Finally, Hard Evidence Against The "Autism Epidemic"?

The idea of an 'autism epidemic' has a lot of people very worried.

No-one disputes that diagnosed rates of autism have increased enormously over the past 15 years or so, around the world. However, other people write it off as essentially a cultural phenomenon: we're getting better at detecting the disorder and more willing to label kids as having it.

I subscribe to the latter view, but there's very little hard evidence for it. To prove that diagnostic changes have occurred, rather than a true increase in autism, you'd have to know what would have happened to today's kids, say, 20 years ago. Would they have been diagnosed? We have no way of knowing. At least not until someone invents a time machine.

However, a new study just out offers a valuable new perspective on the debate: Spatial clusters of autism births and diagnoses point to contextual drivers of increased prevalence.

According to authors Soumya Mazumdar and colleagues, there's a zone of high autism prevalence in California, areas where kids aged 0-4 years old are more likely to be diagnosed with the condition. The epicentre is L.A.; there's actually three overlapping hotspots centred on Santa Monica, Alhambra and North Hollywood.

In these clusters, autism rates are between 2 and 6 times higher than the rest of the state.

Now an interesting thing about these areas was that they're rich in paediatricians, autism advocacy organizations, and money. In other words, there's better access to health services and probably more awareness of autism. This is suggestive evidence that the reason lots of kids get diagnosed here is about diagnosis, not autism per se.

But the blockbuster result is that children born outside the cluster, who later moved home into one, had a higher chance of getting a diagnosis than those who stayed out. The effect was smaller than for kids born inside the hot zone, but it was significant.

That's also consistent with the idea that the clusters are clusters of diagnosis, not autism.

It's not proof. You could argue that there's some toxic chemical, say, present in the rich parts of L.A. that causes autism, even if you move into the toxic area only at age 3 or 4, and that's been getting worse recently, leading to rising rates.

But it seems a stretch. What's the chemical? And why hypothesize one, when the diagnostic services hypothesis nicely accounts for these findings? As the authors say:

The findings reported in this article do not fully reject the possibility that environmental toxicants drive some of the risk of autism ... since there are a plethora of possible toxicants, it is impossible to falsify all hypotheses that researchers have started to explore.

 Mazumdar S, Winter A, Liu KY, and Bearman P (2012). Spatial clusters of autism births and diagnoses point to contextual drivers of increased prevalence. Social Science And Medicine PMID: 23267775

Autism Brain Scans Flawed? You Read It Here First

According to a piece in Nature today, a major line of research about autism might be seriously flawed:

One of the most popular and widely accepted theories on the cause of autism spectrum disorders attributes the condition to disrupted connectivity between different regions of the brain.

This 'connectivity hypothesis' claims that the social and cognitive abnormalities in people with autism can be explained by a dearth of connections between distant regions of the brain. Some flavours of this theory also predict more connections between nearby brain regions.

Recent studies, however, have found that when a person moves their head while undergoing functional magnetic resonance imaging (fMRI) - a method that maps how different neuroanatomical structures of the brain interact in real time, its functional connectivity - it looks like the neural activity observed in autism. That's a sobering discovery...

So the characteristic pattern of "abnormal connectivity" in autism might not be real: it might just reflect the fact that people with autism move around more during the scan.

A sobering idea, indeed... but not an entirely new one. I suggested it over a year ago:

Head motion affects estimates of functional connectivity. The more motion, the weaker the measured connectivity in long-range networks, while shorter range connections were stronger... Disconcertingly, this is exactly what's been proposed to happen in autism (although in fairness, not all the evidence for this comes from fMRI). This clearly doesn't prove that the autism studies are all dodgy, but it's an issue. People with autism, and people with almost any mental or physical disorder, on average tend to move more than healthy controls.

Ben Deen, and Kevin Pelphrey (2012). Perspective: Brain scans need a rethink Nature

Kids Today Are Not Inattentive

There's no evidence that children today are less attentive or more distractible than kids in the past, according to research just published by a team of Pennsylvania psychologists: Long-Term Temporal Stability of Measured Inattention and Impulsivity in Typical and Referred Children.

The study gave a large sample of kids the "Gordon Diagnostic System" GDS test of sustained concentration ability. This dates to the 80s and it consists of a box, with a button, and a display with three digits. There are three different tasks but the main one is a sustained attention test. The goal is to watch a series of numbers and quickly press the button whenever a "1" is followed by a "9". Easy... but it takes concentration to do well.

