Sheldon Cooper, BBC Sherlock and Abed from Community walk into a bar. The bartender looks up and says “Is it gonna be a joke about media overusing the Autism trope?”.
My awesome sense of humour aside, If there is a mental disorder overrepresented in the media then it’s (high-functioning) autism. The writers love themselves some genius socially awkward nerds solving unsolvable riddles and making ordinary people look adorably illogical. But how true is this stereotype? And what does autistic mean, if it’s not exactly Sheldon Cooper? Some people believe it equals the Rain Man-esque ability to count all matches in a box at one glance and others might think it means over-the top lack of social skills and having a huge bottle cap collection. Mostly, the reality is somewhere in between: autism is very broad (it’s called autistic spectrum disorder for a reason!) and no two diagnoses are the same. So let’s see what it really is and how the brain is involved.

Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a name for a whole group of brain development disorders. It is quite common: about one percent of the world population has it (with men being diagnosed 4-7 times as often as women). Apart from the -- obviously -- autistic disorder it includes Asperger’s (commonly known as milder, high-functioning autism) and pervasive developmental disorder (which is somewhere between Asperger’s and autism). All of these conditions are characterized by impaired social and communication abilities and repetitive/structured behavior and interests; the severity of particular impairments determines where on the spectrum the person will land. Someone might be silent and completely locked in some repetitive kind of activity for hours, while someone else would talk non-stop about their special interests, not take a clue about when to stop and completely miss irony or sarcasm.
What ASD does not automatically mean, however, is genius intelligence (sorry, Sheldon!). Level of cognitive functioning in autism ranges from profound disability to superior intelligence ¹ . While the view that autism is generally associated with lower IQ is becoming a bit outdated (as scientists start to acknowledge that it might result from the common IQ tests not tapping the true cognitive ability of many autistic children), more recent studies show that almost half of the children with ASD had average or above average intelligence ² . Also, to make everything a bit more complicated, a relatively new study published in Nature showed that genes linked with a greater risk of developing autism may also be associated with higher intelligence (also people who were carrying the genetic combination in question but didn’t have ASD scored better on cognitive tests) ³ .
ASD has no single known cause; generally, it is agreed that genetic components play a very important role ^{4, 5, 6} (autism tends to run in the family, identical twins are more likely to both have it than fraternal twins etc etc). Still, it is not clear, what exactly happens there: there is not one "autistic gene" but rather a complex bundle of interactions. However, another thing that is clear (and important for this blog post) is that at least some of the involved genes are responsible for the mishaps in the ASD brain development.

Autistic Brain
There are quite some aspects in which autistic brains differ from the “neurotypical” ones. First of all, children with ASD generally have bigger brains. ^{7, 8, 9} One of the possible reasons is the larger amount of white matter as compared to non-autistic people. In the period between 6 and 14 months children normally undergo a phase of rapid synapse (=connection between nerve cells) growth which is then followed by a process called “pruning” where unnecessary connections are eliminated. It is thought that pruning doesn’t go as planned for children with ASD leaving them with an unusually large number of synapses that are in the way of efficient information transfer. One study has examined brains of autistic children of different ages (who died of some unrelated causes) and found that by the late childhood, the number of synapses in their brains had dropped by only 16 percent, whereas in the control brains it dropped by about half ¹⁰ . They also found the possible cause behind it: a protein which is normally supposed to help the cells to, however harsh it might sound, destruct some of their parts (=autophagy) was defective. It resulted in these excess synapses and brain cells filled with old and damaged parts which couldn’t have been disposed properly. The scientists managed to restore normal autophagy and pruning and reverse autistic-like behaviour in mice by giving them a drug that made this defective protein function normally again.
Another factor which might contribute to the larger brain size is the number of neurons in the prefrontal cortex, the brain area responsible for complex stuff like reasoning, communicating, managing social interactions etc. It was found that autistic boys have 67 percent more neurons in their prefrontal cortex (and 17 percent heavier brains) than their non-autistic peers ¹¹ . Quantity does not equal quality in this case, however: it means a huge increase in potential connections and thus a potential for faulty wiring between brain cells. It is also interesting to say that the prefrontal cortex neurons are born during pregnancy meaning that autism starts as early as in the womb. This paves the way to understanding the exact molecular mechanisms behind the abundant neuron production and possibly -- let a girl dream a bit -- developing treatments counteracting it.

