BOUNTIFUL BRAINS: Eric Courchesne's studies suggest that autistic brains brim with too many neurons for their own good.
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As a baby grows inside the womb, its brain does not simply expand like a dehydrated sponge dropped in water. Early brain development is an elaborate procession. Every minute some 250,000 neurons bloom, squirming past one another like so many schoolchildren rushing to their seats at the sound of the bell. Each neuron grows a long root at one end and a crown of branches at the other, linking itself to fellow cells near and far. By the end of the second trimester, neurons in the baby's brain have formed trillions of connections, many of which will not survive into adulthood—the least traveled paths will eventually wither.
Sometimes, the developing brain blunders, resulting in "neuro-developmental disorders," such as autism. But exactly why or how early cellular mistakes cause autism has eluded medical science. Now, Eric Courchesne of the University of California, San Diego, thinks he has linked atypical gene activity to excessive growth in the autistic brain. With the new data, he has started to trace a cascade of genetic and cellular changes that he thinks define autism. Although intrigued by Courchesne's work, other researchers caution that explosive neural growth is not necessarily a defining feature of all autistic brains.
Since 1998 Courchesne has been searching autistic brains for unusual structural features. His studies suggest that while in the womb, the autistic brain sprouts an excess of neurons and continues to balloon during the first five years of life, as all those extra neurons grow larger and form connections. Sometime after age four or five, Courchesne has also found, autistic brains actually start to lose neural connections, faster than typical brains.
In a study published November 2011 in JAMA, The Journal of the American Medical Association, Courchesne reported that children with autism have 67 percent more neurons in their prefrontal cortex (PFC) than typical children. Located in the area of the brain just behind the eyes, the PFC is responsible for what psychologists call "executive functions"—high-level thinking, such as planning ahead, inhibiting impulses and directing attention. In his 2011 study Courchesne sliced up brain tissue from six autistic children and seven typical children who had passed away and counted the number of cell bodies in the sections to estimate the total number of neurons in their PFCs.
Now, Courchesne and his colleagues have analyzed DNA and RNA in 33 cubes of brain tissue from people who passed away, 15 of whom were autistic (nine children and six adults) and 18 who had typical brains (seven children and 11 adults). Looking at the order of DNA's building blocks reveals whether individual genes have mutations; measuring levels of RNA indicates how often those genes were translated into proteins. Such gene expression, Courchesne and his colleagues found, varied between autistic and typical brains. In brain tissue from both autistic children and autistic adults, genes coding for proteins that identify and repair mistakes in DNA were expressed at unusually low levels. Additionally, all autistic brains demonstrated unusual activity levels for genes that determine when neurons grow and die and how newborn neurons migrate during early development. Some genes involved in immune responses, cell-to-cell communication and tissue repair, however, were expressed at unusual levels in adult autistic brains, but not in autistic children's brains. The results appear in the March 22 issue of PLoS Genetics.
By combining his new findings with his earlier discoveries, Courchesne has started to construct a kind of timeline of autism in the brain. Perhaps, as the brain of a future autistic child develops in the womb, something—an inherited mutation or an environmental factor like a virus, toxin or hormone—muffles the expression of genes coding for proteins that usually fix mistakes in sequences of DNA. Errors accumulate. The genetic systems controlling the growth of new neurons go haywire, and brain cells divide much more frequently than usual, accounting for the excess neurons found in the PFC of autistic children. Between birth and age five, the extra neurons in the autistic brain grow physically larger and form more connections than in a typical child's brain. Unused connections are not pruned away as they should be. Later, in adolescence and adulthood, the immune system reacts against the brain's overzealous growth, which might explain the unusual levels of immune genes Courchesne found in his new study and why, in earlier work, he had discovered that when autistic children become teenagers, some brain regions actually start shrinking compared with typical brains.