Over the period of 2000-2006, the researchers gave the GDS to 445 healthy American kids, not diagnosed with any learning or behavioural disorder and not taking medication. They compared their scores to the standardized norms - which were based on a sample of American kids back in 1983.

The results showed that today's kids scored pretty much the same, on average, as the 1983 kids. The average age-standardized scores were extremely close to the 1983 means, across the board. Children diagnosed with ADHD, as expected, scored much worse. Oddly, kids with an Autism Spectrum Disorder did just as badly as the ADHD ones.

One of the researchers on this study is none other than Michael Gordon, who invented the GDS and, one assumes, makes money selling it. (Each GDS kit costs $1595, so someone is making a killing here.) So perhaps we should take this paper with a pinch of salt, because it's kind of an advertisement for the reliability of the GDS.

Still, these results seem pretty solid. That's good news for American children... but bad news for people like Professor Susan Greenfield, who thinks that the internet and videogames are causing an epidemic of ADHD, and all kinds of other problems.

These data suggest rather that, while ADHD diagnoses are certainly rising, children as a whole are not getting less attentive, suggesting that the rise of ADHD is more of a cultural shift.

Mayes, S., Gordon, M., Calhoun, S., and Bixler, E. (2012). Long-Term Temporal Stability of Measured Inattention and Impulsivity in Typical and Referred Children Journal of Attention Disorders DOI: 10.1177/1087054712448961

That Antidepressants In Water Cause Autism Study

Oh dear. The newspapers this morning are reporting that

Autism 'could be triggered by very low doses of anti-depressants or other chemicals found in water supply'

Here's the study. Young fish were exposed to a combination of three drugs, two antidepressants and an epilepsy med, for 18 days.

First off, this study was tiny with an effective sample size of just 6. Three tanks of fish got exposed to the drugs, and three control tanks didn't. There were multiple fish per tank, five in fact, but those are not five independent observations, because they shared a tank. That's just tiny for a drug trial, or any scientific study really.

Next, the drug doses were much higher than in the water supply. Levels of fluoxetine (Prozac) were 700 times higher than observed in drinking water, for carbamazapine it was 400 times higher. And that's based on the authors' figures for drinking water which they admit are "the highest observed concentrations from various systems". The authors defend this by saying that in drinking water there will be other related compounds, on top of the drugs themselves, adding up to a higher dose. OK - but 400, 700 times higher? We've no idea if that's realistic. They don't justify this number.

What did the drugs actually do to the fish? After 18 days of exposure to the drugs, the fish - juvenile fathead minnows - had their brains removed and the expression levels of various genes measured using a genetic microarray.

The drugged minnows had significantly increased expression of a set of 324 genes dubbed "autism genes" ("autism_ideopathic" in the paper.) I'm not going to get into the question of whether these really are autism genes in humans, or whether fish brains are a good of model of humans. Those are hard issues. But what's easy to see is that while this set of genes were apparantly increased, so were many others. It was not specific to 'autism genes'.

The autism genes were upregulated by an average factor of +1.621... but this was only slightly more than the "Parkinson's Disease genes" at +1.56 and the "Multiple Sclerosis" ones at +1.375. Meanwhile, "Bipolar Disorder" genes were down by -1.172. So if antidepressants in the water are causing autism, they're probably also causing (or preventing!) a lot of other problems too.

The authors note that only three of the gene sets were statistically significantly altered, but that doesn't mean those sets were special, this is the fallacy of treating differences in significance levels as evidence of significant differences.

Of 10 more specific "autism gene" sets that they also examined (in the same fish), all were increased by various amounts (+1.050 to +1.537), some of which were significant - but one of those was a set of genes previously reported decreased in autistics, not increased (it was the "synapse" genes from this study).

What these changes in gene expression mean is anyone's guess. Given the small sample size they could be just noise. If not, all they really show is that levels of psychoactive medications that are quite low, but much higher than in drinking water, have affect the brains of fish. We don't know what that effect means, for the fish, let alone humans.

Early life antidepressant exposure might cause autism. I don't know. Stranger things have happened. We know that fetal anticonvulsant exposure can do it but that's when mothers are actually taking the pills. It's one giant leap from that to traces in drinking water. It's the difference between falling off your chair and falling off the Empire State Building.

Michael A. Thomas, and Rebecca D. Klaper (2012). Psychoactive Pharmaceuticals Induce Fish Gene Expression Profiles Associated with Human Idiopathic Autism PLoS ONE

Who Invented Autism?

