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.
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
13 comments:
Where'd the brains come from? Accidental deaths? One of the big problems in post-mortem studies of psychiatric illness if finding similar causes of death because we know that the manner of death (e.g. if its traumatic or particularly slow) can alter the brain tissue.
I imagine that is even more of an issue with the brains of children which can't be that easy to come by. PM studies of conditions like schizophrenia or depression use significantly older subjects than, e.g., imaging studies because, fortunately, young people tend not to die so much, making tissue scarce. I imagine the brains of children are very rare indeed.
Well, one of the obvious questions about this study is how much variability there is in brain weight and PFC cell counts within the control population. Even in this small sample, there is some overlap between controls and cases, suggesting that increased cell numbers per se may not have a causal relationship to autism. Moreover, I suspect with a larger sample we will see significant overlap in these measures between cases and controls.
Nonetheless, this study certainly supports the idea that some genetic or environmental abnormalities during development may affect both cell proliferation and psychosocial outcomes, which certainly helps narrow down some of the causal factors which may underlie autism.
I'm not sure this study means the origin of the effect must be prenatal. Babies with / without ASD could be born with the same number of prefrontal neurons, but neurons are lost (pruned?) faster in the typical kids, leaving the ASD kids with more. This could be happening at any age.
You can see the variability in the figures reproduced in the post.
Thanks for this.
Like Anonymous above, I was a little unclear how they could infer that the causes must be prenatal. They make a big thing about the need to look at kids because brains change over time. But then argue that the changes they're interested in are fixed at birth. Showing my ignorance here, but is it the case that only connections are pruned in childhood and actual cell bodies are not?
The SFARI website have some quotes from other researchers. This one is particularly damning:
"I know that sample," says Lange, who is on the advisory board of the Autism Tissue Program, which manages some of the samples in the study. "It's of varying quality, from poor to acceptable."
I'm fully appreciative of the rarity of child autism post mortem brains. But the main limitation for me is the low number of control brains. Surely these would be much easier to come by. At least if you had, say, 20-30 control brains, you'd be able to say with some confidence which of the autism brains were outside of the normal range.
Sorry. Link to the SFARI piece here:
http://sfari.org/news-and-opinion/news/2011/autism-brains-have-too-many-neurons-study-suggests
Considering that it is now more and more generally acknowledge by the scientists and clinicians in the field -except in France where too many psychoanalysts psychiatrists and psychologists still apply their idiosyncratic way of thinking about autism- that The Autism is to be replaced by The Autisms would you not need a very larger number of autistic brains and control to obtain sound results and why not use adults brains since autism is a lifelong condition? (Of course I understand that studying the brains of autistic children would be interesting if in sufficient quantity).
The new geneticists electronic toys has given them a bit of a headache: they are no longer studying painfully a few mutations and looking for it in persons affected, their relatives and controls; now they have access to any mutation without particularly looking for it and they found too many CNVs (copy number variations) for the autisms not replacing the autism. In addition to that some scientists are now considering that the same CNV could predispose to autism and schizophrenia (to say nothing about the new blurred frontiers between schizophrenia and mood disorders).
The replacement of autism by the autisms is congruent with the many different clinical pictures and different clinical outcomes of a given clinical picture(natural history as well as effects of the therapeutic approaches) of the autistic children and adults.
In addition to the questions about validity in details and how representative of their constituents these 7 may be, I think it should be noted that these findings should not be entirely surprising.
It has been shown previously that denser, smaller minicolumns are highly correlated with autism. A more dense organization of neurons should of course relate to a greater number of neurons.
pseudonymoniae
When seven boys with autism's brain and six controls, ranging in age from 2 to 16 years have been studied, you wrote:
"(...)This study certainly supports the idea that some genetic or environmental abnormalities during development may affect both cell proliferation and psychosocial outcomes
which certainly helps narrow down some of the causal factors which may underlie autism."
Can you elaborate a little more since so many things happen to humans in 16 years of life?
Sure. If indeed the hypothesis which this study supports is correct, namely that there is a causal association between abnormally high numbers of cells in cortex and ASD (at least in some individuals), then it is highly suggestive of certain factors which might be important determinants of autism. For example, it has been pointed out that mutations in the tumor suppressor PTEN has been associated with some cases of autism. Other factors influencing cell proliferation, both genetic and environmental, might similarly affect the probability that an individual is diagnosed with ASD. Hence, common pathways associated with macrocephaly and ASD are obvious targets for further exploration.
Nonetheless, this relationship is hardly a new idea, so it's not as though this paper does much except add a touch of support to the hypothesis.
pseudonumoniae
Thanks for answering me and reassuring me: I didn't miss major advances on the etiological front in ADS.
You seem to me very likeable as a person for many reasons starting with the fact that you choice of an uncommon pseudo makes it possible to follow your line of thinking. You have many valid reasons to write under a pseudo if you are indeed a PhD candidate. I hope you are one because societies in general need good enthusiastic and generous open minded researchers.
Nb: the lack of abilities of clinicians probability to diagnose ASD (and not misdiagnosed Asperger with personality disorder like antisocial for example) could biases the result of analyzing even a huge anatomic samples of brains from a brain bank b it only if you have a lot of undiagnosed Asperger in the control group (first educated guess of mine when the data show an overlap).
The quality of education and beliefs of the clinicians involved in the process is a key factor Neuroskeptic produced a very interesting post with a brilliant metaphor Mountains of Mental Disorders about “spectrum disorder” (some of the comments are worth reading too).
In France the people on the spectrum and family may of course understandingly do everything in order to avoid being diagnosed by ignorant and dangerous psychoanalyst clinicians. See another post of Neuroskeptic in October on packing , a cruel and paternalistic imposing of abuse of suffering people and family by people maintaining themselves out of the progress of medical science in the field of autism (still accusing the mother to be responsible because of their lack of love of the condition is still encouraged in France by academics.
Hi Neuroskeptic -
I was wondering about whether or not this paper:
http://www.ncbi.nlm.nih.gov/pubmed/21964341
Indicated that perhaps, there are mechanisms by which new neurons can be generated in the prefrontal cortex during infancy.
he subventricular zone of many adult non-human mammals generates large numbers of new neurons destined for the olfactory bulb. Along the walls of the lateral ventricles, immature neuronal progeny migrate in tangentially oriented chains that coalesce into a rostral migratory stream (RMS) connecting the subventricular zone to the olfactory bulb. The adult human subventricular zone, in contrast, contains a hypocellular gap layer separating the ependymal lining from a periventricular ribbon of astrocytes. Some of these subventricular zone astrocytes can function as neural stem cells in vitro, but their function in vivo remains controversial. An initial report found few subventricular zone proliferating cells and rare migrating immature neurons in the RMS of adult humans. In contrast, a subsequent study indicated robust proliferation and migration in the human subventricular zone and RMS. Here we find that the infant human subventricular zone and RMS contain an extensive corridor of migrating immature neurons before 18 months of age but, contrary to previous reports, this germinal activity subsides in older children and is nearly extinct by adulthood. Surprisingly, during this limited window of neurogenesis, not all new neurons in the human subventricular zone are destined for the olfactory bulb--we describe a major migratory pathway that targets the prefrontal cortex in humans. Together, these findings reveal robust streams of tangentially migrating immature neurons in human early postnatal subventricular zone and cortex. These pathways represent potential targets of neurological injuries affecting neonates.
Any insight would be appreciated.
- pD
pD - Wow. That is extremely interesting. I'll have a read of the full paper. Thanks for the tip off!
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