Not all researchers, however, accept that the patterns of brain growth Courchesne has discovered are relevant to everyone with autism. Nicholas Lange, a biostatistician in the psychiatry department at Harvard Medical School, says that Courchesne analyzed too few samples in his new study to generalize the results to the larger autistic community. Some researchers have surfaced evidence that around 15 percent of autistic children have smaller than usual heads, a condition known as microcephaly, which indicates an abnormally small brain. David Amaral of the University of California, Davis, has previously told reporters that in an unpublished neuroimaging study, he found that only about 11 of 114 autistic children had unusually large brains. Other researchers point out that, in his research with tissue samples from brain banks, Courchesne fails to compare the number of neurons in the cerebral cortex with other parts of the brain—it remains unclear why only the PFC would explode in growth.
But acquiring enough preserved tissue from brain banks to conduct meaningful studies is no easy task—they are incredibly coveted resources, and Courchesne's new study relies on a respectable sample. Looking at gene expression in postmortem brain tissue offers insights into the biology of autism that neuroimaging studies and analysis of DNA and RNA in blood cannot provide because different cell types express different sets of genes. Courchesne's newest findings at least partially echo earlier research by Daniel Geschwind of the University of California, Los Angeles, who also linked autism to unusual activity of genes that control immune responses and how neurons organize themselves in the developing brain. Although Courchesne's concept of autistic brain development is far from flawless or complete, it remains one of the most cohesive theories offered so far—one that suggests the possibility of treatment as well. If scientists definitively link autism to a characteristic sequence of changes in gene expression and unusual neural growth, then it becomes possible to target and reverse any one of the thousands of steps in that sequence.
"Each individual autistic person likely has their own specific profile of dysregulated [sic] genes," Courchesne says, "which means that autism is a very complicated problem. But it's now knowable. We are getting at core knowledge. If we confirm that the starting point is gene activity, we can do something about it, because gene activity can be modified."
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14 Comments
Add CommentWow, this seems to be such an obvious area for investigation - why didn't we all think of it before?
Reply | Report Abuse | Link to thisThe normal pruning of unused circuits that has been previously identified by the loss of unused language capabilities at around 5 years of age (Japanese language speakers' loss of the inherent ability to pronounce 'r' & 'l' sounds, for example) seems to be such a likely candidate for many of the common effects of autism.
It would seem that Japanese only speakers who exhibit symptoms of autism might then be expected to NOT lose the inherent ability to pronounce 'r' and 'l' sounds, for example...
Red flags should be raised when a researcher claims to have disovered a single causal mechanism that explains most or all cases or when the timing of the onset of disuption in brain development starts.
Reply | Report Abuse | Link to thisCerebral Palsy has many etiologic causes, genetics, prinatal complications and infections that can occur prenatally or postnatally. The CDC as part of their autism monitering network identified all 8 years in the network with a diagnosis of cerebral palsy + autism. In 8 year olds known to the network 8% had a diagnosis of cerebral palsy + autism (39/476). That result is 8 times greater that the CDC own published prevelance rate of 1/110 and is statistically significant.
http://www.ncbi.nlm.nih.gov/pubmed/21273041
Twenty years ago Courchesne proposed another hypothesis of a single causal mechanism that explained autism in most cases. His 'cerebellar' hypothesis referencing MRI studies and autopsy reports claimed the not brain overgrowth but rather massive losses of cerebellar Purkinje neurons was the mechanism involved in most cases:
Reply | Report Abuse | Link to thisThe Bauman and Kemper autopsies reported massive losses in cerebellar Purkinje cells and curtailed development in the amygdala and hippocampus (too many neurons and they were too small).
http://www.nejm.org/doi/pdf/10.1056/NEJM198805263182102
http://webpub.allegheny.edu/employee/j/jhollerm/558_web/autism_cerebellum/autism_cerebellum_baumanandkemper_2005.pdf
I'm not a scientist, just a Dad who tries to follow the research to help his son, but from what I read, this study should not be overblown. I saw a lecture where Professor Rubinstein of UCSF was asked how many things could go wrong with brain development, and he said "hundreds", and pointed out many things go wrong in some body processes which are vastly simpler, (think it was insulin). The idea that the problems are often not in the DNA, but rather gene expression, epigenetic effects and so forth seems to be commonly accepted, but seems like oversized brains are not the typical result, in fact it almost seems like there is no typical result. A very complex problem.