The concept of "autism" is widely believed to have been first proposed by Leo Kanner in his 1943 article, Autistic Disturbances Of Affective Contact.

But did Kanner steal the idea? That's the question raised in a provocative paper by Nick Chown: ‘History and First Descriptions’ of Autism: A response to Michael Fitzgerald. The piece stems from a debate between Chown and Irish autism expert Michael Fitzgerald, who first made the accusation in a book chapter.

On the evidence presented, I don't think there's good reason to believe that Kanner did "steal" autism, and Chown doesn't seem convinced either. But there's an interesting story here anyway.

Fitzgerald says that in 1938, Hans Asperger - of Asperger's Syndrome fame - gave a series of lectures in Vienna. These were published in a Vienna journal called Wiener Klinischen Wochenzeitschrift as an article called "Das psychisch abnorme kind" ("The mentally abnormal child").

In this article, Asperger put forward the concept of autism. The term was coined by Eugen Bleuler in 1911 in reference to symptoms seen in 'schizophrenia' (he came up with that word too), but that was nothing to do with children.

In 1943, Kanner published his landmark paper, in which he did not mention Asperger. Asperger published his first major description of 'autistic psychopathy' in 1944. The big question, then, is - had Kanner read or heard of Asperger's ideas before 1943?

Asperger was working in Austria while Kanner, although Austrian-born, was in the USA. WW2 would have made it impossible for them to have communicated directly - however, word of Asperger's ideas could have reached Kanner via one of the many European doctors who fled to America, over that period.

There is however no direct evidence that this happened. Fitzgerald makes much of the fact that Kanner opened his 1943 paper by saying "Since 1938, there have come to our attention a number of children..." This could be a reference to Asperger's 1938 work - but Kanner said it referred to his first "diagnosis" of autism, Donald T.

This leaves us with a fluke: two Austrian-born psychiatrists independently discovered the syndrome we now call childhood autism, decided to borrow Bleuler's term "autism" for it, made their first observations in 1938 and first published properly in 1943-1944.

Personally, I think that while that is a remarkable coincidence, such things are not uncommon in science. I see no reason to think that Kanner plagiarized Asperger, although it remains possible. If someone were to discover a copy of Asperger's 1938 article tucked away in one of Kanner's old notebooks, then I'd change my mind, but not before...

Chown, N. (2012). ‘History and First Descriptions’ of Autism: A response to Michael Fitzgerald Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-012-1529-5

Bias in Studies of Antidepressants In Autism

There's little evidence that antidepressants are useful in reducing repetitive behaviors in autism - but there is evidence of bias in the published literature. That's according to Carrasco, Volkmar and Bloch in an important report just out in Pediatrics: Pharmacologic Treatment of Repetitive Behaviors in Autism Spectrum Disorders: Evidence of Publication Bias

They looked at all of the published trials examining whether antidepressant drugs (mostly SSRIs, like Prozac) were better than placebo in reducing repetetive behaviours in children or adults with an autism spectrum disorder (ASD).

A meta-analysis showed that there was a statistically significant benefit of the drugs overall, but it was marginal, with a small effect size d=0.22, and it was driven mainly by two old, very small studies that found big benefits. One of them only had 12 subjects. By far the largest study, King et al (2009) with 149 people, showed zero effect.

This plot shows all of the studies, with the red line being no benefit of drug vs placebo. The further to the right of the line, the bigger the benefit, but the grey horizontal lines show the uncertainty. As you can see, two small, messy studies found big effects, the others didn't.

Worse yet, although there were 5 published studies, the authors also found that there had been 5 studies that had been completed, but never published. Carrasco, Volkmar and Bloch wrote to the people in charge of those studies and asked for data; only one out of 5 replied. The data showed no benefit.

We don't know what the other 4 unpublished studies found, but the way science works means they probably came out negative. If we assume that they did, then even the small benefit seen in the published studies disappears.

This paper, incidentally, is great example of why trial registration is a great thing. Without mandatory pre-registration on clinicaltrials.gov, no-one would know about the 6 unpublished trials at all. It would have been even better if the researchers had been forced to make public the results, as well as the existence, of the unpublished trials; but it's a lot better than nothing.

Finally, the authors of this paper stress that this doesn't mean antidepressants don't help at all in autism - just that they probably don't help with repetitive behaviors.