The small white blobs (=dendritic spines) are the connection sites of a neuron. Right: too many spines. Left: the autophagous protein is back in the game and the number of spines is reduced back to normal. Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center

Speaking of connections gone awry. We know that autistic brains are wired differently but we don’t really know exactly how (as the results of connectivity studies are quite inconsistent due to different methods and samples). Some studies have found that ASD brains are hyperconnected^{12, 13}, while others say that the connections are too weak^{14, 15}. Nevertheless, scientists believe that they start to see some converging themes in all that clutter, such as fewer (and weaker) long-range connections between far-flung areas and more short-range local connections within brain regions¹⁶.

These findings is what the “intense world theory”¹⁷ of autism bases upon: it says that local hyperconnectivity in distinct brain regions leads to excessive functioning which in turn leads to hyper-responsiveness to information and extremes in attention and perception. While it sounds like a good thing (and might explain the abilities of savants), the weak long-range connections make it harder to make sense of all the incoming information and to figure out which of the sources of information to pay attention to (as the information can’t get properly integrated). This can be quickly become overwhelming, the theory claims, so that people with ASD try to deal with this sensory overload by social withdrawal or repetitive behaviours (to create some sense of stability and keep the painfully intense world at bay). While this theory definitely sounds interesting, caution is urged until it is sufficiently investigated.

Upper row: connections that are weaker in ASD patients as compared to healthy controls. Lower row: connections that are stronger in ASD. From http://www.nature.com/mp/journal/v19/n6/fig_tab/mp201378f2.html

A large component of ASD is impaired ability to engage in social relationships. Autistic people may appear either not interested or not able to read social clues. Most common problems include, to a greater or lesser extent, inability to understand facial expression, sarcasm and irony, feelings and perspective of others. There are a couple of things in the brain that might explain this.
There is a model of the development of social skills¹⁸ which posits that we have an inborn perceptual bias for faces and that amygdala, one of our emotional centers, reinforces this bias by making babies feel good when they look at their hopefully happy and loving caregivers. As a consequence we look at faces a lot and get a lot of experience with processing and “reading” them. This happens with the help of an area called “fusiform face area” (FFA) which, with all this experience, really steps up the computational analyses involved in the face perception. The model hypothesizes that these skills provide the “scaffolding” for understanding non-verbal communication and more complex social interactions. Its conclusion for autistic children is that that they have some early dysfunctions in amygdala and fusiform face area which in turn impairs the whole social skill development.

And there is some evidence for it. Eye-tracking studies revealed that people with ASD have a distinct gaze pattern: they either spend much less time looking at faces in a video showing people talking than healthy controls¹⁹ or, when looking at the face at all, prefer to put their gaze on the mouth instead of the eyes (like healthy controls would do)²⁰. This gaze behavior falls in line with missing social cues and having trouble interacting with others, which are often found in ASD people. Another study showed that autistic people tended to move their eyes away from other persons eyes and the longer the eye contact the more active amygdala was -- implicating higher avoidance processing (avoiding bad stuff is another thing amygdala is useful for)²¹. Moreover, with increasing age amygdala decreases in size in autistic people in comparison to neurotypical ones²²; fusiform face area also suffers some atypical changes: its activation in response to faces is much weaker in autistic brains^{23, 24}, as is its connection to amygdala²⁵ (falls in line with findings showing how autistic children have problems interpreting facial expressions).
Furthermore (finally, all these fancy conjunctions words I learnt in my English lessons are useful for once!), in a very recent study scientists turned on and off empathy-like behavior in rats by manipulating a specific circuit in amygdala²⁶. When the medial part of amygdala was shut down rats cold-bloodedly regarded a fellow rodent receiving an electric shock; when it was turned back on they suddenly showed empathy again (which for the rats means freezing in solidarity with the hurt buddy). Another potential target for a pharmacological intervention to help people gain social abilities!

