Do kids with autism have big brains?

Like most things in autism research, the idea that people with autism have big brains goes back to an observation in Leo Kanner’s original autism paper, where he noted that some of the kids in his group had larger than normal heads. Over the years, there have been dozens of studies looking directly or indirectly at the issue of brain size in autism. In 2005, Martha Herbert provided a comprehensive review [pdf] of 25 such studies, describing the tendency towards large brains as "the most replicated finding in autism neuroanatomy".

Redcay & Courchesne 2005

Also in 2005, Elizabeth Redcay and Eric Courchesne published a meta-analysis, in which they ingeniously plotted how much bigger or smaller than average the autism brains in different studies were as a function of the mean age of the participants in the study. They concluded that there is an early period of brain ‘overgrowth’, with autistic brains being on average 10% larger than normal. But then growth slows down and typically developing kids eventually catch up.

Redcay & Courchesne's meta analysis. Red circles (my annotation) indicate studies in which brain volume was inferred from head circumference measures.

Redcay and Courchesne's paper has been extremely influential. But their analysis rests on a number of assumptions that are worth highlighting.

First, the data are cross-sectional. Different people are being measured at each of the different ages. This is inevitable because brain imagining technology hasn't been around long enough for a proper longitudinal study be conducted, following individuals over the first decades of their life. But if we think of the curve as being the actual growth trajectory of a person with autism (as Redcay and Courchesne want us to) then we are essentially assuming that a 30-year-old autistic adult in one study is what a 5-year-old in another study will be like a quarter century from now. This is a pretty big assumption.

Second, data for the youngest age groups actually came from measurements of head circumference taken during regular infant check-ups, rather than actual brain scans. Head circumference is correlated with brain size in infants, and realistically it's the only way to study brain size in autism pre-diagnosis. But in order to plot the data on the same graph, Redcay and Courchesne had to make quite a few assumptions about the relationship between head size and brain volume [1].

Courchesne et al 2011

More recently, Courchesne and colleagues published an update, pulling together data from all of their MRI studies. The data were still largely cross-sectional but, this time, they fitted growth curves to the data from autistic and non-autistic individuals.

This gives a clearer sense of the variation within each group, which, even for typically developing children (blue circles), is huge. Having a brain that is 10% bigger than average (as Redcay and Courchesne's analysis suggests) isn't actually all that abnormal. Nonetheless, Courchesne et al.'s curve-fitting led them to again conclude that autism is associated with “early brain overgrowth”.

Individual brain volume data as a function of age (Courchesne et al., 2011). Red squares are boys with autism. Blue circles are typically developing boys.

Comparing the two curves suggests that the difference between autistic and non-autistic brains is largest in the period between around 20 and 32 months (which I've conveniently highlighted). However, if we look at the actual data in this period, ignoring the curves, then we see that none of the autistic kids had brains that were unusually large for their age.

The curve for the typically developing boys is strongly curved because it has to fit the data from the youngest kids (12 to 18 months). The autism data don’t start until around 20 months, so the curve is inevitably less curvy. This gives the impression of a big difference in brain size at around 2 years of age, which I don't think really exists in the data.

That being said, there were quite a few 3- to 4-year-olds who did appear to have relatively large brain volumes.

Nordahl et al 2011

Just before Christmas another MRI study of brain size in autism came out. Christine Nordahl and colleagues focused on a narrow age range, around 3 years, when the "overgrowth" appears most evident.

Before discussing their results, it's worth mentioning their methods: While previous MRI studies have involved sedating the kids with autism in order to keep them still (and get them near the scanner in the first place), Nordahl and colleagues' solution was to scan the kids in the dead of night while they slept. Heroically, they scanned 114 autistic kids and 66 non-autistic control children in this way. I imagine a lot of coffee was drunk.

13 of the 114 autistic children met the criteria for megalencephaly - the technical name for a big brain - defined here as having a brain volume that was more than 2 standard deviations greater than the control group mean. Put another way, 89% of the autistic kids had normal-sized brains. This shouldn't be surprising. Courchesne et al.'s study appears to show something similar, as indeed do most of the previous studies of head and brain size.

Nordahl et al. noted that 11 of the 13 autistic kids with large brains were boys who were reported by their parents as having undergone regression - losing skills that they had previously acquired. In fact, when they looked at all the boys who had regressed, they found significantly larger brains than for typically developing boys. And when they looked back at head circumference measures from the first year of life, the boys who went on to regress had significantly larger heads than the typically developing boys from as early as 6 months [3].