Carrasco, M., Volkmar, F., and Bloch, M. (2012). Pharmacologic Treatment of Repetitive Behaviors in Autism Spectrum Disorders: Evidence of Publication Bias Pediatrics, 129 (5) DOI: 10.1542/peds.2011-3285

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

Science Majors are from Mars...

According to a new study, students with a family history of autism tend to major in math and science, while substance abuse and depression are more common in the ancestors of humanities fans.

In an online survey, over 1,000 new Princeton undergrads were asked about their intended major and whether anyone in their family had been diagnosed with one of 16 neurological and psychiatric disorders. More details here.

Of the 16 maladies, 5 were so rare that there wasn't enough data to analyze. Of the remaining 11, there were significant differences between the three types of students in four. The categories being humanities, social sciences, and "technical" i.e. science, engineering and maths. Social science majors were in the middle, except for autism.

See the graph I made above.

It's an interesting study. The autism result seems tenuous though because only 24 of 1077 students reported any autism in their immediate family. That's 3% of "technical" students and 1% of others, so not very many. The authors excluded schizophrenia and epilepsy from the analysis on the grounds of being too rare - and they had 18 each. Substance abuse and depression had over 150 each, so those differences are rather more solid.

The authors note that this fits with various previous studies and they discuss their findings in Baron-Cohen-esque terms:

It has been suggested that autism represents an extreme manifestation of a ‘‘systemizing’’ nature. Since ASDs have complex inheritance, shared genetic variation between close relatives might establish a continuous phenotype which in milder forms confers interest or benefits in understanding highly structured fields... Similarly, affective disorders may represent an extreme phenotype of emotional lability that, in milder forms, is commensurate with interest in the humanities.

Hmm. OK, but does that really make sense? Sure, it fits with the popular image of the Geeky Scientist vs the Tortured Artist - but that's not science, that's stereotypes. Why would emotional lability make you favor the humanities, exactly?

Imagine if the stereotype was the Geeky Artist vs the Tortured Scientist (and there really have been plenty of both, over the years). Couldn't we rationalize that equally well? Picture the scene... -

"People with autistic traits are drawn to study the humanities because they wish to learn about humans and their emotions, something they find hard to do in day-to-day life... While emotionally volatile people like science and maths because they offer a calming sense of order and stability..."

Campbell BC, and Wang SS (2012). Familial Linkage between Neuropsychiatric Disorders and Intellectual Interests. PloS one, 7 (1) PMID: 22291951

The Age (Cohort) of Autism

New data shed light on the recent mysterious rise in the number of kids being diagnosed with autism.

The new research doesn't explain the increase, but it tells us more about it. It shows that the rise in Californian autism diagnoses (reported to the state DDS) over the period 1996 to 2005 was a cohort effect, meaning that the rates of diagnosis have got higher, the later a child was born.

A child who's 10 today (born 2002) has double of the chance of having a recorded diagnosis compared to a 14-year-old born just four years earlier, in 1998.

"That doesn't tell us anything new!" you might object (I did at first). "All that means is that rates have risen, and we knew that already". But actually it does tell us something important. Because the data could have turned out differently; rates could have risen without a cohort effect, if, in recent years, lots of diagnoses were being handed to children regardless of their age.

That didn't happen. Almost all children in California who get a diagnosis, get it at age 3 or 4. In more recent years, the average age at diagnosis actually fell slightly. The peak used to be age 4, it's now 3.

So it's not that children in general have been getting diagnosed with autism more. It's that young children are getting diagnosed more; children aren't being diagnosed "retrospectively", as it were.

Another interesting finding is that the rise in rates of 'high-functioning' autism has been much bigger than the rise in low-functioning autism (i.e. autism alongside intellectual disability), although that has risen as well. Edit: but note that their defintion of 'functioning' is rather unique; see the comments.

So what does this mean?

These data are consistent with various interpretations. It could be that rates of autism have really risen in California over this time period. But it could also be that people are getting more likely to detect and diagnose it - in young children.

Keyes, K., Susser, E., Cheslack-Postava, K., Fountain, C., Liu, K., and Bearman, P. (2011). Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California International Journal of Epidemiology DOI: 10.1093/ije/dyr193

Scientific Databases - or Filters?

A new online database called AutismKB offers a quick way to find the evidence linking genes to autism.

You can read up on it in a paper describing the project.