The red lines show the gaze path used by people with (right column) and without (left column) autism to explore faces. Modified from Pelphrey et al., (2002)

Another thing autistic brain can cause problems with is empathy (of which there are two kinds: cognitive, as in “I understand what this person is feeling” and affective, as in “I can feel for this person”) and Theory of Mind. ToM means the ability to understand that other people have their own thoughts, emotions and points of view. It allows us to predict behaviours of others based on what we think they might be thinking. And of course, it is overly simplistic to say that all autistic people do not understand that other people have their own point of views, beliefs and whatnot. Depending on the position on the spectrum, a lot of them do understand it; it’s just that these beliefs are often a mystery to them. A to-go task to see whether a child is lacking ToM is Sally-Ann task pictured below (and autistic children are mostly failing to resolve it correctly).

It is generally harder for autistic kids to realize Sally will look in the basket, where she originally hid the marble.

Problems with empathy are also not that straight-forward. Some studies have suggested that ASD people mostly have problems with the cognitive empathy -- it is difficult for them to 'step into another person's shoes' and understand what they are feeling^{27, 28, 29}. The affective empathy, however, seemed to be less of a problem -- as soon as they understood what the other person was feeling they were able to “feel for the others” and showed an emotional response to their affective state. The psychopaths, on the other hand, are thought to show an opposite pattern: they are good in understanding what’s up with others’ feelings but completely fail to feel along with their distress or happiness²⁹.

There are some candidates for neural underpinnings of ToM. A structure called TPJ (tempoparietal junction) is one of the top players in this network; it is implicated in representing mental state information of others (what does this person believe/feel?)³⁰, visual perspective taking (how does the other person see it?)³¹ and other processes important for ToM³². It was found to show lower activation during a ToM task in ASD patients and this activation also correlated with how severe the symptoms were (the worse the symptoms the weaker the activation)³³. Not only that, the whole network of regions implicated in ToM was found to be hypoactive in autistic people³⁴.
A couple of other studies got down to action and looked whether they can influence how empathetic or ToM-savvy a person is by using non-invasive brain stimulation (which manipulates brain activity by applying either electromagnetic fields or electrical current to the skull). And see there: when TPJ was inhibited people became much worse in ToM and cognitive empathy tests³⁵. When it was excited people got better in taking visual perspective of other people³⁶. Interestingly, in one study, while not specifically intended to cause an emotional awakening (the aim was simply to to measure the impact of the stimulation on object naming) six months of weekly transcranial magnetic stimulation still has caused a man with Asperger’s to experience the following: "Somehow I had read the expressions in her face and answered them instinctively – and correctly. Most people take such abilities for granted, but I had a lifetime of experience missing those cues and saying the wrong things – sometimes the worst possible things – in response to the logical words others spoke to me. . . . You are seeing into their souls, a little voice said. Just then, I felt another flood of emotion and I had to step outside as the wave washed over me. Human eyes had become windows, and the surge of emotion pouring from them was very powerful. And somehow my new ability felt completely instinctive and natural, as if it had been there forever."³⁷ Wow. I experience my emotions every day and I am still overwhelmed by them. Must have been pretty intense for this guy.
Taken together, it seems that non-invasive brain stimulation offers a promising treatment possibility for ASD. Several explorative studies have successfully utilized TMS to alleviate repetitive behaviors, improve speech production and mentalizing etc. tDCS (stimulation type using electrical currents), simple and cheap as it is, also seems to be very worth trying out more. Wouldn’t it be cool if we reliably identified a switch to flip to turn on empathy and ToM?

And last but not least, an answer to the burning question. Do vaccines cause autism?
No.