A Grand Unified Theory of Autism?

Neuroskeptic iconNeuroskepticBy NeuroskepticJan 5, 2011 8:25 PM


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A physicist famously wanted to find the grand unifying equation behind the laws of nature, in a form that you could put on a t-shirt.

Neuroscientists Kamilla and Henry Markram have proposed a grand unifying theory of autism, and the key to it is in this picture. I wouldn't want to be seen wearing it quite yet, but if the theory pans out, I'm sure we could come up with a more torso-friendly diagram.

So what does this mean? The Markrams call their idea the Intense World Theory. Essentially, they propose that all of the diverse symptoms of autism are direct or indirect consequences of the autistic brain's being hyper-responsive to stimuli. (They published an earlier version of this theory in 2007).

Not the brain as a whole, and not each individual cell, either. Rather, they say that the abnormality lies in local microcircuits. The best known of these are the cortical columns and minicolumns. Neurons in any given microcircuit are connected both with their neighbors, and with more distant cells. A bit like a large company with offices in different cities: people within each office talk to each other, but they also phone and email the other branches.

The theory goes that the autistic brain has too many connections within any given microcircuit. So, when the circuit is activated, it reactivates itself too strongly, and shows a stronger, and longer, excitation. A bit like if the offices were open-plan, so everyone can overhear everyone else, and it all gets very noisy.

So what's the evidence for this? There's circumstantial support. It "makes sense", if you're willing to accept an analogy between hyperactive local neural circuits and hyper-intense psychological phenomena.

We know that a given cortical minicolumn responds to a particular type of stimulus, or aspect of a stimulus; there are minicolumns for horizontal lines, for lines at 10 degrees to the horizontal, and so on. People with autism are often fixated on little details. It's a leap, but not an impossible one, to see these as related.

But the only really direct biological evidence is from rats. The story starts with valproate (VPA), an effective anticonvulsant also widely used in bipolar disorder. VPA has to be used with extreme caution in women because of the risk of birth defects.

Children whose mothers take VPA (and to various degrees other similar drugs) during pregnancy often suffer various physical and behavioural problems, the fetal anticonvulsant syndrome. Sadly, this happened quite a lot in the past, before the risks were appreciated. The key point is that autistic symptoms extremely common in children exposed to high-dose VPA.

Markram (and other people) have studied rats exposed to valproate in the womb. They found that, well, they're weird. Proponents would say that they behave a lot like how an "autistic" rat would: they are less sociable, prone to repetitive behaviours, highly anxious, etc.

Can a rat "have autism"? That's one to ponder. On the one hand, rats are surprisingly smart, sociable animals. For every human brain region, there's a rat equivalent in roughly the same place, which does roughly the same thing. They have cortical columns and minicolumns like ours (we just have more of them). They even "laugh" when you tickle them. On the other hand... they're rats. They run around gutters eating trash.

The t-shirt image at the top of this post is based on Markram and colleagues work on the cortical network properties of VPA-exposed rats (e.g. this and several other studies). These studies revealed hyper-connectivity within local microcircuits, and have also shown that circuits from VPA-exposed rats "learn" faster: they form new synaptic connections via the process of LTP at an accelerated rate, likely due to over-expression of NMDA glutamate receptors.

They admit that it's a big leap from that to human autism. But it's not an impossible leap. As they say:

This provided the potential cellular and circuit explanation for how an autistic brain could be easily trapped in a painfully intense world, potentially explaining a broad range of common autistic symptoms such as sensory sensitivity, withdrawal, repetitive behavior, idiosyncrasies, and even exceptional talents.

The major attraction of the theory is that it is a unified one: it seems to explain everything about autism, although maybe it's just vague enough to be stretched to cover anything. For example, Markram attributes the social awkwardness of autistic people to an overactive amygdala, which makes them extremely anxious in social situations, especially when meeting people's gaze; this, he says, means that they quickly learn to avoid other people in an attempt to cope with this Intense World.

Henry Markram is best known as the leader of the Blue Brain Project, which aims to simulate a brain using supercomputers. So he's no stranger to big ideas. Whether this idea is as solid as it is big remains to be seen, but I think he's to be applauded for at leasthaving a crack at a unified account of autism, something which, as far as I know, no-one else has had the guts to try yet

(Edit: But see the comments for a debate on that question)


Markram K, & Markram H (2010). The intense world theory - a unifying theory of the neurobiology of autism. Frontiers in human neuroscience, 4 PMID: 21191475

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