You can browse by chromosome or gene name, it includes data on all kinds of genetic variants from SNPs to CNVs and it gives each variant a score according to the strength of the evidence. I haven't had a chance to really tell how useful these scores are, but there's an option to create your own score based on how much weight you give different kinds of evidence. The dataset is huge although it doesn't seem to have been updated for a few months.

Overall, it's a new tool and there's sure to be bugs to iron out, but it seems like it could be very useful. I do worry though that this kind of database encourages misleading ways of thinking about autism genetics.

There are numerous genetic variants which have been strongly linked to autism, although none of them account for more a small proportion of cases because these variants are rare. But many (most, actually, is my impression) of them have also been observed in people with other symptoms ranging from ADHD to epilepsy to schizophrenia.

So searching a database of "autism genes" could encourage you to think that these were only autism genes, which is far from true. Genetics, it is becoming increasingly clear, doesn't respect our current concepts of psychiatric illness or our academic specialities. There are few (if any) parts of the genome that can be neatly fenced off and declared exclusive to ADHD experts, schizophrenia researchers or whatever.

But disease-specific databases encourage the illusion that they do exist. It's the same old problem of the filter bubble which many people have warned about in the context of general purpose search engines. Scientists have filter bubbles too.

This is not of course a criticism of AutismKB in particular - the same goes for any similar "disease-gene" database. And to be fair AutismKB does provide links to a schizophrenia database, and a couple of others but you have to dig quite deep to get there. The "main page" of results for any given variant is pure autism.

That's the whole problem with filter bubbles - they make it too easy to hear what you want to hear, compared to getting a new perspective, so you don't even think to look outside the filter.


Xu LM, Li JR, Huang Y, Zhao M, Tang X, and Wei L (2011). AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic acids research PMID: 22139918

The Gene That's "For" Nothing

Scientists like to warn you not to talk about "the gene for" a particular disease or trait.

I've done so in previous posts e.g. this one or this one.

But such scalding is not always very effective. We like simple explanations, so we like to find simple connections between genes and phenotypes.

Which is why a new paper is important. The authors, a large Turkish-American collaboration, found that mutations in a gene, WDR62, are associated with severe brain malformations in 9 patients. But what's interesting is that it doesn't cause any particular malformation.

If you have two faulty copies of this gene, your brain won't be normal, but what goes wrong varies widely amongst different people. Although the 9 cases had some features in common, such as microcephaly (small head and brain), in other respects they differed greatly.

As the authors put it, mutations in WDR62 cause

a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients... had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities.

These are distinct entities, in the sense that you can have any one of them, without having the others. And they are different brain changes. What the authors mean is that everyone assumed that, because they're  different, they must have different genetic causes. They've just shown that this is wrong.

So what is WDR62 "for"? Experiments in mice showed it to be involved in the migration of new neurons from their origin to their final location in the brain. So it's "for" correct neuronal placement, although how it works remains unclear.

WDR62 ought to remind us that there's a long and winding road from gene to phenotype, and that the same gene can, when mutated, cause very different symptoms. This is especially interesting in the light of recent evidence showing that the same mutations can cause a range of behavioural disorders from autism to ADHD to schizophrenia.

Bilgüvar K, et al (2010). Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467 (7312), 207-10 PMID: 20729831

Potential Personal Genomics

A while ago I wrote about how new findings in genetics could herald a new kind of "eugenics", based not around selective breeding to ensure that "bad" genes aren't passed on, but rather based on using fetal genetic testing to choose which variants enter the gene pool in the first place.

I said-

In the near future, we might be able to routinely sequence the genome of any unborn child shortly after conception

But I didn't realize that this may be really very near indeed. Two recent reports have shown that it's possible to sequence fetal DNA from a maternal blood sample. In one case it was used to diagnose a 35 week fetus with a genetic deletion on chromosome 12 seemingly associated with autism, developmental delay and shortness.

In this case it was inherited from the father (which is why they decided to test for it), but this approach could equally be used to screen for the de novo mutations that account for much disease, as I discussed in the last post.

This is big. Currently, the main way to get fetal DNA is through amniocentesis, i.e. inserting a needle into the womb. It's a substantial and not entirely safe medical procedure. A blood sample would be an order of magnitude cheaper and safer, but most of all it would be something you could do at home.

No longer would you need to go to a hospital and discuss everything with a doctor. You could take some blood, send it off anonymously to a sequencing company, and get the results in an email. It would take it out of the hands of professionals and open up a space for individual choice.