In contrast, increased brain and head size was not found in the autistic boys with no history of regression. Nor was it a characteristic of autistic girls, regardless of whether or not they had regressed.

Distribution of head sizes in Nordahl et al (2011). Green line (added) shows the approximate cut-off for magalencephaly in boys

It's fair to say that Nordahl et al.'s results are still preliminary. As the authors note, they rely on parents' reports of their child's early development, which may not be very accurate. Also, there isn't, as far as I can tell, any precedent for a link between regression and increased brain size [2]. So the results should be treated with more caution than if they had been grounded in previous research findings.

Finally, Nordahl et al. only report total brain volume. They didn't look at what parts of the brain were enlarged or otherwise, or whether different types of brain tissue were affected differentially.

Mechanisms of overgrowth

This brings us to the really interesting question, which is not whether kids with autism have large brains (the answer, if you hadn't gathered by now, is that some do and some don't); but why?

A recent study by Courchesne and colleagues linked increased brain size in autism to an increased number of neurons in prefrontal cortex. But in an earlier MRI study, Courchesne et al (2001) reported that it was the white matter (essentially the axons that connect different brain regions) that was disproportionately enlarged in young autistic children.

In her 2005 review, Martha Herbert speculated that increased brain size might be related to reduced brain connectivity (see also this intriguing paper by Sarah White). It's not entirely clear to me how that would work and I'm not aware of any research showing that larger brains are less well connected. It might be that the link is less direct - perhaps a genetic variation that leads to increased brain size also puts a child at increased risk of autism through a different mechanism.

One thing we can be sure of. Making sense of the association between autism and large brains is going to be far from straightforward. Not only do most people with autism not have large brains, but most people with large brains don't have autism [4]. Large brains have also been reported in relation to other disorders including language impairment and ADHD. And just to add further complication and intrigue, there's evidence that relatives of people with autism tend to have large heads, even if they don't have autism themselves. 

Here, I think, we have autism research in microcosm. A finding that dates back to Kanner, that consistently holds up across studies, but doesn't hold up across individuals within those studies; overlap with other developmental disorders and continuity with non-autistic family members; and theories that don't quite stand up to close scrutiny. It's an illustration of how complicated the answers we're looking for are likely to be, and the fact that the answers are likely to be different for different individuals.

Footnotes:

[1] In order to convert head circumference into brain volume, Redcay and Courchesne adopted the following procedure:

• They took normative data on brain weight at different ages from a Danish post-mortem study and converted this to brain volume based on an estimate of brain density from one of their own studies. 
• They then matched up the brainweights with normative data on head circumferences from an American study.
• These pairs of values were entered into a linear regression analysis, along with data from MRI scans of older children.
• The regression equation was used to convert circumference into volume.

It's difficult to see what else they could have done, but given how influential the study has been, it's important to highlight how many assumptions were involved. It's also a little strange that they assumed (or found) a linear relationship between head circumference and brain volume - when mathematics teaches us to expect a cubic relationship between circumference and volume.

[2] I recently came across a blogpost discussing the fact that none of the kids in Kanner's 1943 study had regressed. I can't track this down (please comment if you know what I'm talking about). But, given that Kanner first noted the children's big heads, it would put him at odds with the authors of this paper.

[3] It's not reported whether the boys with large heads at 6 months were the same boys who had large heads at age 3.

[4] I'm not sure if there is any research on this, but if we define megalencephaly as 2 standard deviations from the mean then roughly 2.5% of the population have megalencephaly (assuming a normal distribution). Even with a generous 1% prevalence for autism, I think it's safe to say that the majority of people with megalencephaly are not autistic.

References:

Courchesne, E., Campbell, K., & Solso, S. (2011). Brain growth across the life span in autism: Age-specific changes in anatomical pathology Brain Research, 1380, 138-145 DOI: 10.1016/j.brainres.2010.09.101

Nordahl, C., Lange, N., Li, D., Barnett, L., Lee, A., Buonocore, M., Simon, T., Rogers, S., Ozonoff, S., & Amaral, D. (2011). Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders Proceedings of the National Academy of Sciences, 108 (50), 20195-20200 DOI: 10.1073/pnas.1107560108 Download PDF

Redcay, E., & Courchesne, E. (2005). When Is the Brain Enlarged in Autism? A Meta-Analysis of All Brain Size Reports Biological Psychiatry, 58 (1), 1-9 DOI: 10.1016/j.biopsych.2005.03.026 Download PDF