Reply | Report Abuse | Link to thisRather than performing autopsies on large numbers of autistic children, this hypothesis could be statistically evaluated by identifying inherent capabilities related to neurons that are usually pruned in normal population, such as the phoneme pronunciation capability of specific language speakers, that are not disabled in children diagnosed with autistic symptoms.
Reply | Report Abuse | Link to thisObviously, this example could not be used to test children with severe symptoms who could not speak - there are likely many causes for the broad range of 'Autism Spectrum Disorders'. Personally, my grandson has been diagnosed with Asberger's Syndrome, and I suspect there is a strong familial predisposition. Of course, the diagnosis did not exist when I was a child... In these cases there might be some incidence of slightly larger than usual head sizes.
In the cases of microcephaly there is obviously some marked developmental disorder at work that could produce a broad range of symptoms. With the large number of symptoms thrown together under the ASD 'umbrella', I have to wonder what other conditions my be diagnosed as exhibiting ASD symptoms?
I for one would simply like to see an extensive study conducted to specifically identify whether inherent capabilities that are usually disabled in specific populations after the age of around five. IMO, the results of such a study could offer more compelling corroborating evidence than the analyses of a few autopsies.
It really isn't a new theory. Read "Born on a Blue Day" by autistic savant, Daniel Tammet. He theorized, from personal experience, that autisim is an indication of hyperconnectivity in the brain.
Reply | Report Abuse | Link to thisPerhaps the odd wiring risk of autism, like schizophrenia, is the evolutionary price we simply have to pay for our rather 'recent'brain updates, starting from our ancient hominid 'motherboards'..
Reply | Report Abuse | Link to thisWith 'consolation' prizes of Mozartian Wunderkind calibre, our human lothas been made much more bearable, though.
Epigenetically, we can aim to help as best we can to optimize the balancing act of nature/nurture; luckily this applies to an optimal, species-specific nutrition concept as well, at any age!
Youthevity.com
I find it interesting that people accept that cancer is caused by a pretty broad spectrum of vectors such as a variety of viruses and exposure to certain chemicals. Then these same people look for a magic bullet cause for a spectrum disorder that covers over a hundred distinct characteristic groupings.
Reply | Report Abuse | Link to thisFor a meaningful study on humans and Autism there would have to be some form of neonatal brain tracking on live humans that would continue into adulthood. Each set of symptoms would have to be sorted and then the brain characteristics of each part of the brain compared to determine if particular genetic or genetic expression characteristics are common to all forms, some forms or are specific to only one form. Then you may be able to find a cure for one or more forms or maybe all forms of Autism.
As for my enthusiasm, it's mostly the result of the apparent correspondence of the idea of 'extra', unpared circuitry to the effects experienced by those diagnosed with Asperger Syndrome. It is significantly distinguished from autism in that there is no delay in language development or cognitive abilities. There is a propensity for unusual speech patterns, a tendency towards obsessive-compulsive type behaviors and intense focus. It seems to me that all of these characteristics could be caused by the retention of neurons that are not used and therefore pruned by others in their societies.
Reply | Report Abuse | Link to thisI don't think Asperger Syndrome should have been (recently) lumped into the ASD 'umbrella' by the medical community, primarily because does have basic features that are fundamentally very distinct from those of most autistic disorders and therefore seems less likely to share a common cause. That Asperger Syndrome would be categorized as a ASD would seem to indicate that the medical community considers that there are either common causes or treatments or something...
So, I admit that my comments should have been directed to Asperger Syndrome - that 'extra' neuronal networks produce their specific symptoms and that language testing could be used to confirm the retention of unused speech capabilities that are normally lost during the process in which unused neurons are eliminated at about the age of 5 years.