The cost of whole-genome sequencing has been falling exponentially and many think it will fall below the $1000 mark within a few years. Combine that with fetal DNA testing and we might see moderately well-off parents able to sequence fetal DNA within the next decade.


When this happens I think the personal genomics industry will suddenly become extremely "hot". At the moment you can sequence your own DNA for a few thousand $ if you want. The results may be interesting but they're of little obvious use. Whatever your genes are, you're stuck with them.

But as soon as we're talking about potential human genomes, it'll kick things up a notch. Media interest and political controversy is sure to follow. Personally I think it'll the debate will begin in earnest when we start seeing selective abortions on the basis of genes for "normal" variants rather than "disease" genes.

It's one thing to not want a child with blindness, or a high risk of leukaemia. But as a society I don't think we're ready for not wanting a child because they're predicted to be a B student rather than an A student, or brunette rather than blonde. At some point soon, though, we'll have to decide what we think about that.

Peters D, Chu T, Yatsenko SA, Hendrix N, Hogge WA, Surti U, Bunce K, Dunkel M, Shaw P & Rajkovic A (2011). Noninvasive prenatal diagnosis of a fetal microdeletion syndrome. The New England journal of medicine, 365 (19), 1847-8 PMID: 22070496

Srebniak M, Boter M, Oudesluijs G, Joosten M, Govaerts L, Van Opstal D, & Galjaard RJ (2011). Application of SNP array for rapid prenatal diagnosis: implementation, genetic counselling and diagnostic flow. European journal of human genetics : EJHG, 19 (12), 1230-7 PMID: 21694736

Autism: What A Big Prefrontal Cortex You Have

A new paper has caused a lot of excitement: it reports large increases in the number of neurons in children with autism. It comes to you from veteran autism researcher Eric Courchesne.

Courchesne et al counted the number of cells in the prefrontal cortex of 7 boys with autism and 6 non-autistic control boys, aged 2-16 years old. The analysis was performed by a neuropathologist who was blind to the theory behind the study and to which brains were from which group. That's good.

They found that the total brain weight of the brain was increased in autistic boys, by about 17% on average. But the number of neurons in the prefrontal cortex was increased by an even higher margin - about 60%. The difference was specific to neurons - glial cell counts were normal. Of the 7 autistic boys, 4 also had intellectual disability - an IQ less than 70. However, the 3 without showed broadly similar results.

As well as having more prefrontal neurons, there were also some other issues in some but not all of the autism brains. Two had prefrontal cortical abnormalities - dysplasia in one case and abnormal cell orientation in another. And no fewer than 4 had flocculonodular lobe dysplasia in the cerebellum.

None of the nonautistic brains had any abnormalities reported but they don't seem to have looked very closely in the controls because that was based on "coroner's report only", rather than a detailed neuropathological exam...

It's a nice piece of work, but very small. These postmortem neuropathology studies always are because postmortem brain samples are in short supply, especially for disorders like autism.

In fact, it's so small, that doing statistics on these data is not really meaningful. The authors do some stats and get some impressive p values but we should take those with a pinch of salt and just look at the individual data (see the scatterplots above).

Now, prefrontal cortical neurons are generated while you're still in the womb. New ones can't be created after you're born - numbers can only decrease. So the increased neuron count in autism must have a very early origin, either genetic or caused by pre-natal environmental factors. Unless the timeline for cell genesis is totally different in autism.

Still, it casts doubt on the idea that, in the brain, bigger is always "better". Assuming that we consider autism to be "bad" - which I'm not saying is necessarily right, but it's fair to say most people do assume that - then the common practice of equating volume increases with all kinds of good things seems rather silly.

Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, & Pierce K (2011). Neuron number and size in prefrontal cortex of children with autism. JAMA : the journal of the American Medical Association, 306 (18), 2001-10 PMID: 22068992

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.

Mountains of Mental Disorders

This is a story about a man who lived in a house. Here it is:

The house was a lovely thatched cabin, situated in a wooded valley between two little hills, set against the spectacular scenary of a snow-capped mountain. He'd been born there, and he'd lived there all his life.

One day, there was a knock on the man's door. He opened it to find two official-looking people carrying clipboards, with serious expressions on their faces.

