of why they happen is that the brain areas that used to receive sensations from the lost appendage respond to input "spilling over" from nearby brain regions.

Anyway, a phantom limb is bad enough, but a paper just out reports on the case of a phantom finger that was never there in the first place.

A woman, RN, was born with an abnormally short right arm; her right hand was also malformed, with a shortened thumb, no index finger, and immobile ring and middle fingers. Only the little finger was present and correct.

At the age of 18, she then had the misfortune to suffer a car crash; the injuries meant that her right hand had to be amputated. She soon found herself experiencing a phantom hand - with all five fingers. Three of them felt like they were normal length; the "thumb" and "index finger" felt shorter than normal, but remember that the original hand had no index finger at all.

RN also suffered from phantom pains and was distressed by the fact that the "hand" felt like it was bent into an impossible posture. Fortunately, the mirror box technique was able to set things right; while the phantom was still there, it was no longer painful, and all the fingers were the right length.

This is a remarkable case. The authors of the paper, Paul McGeoch and V. S. Ramachandran (perhaps the best known phantom-limb expert) say that it could mean that we're born with an innate, hard-wired "body plan" in the brain, regardless of the way our body actually develops -

While RN’s phocomelic [abnormal] hand was present she did not experience any phantom sensations. Thus, although severely deformed, the mere presence of the hand was sufficient to inhibit the innate representation of her normal hand and prevent any phantom sensations from emerging, presumably from tactile, proprioceptive and visual feedback... the amputation of her hand appears to have disinhibited these suppressed finger representations in her sensory cortex and allowed the emergence of phantom fingers that had never existed in her actual hand.

They do consider alternative explanations though -

Clearly it is beholden on us to consider whether RN’s descriptions do not describe a genuine sensory experience, but rather are confabulatory in origin. We do not believe this to be the case, since if she were confabulating then it would seem unlikely that she should report that her phantom hand had five fingers, but that they were not all of normal length; if this were simply ‘wishful thinking’ then she would likely claim to have five normal length fingers. This appears a persuasive, although not definitive argument, against confabulation.

Seems like a fair assessment.

I don't even know what you'd call the phantom "index finger". A pseudo-phantom? A phantom phantom?

McGeoch, P., and Ramachandran, V. (2012). The appearance of new phantom fingers post-amputation in a phocomelus Neurocase, 18 (2), 95-97 DOI: 10.1080/13554794.2011.556128

Ketamine - Magic Antidepressant, or Expensive Illusion?

Not one but two new papers have appeared from the Carlos Zarate group at NIMH reporting that a single injection of the drug ketamine has rapid, powerful antidepressant effects.

One placebo-controlled study found a benefit in depressed bipolar patients who were already on mood stabilizers. The other found benefits in treatment-resistant major depression, though ketamine wasn't compared to placebo that time. Here's the bipolar trial:

There have now been several studies finding dramatic antidepressant effects of ketamine, a compound that all journalists seem contractually bound to call either a or a "club drug" or a "horse-tranquilizer". Great news?

If you believe it. But hold your, er, horses... there's a problem. As I said almost 3 years ago about one of the earlier ketamine trials:

In theory, the trial was double blind - neither the patients nor the doctors knew whether they were getting ketamine or placebo. But you'll know when you've been injected with 0.5mg/kg ketamine. You get high. That's why people take it [recreationally]. The study can't really be called double blind.

To their credit, Zarate et al did acknowledge this, and suggested that in future ketamine could be compared to another drug which produces noticeable effects. But they really should have done that to begin with.

It's now 2012, and there have still not been any published studies comparing ketamine to an active comparator i.e. a different drug that produces noticable psychoactive effects, to avoid unblinding. This means it's 12 years since the initial pilot report on ketamine in depression, and 6 years since the first large trial appeared.

The authors of the 2006 paper themselves wrote that "limitations in preserving study blind may have biased patient reporting... One potential study design in future studies with ketamine might be to include an active comparator" and suggested amphetamine for the big role.

Good idea. But six years later, we're still waiting. Which is really a bit silly. There have been dozens of papers written about the possible antidepressant effects of ketamine, from human trials to mouse work. That's a lot of research dollars (and dead mice) on something that might just be an active placebo.

Looking at the registered ketamine research on clinicaltrials.gov, I found that four active-comparator ketamine trials are in the pipeline (1,2,3,4), plus one cancelled (5). Only one is for depression though. The others being for OCD, cocaine dependence and suicidal ideation.

In all of these trials a benzodiazepine is the active comparator. Is that a good idea? Well, it's certainly better than nothing, but I wonder.

An active comparator has to "make an impression" on the patient equal to that produced by the real drug.  The null hypothesis, remember, is that ketamine has no specific antidepressant effect. That means it produces improvement through a combination of a) the placebo effect (expectation) and b) non-specific psychoactive changes.

More on that second one: any psychoactive drug might relieve depression by "taking your mind off it" and a change in mental state, as provided by a drug, also provides a demonstration that "I won't always feel this way". By showing that states of consciousness are products of brain chemistry, almost any drug could therefore offer a "glimmer of hope" to the depressed. If all this sounds very subjective, it is, but that's the point. Psychiatry is.

Would a benzo make as big an impression as 0.5 mg/kg ketamine IV? It's impossible to predict, really; so we'd need to ask people about the subjective strength of the drug effect. Personally, I worry that a lot of people just get sleepy on benzos and don't really feel much, so I'd prefer they used something a bit more hard-hitting like amphetamine, but maybe that's just me.

There's a deeper problem though. Suppose our ketamine-benzo trial finds no difference between ketamine and benzo. A critic could say, ah, but maybe it was just a "failed trial", so it doesn't overturn the positive studies. The patients weren't properly diagnosed, or weren't depressed enough, or were too depressed, etc.

Nitpicking such differences between studies is a well-practiced art.

Critics could complain in other ways if the study did find a benefit of ketamine. As I see it, the only way to settle this once and for all is to do a three-way randomized controlled trial - inactive placebo vs. active comparator vs. ketamine.

That way, if it's a failed trial, we'd know: there'd be no difference between ketamine and the inactive placebo. If there was a difference, but the active comparator was just as good as ketamine, that means it was all about nonspecific effets. Finally, if ketamine was better than the other two conditions, we could be pretty confident it was really working.

Also important is the question of volunteer expertise; subjects shouldn't be able to tell what drug they're on, but people who'd taken ketamine and/or the comparator drug before might be able to do that, so you'd want naive volunteers.

In conclusion: It's possible that ketamine has no specific antidepressant effects. To find out we ideally need a three-way trial, with both active and inactive comparators, careful monitoring of subjective drug effects and patient knowledge and expectations. Until that happens, I will be skeptical of ketamine in depression.

This is not because I just think it's impossible. Ketamine profoundly affects the brain in ways that we don't understand. I've suffered depression and I know it can come and go in a matter of minutes. So I think it's entirely possible that it works - but it's also possible that it's a nonspecific effect.

Look. I really want to know the answer to this. Both as a neuroscientist, and as a depression sufferer, this is very important to me. That's why we urgently need a good trial.

Link: See also the discussion and the comments over at The Neurocritic and this Scientific American piece which is pretty good except that it doesn't cover the active placebo issue.


Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, and Luckenbaugh DA (2012). Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biological psychiatry PMID: 22297150

Ibrahim, L., et al. (2012). Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week, Double-Blind, Placebo-Controlled Study Neuropsychopharmacology DOI: 10.1038/npp.2011.338