"Hello, sir. We are officials from the Ministry of Mountains. Sorry it took us so long."
"Oh... excuse me?", the man replied, puzzled.
"We're very sorry we didn't get here earlier."
"I'm afraid that I don't know what you mean. I wasn't expecting any..."
"Hmm. Let me explain. The Ministry of Mountains exists to help people who live on mountains. So, you see, we're here to..."
"Ask for directions to the mountain? It's about 10 miles down the road. Just look up - you can't miss it."

The official looked unamused.
"No. We're here to help you, sir."
"Help you to cope with the rigors of mountain living!" the other chimed in, helpfully.
"But... I don't live on a mountain."
"I'm afraid you do. Look - " and the first official unfolded a large map. "Do you agree that there is a mountain, here?" and she pointed to a spot 10 miles down the road.
"Yes. Actually I just told you about i..."
"...and, do you agree that you live - here?"
"Of course, but..."

"So you do live on the mountain. The very ground beneath our feet right now is part of that mountain nearby."
"No it's not." The man protested. "This is a valley, miles away. I mean just look outside. We're clearly not on a mountain now, are we?"
"How old fashioned. That's what we used to think. But, thanks to advances in geology, we now appreciate that these hills and valleys are merely a part of the mountain."
"Yes!" the other said, whipping out a textbook and becoming increasingly enthusiastic. "You see, a mountain is merely a mass of rock, and this rock extends underground for a considerable distance... It's impossible, really, to draw a line on the map and say categorically, this side is mountain, this isn't. So 'mountains' are an arbitrary construct. 'Hills' are likewise just protrusions of the underlying mountain and..."

The man was even more confused now. "Umm... well, I suppose, technically...but..."
"...so yes, so you do live on a mountain. And we know that this is very difficult. You're exposed to all kinds of dangers like blizzards, altitude sickness, avalanches..."
"Not really. It's nice here. It doesn't even snow most years."
"That's unlikely. You agree that mountains have blizzards and avalanches? Right. And you earlier agreed that there's no dividing line between you and a mountain. So logically..."
"Er..."
"So you are in danger! Don't worry, though. We're here to help. To start off with, we're going to reinforce your house with six tons of cement, to protect you against rockfalls. The construction crew will arrive tomorrow morning. Now, as for those blizzards..."
The man had had enough of this.
"This is absurd. Now look - there is a guy who really does live on top of the mountain in a rickety old shack. Old Grandpa McHermit. He might actually need your help. I don't. Get out! And if I see anyone with a bag of cement tomorrow morning, I'll shove it right up their..."

---

As you may have guess, this story is a metaphor. There is a movement in psychiatry at the moment, away from a 'categorical' view of mental illness towards a 'spectrum' view. Mental disorders are not things you either have or don't - defined according to some arbitrary cut-off. Rather, they're things that everyone has, to some degree.

This has already happened, or is happening, to autism, schizophrenia, bipolar disorder, personality disorders, and more.

Now, the "spectrum" or "dimensional" approach has much to recommend it. It's true that diagnostic cutoffs are arbitrary. It's true that the categorical approach doesn't capture the true degree of variation that real people display.

My worry is that these new "spectra" are, in practice, merely the old categories, just bigger. We still think of people as being ill or not-ill, although we may call it on the spectrum or off it. Worse, we still think of "ill" in the same way as we used to i.e. as referring to the most severe end of the spectrum. The only difference is that we've expanded the old category of "ill" to cover more people.

This is evident in the fact that we still use the old categorical labels. It's the autism (or schizophrenia or bipolar) spectrum, even though "autism", in the old sense of a discrete disorder, is now supposed to be just one extreme of that spectrum. Yet the point about an extreme is that it's unusual, so why call it that?

We don't call the rainbow the red spectrum. We don't call height the midget spectrum. We don't call hills part of the mountain spectrum.

The point is, we really think of color and height and altitude as spectra, not as approximations to an extreme point, and that's good, because they are. Now it might well be possible to think of autistic or bipolar traits in the same way - but not if we call them autistic and bipolar traits. And not if we just rename them, while keeping the mental associations the same.

Not unless we can find a way of referring to what's currently called the autism spectrum without making anyone think of autism when they hear it. Similarly for "bipolar" and all the rest. Until we get to that point, there's a real risk that "spectra" will just be big categories.

Edit: This post has been very kindly translated into Hebrew over at the alhasapa.com blog.

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

New Mutations - New Eugenics?

True or false: you inherit your genes from your parents.


Mostly true, but not quite. In theory, you do indeed get half of your DNA from your mother and half from your father; but in practice, there's sometimes a third parent as well, random chance. Genes don't always get transmitted as they should: mutations occur.

As a result, it's not true that "genetic" always implies "inherited". A disease, for example, could be entirely genetic, and almost never inherited. Down's syndrome is the textbook example, but it's something of a special case and until recently, it was widely assumed that most disease risk genes were inherited.

Yet recent evidence suggests that many cases of neurological and psychiatric disorders are caused by uninherited, de novo mutation events. Here are two papers from the last few weeks about schizophrenia(1,2) - but the story looks similar for autism, intellectual disabilities, some forms of epilepsy, ADHD, and others. Indeed they're often the same mutations.

Biologically, a given mutation is what it is, whether it's de novo or inherited. But on a social and a psychological level, I think there are crucial differences, and in particular I think that if it turns out that de novo mutations are important in disease, we're going to see attempts to take these variants out of circulation - far more so than in the case of the very same genes, were they inherited.

The old eugenics movement was based on the idea that if we stop people with bad genes from breeding - by sterilization, voluntary or otherwise, say - we'll be able to eliminate diseases and other undesirable traits. This idea is now generally regarded as extremely unethical, but many of its opponents have shared with the eugenicists the belief that it could work.

But if de novo mutations are what cause the majority of disease, then this approach would be pointless. Sterilizing certain people, or encouraging the healthy ones to have more children, would never be able to eliminate the 'bad genes' because new ones are being created every generation, pretty much at random.

So the de novo paradigm ought to be welcomed by opponents of eugenics. It wasn't just morally wrong - it was biologically misguided too.

But hang on. This is the 21st century. We have in vitro fertilization (IVF), and you can analyze the genes of an IVF embryo before you decide to make it into a child. In the near future, we might be able to routinely sequence the genome of any unborn child shortly after conception.

From there, it would be a small step to allowing parents to decide not to have children with de novo mutations.

This would be, in its effects, a form of eugenics - in the sense that it would produce the effect that the old eugenicists wanted. No more 'bad' variants, or not nearly as many. Opinions will differ as to whether it's morally different. But I would have said that politically, it's a lot more likely to happen.

I can't see forced sterilization returning any time soon. But if you were expecting a baby and you knew that it was not just carrying your and your partner's DNA, but had also suffered a mutation - might you not want to avoid that?

Psychologically, it matters that it did not inherit the variants. It would be a big step to decide that your child should not inherit part of your own DNA. Of course, some variants are obviously harmful, like one that raises the risk of cancer, and I can't see how anyone would want to pass those on. But think about the grey areas - a variant for social anxiety, mild autistic symptoms, obesity, a personality trait.

You might well feel that carrying that variant is what makes you, you; and so it would be natural for your child to have it. You might decide that if it was good enough for you (and all your ancestors), it's good enough for your children. You might well resent the very idea that it's a 'bad gene' at all, as an attack on your own self-worth.

But none of that applies if it's a de novo mutation. Indeed, quite the opposite - all those same considerations would probably lead you to want your children to carry as close as possible to a carbon copy of your DNA, with no random changes. It was good enough for you.

My point is that I think there will be much more support for the idea of genetic screening or other action against de novo variants than against inherited ones. More people will want it, it will be more socially acceptable, and used more widely. I'm not saying this would be a good or a bad thing, just making a prediction. In the future, diseases and traits that are primarily caused by de novo mutations will increasingly selected against.

Susan Greenfield Causes Autism

British neuroscientist Susan Greenfield has caused a storm with her suggestion that the recent rise in the use of the internet and social media may be related to the recent rise in autism.

I point to the increase in autism and I point to internet use. That's all. Establishing a causal relationship is very hard but there are trends out there that we must think about.

This has led to fellow Oxford neuroscientist Dorothy Bishop of BishopBlog writing an Open Letter asking her to "please, please, stop talking about autism". Twitter has been enlivened by #greenfieldism's such as "I point to the rise of Rebecca Black and the Greek sovereign debt crisis, that is all."

However, in a Neuroskeptic exclusive, I can reveal that the situation is far worse than anyone feared. Greenfield is not merely spreading unwarranted speculations about the recent rise in autism diagnoses.

She caused that rise.

The graph above shows the total number of scientific citations for Susan Greenfield's papers, over time. This is as good a measure as any of the influence Greenfield has had over our culture.

The trend is obvious, the growth is dramatic, and the correlation with the modern autism epidemic is undeniable.