The failure to learn how to pronounce certain sounds is a loss in the ability of muscles to respond properly. A language is, essentially lost of a person doesn't use it through their early teen years. I would think that these abilities would be associated with different parts of the brain, and not the PFC.
Reply | Report Abuse | Link to thisI have to disagree, especially if your contradictory declarations cannot be supported by references.
Reply | Report Abuse | Link to thisWhile I have been relying on my own ancient memory, I was able to locate some references supporting my assertions. The clearest is:
Centre for Educational Research and Innovation, Organisation for Economic Co-operation and Development, (2007), "Understanding the Brain: The Birth of a Learning Science, Volume 2", (Google Books), P167, Box A.2., "Initial language Development"
"Human infants are also able to perceive any phoneme contrast existing in any language in the world, even if parents cannot either pronounce or perceive it (like Japanese very young infants, who can perceive the English /r-l/ contrast that their parents are unable to perceive). Thus, at birth, humans are able to make different "computations" with the speech signal; these computations are language-universal, in the sense that they allow newborns to equally well any language of the world. In the following months, infants will start tuning their language processing capabilities to the properties of the language of the environment. Indeed, from 6 to 12 months they will lose both their capacity to perceive some foreign contrasts (like Japanese infants losing their capacity to perceive /r-l/) and at the same time, they will refine their own language phoneme categories. It can be said that infants are becoming skilled native skilled native-hearers (as opposite to mediocre universal listeners). There is some evidence that the capacity to adjust properly, initial perceptual capacities to the properties of the native phoneme system, is related to later successful language acquisition: that is, the earlier and better infants are able to lose the perception of foreign contrasts, the faster they seem to learn their first language."
In this process of initial language acquisition, it is the inherent perception of phonemes that is most crucial to speech acquisition and subsequent phoneme pronunciation capabilities.
While this study focused on functions of the prefrontal cortex, synaptic pruning is thought to apply more universally to provide for general brain plasticity.
The potential failure of synaptic pruning operations might be involved in most autistic childrens' generally delayed and impeded acquisition on speech capabilities, as described above. Perhaps Asperger Syndrome simply affects different brain functions...
Is autism perhaps a step in evolution? A bigger front brain seems like a good idea. Wasn't Einstein autistic?
Reply | Report Abuse | Link to thisAutism is often a severely debilitating condition. In almost all cases socialization is to some degree difficult for sufferers. However, there are some special capabilities that may also be endowed. Special categories include savant autistic, high functioning autism and Asperger Syndrome. One theory of a mechanism responsible for producing autism, Enhanced Perceptual Functioning, focuses more on the superiority of locally oriented and perceptual operations in autistic individuals. Please see: Mottron et al, (2006), "Enhanced Perceptual Functioning in Autism: An Update, and Eight Principles of Autistic Perception", http://dx.doi.org/10.1007%2Fs10803-005-0040-7
Reply | Report Abuse | Link to thisThere are a number of famous people who have exhibited some unusual behavioral characteristics that have been subjects of speculation as to their having autism or Asperger Syndrome. Of course, many died long before autism or Asperger Syndrome were described as disorders. As I understand, adult diagnoses focuses on often unconfirmed anecdotes of childhood behavior, when symptoms are often most pronounced. Please see: http://en.wikipedia.org/wiki/Historical_figures_sometimes_considered_autistic
Curiously, in the "Arguments Against" section it's stated:
"Tesla was more commonly assumed to have suffered from some form of OCD, which is not related to the autism spectrum disorders. There is no indication that Tesla had a late onset of speech or other disabilities during childhood."
Actually, OCD symptoms are very often associated with Asperger Syndrome, which also does not include delayed acquisition of speech.
BTW, re. autism & evolution, any genetic mutation that produces biological change may offer benefits or detriments to that affected individual's successful reproduction, depending on then current environmental and/or social conditions.
Reply | Report Abuse | Link to thisThe increase in the number of autism diagnoses in Western cultures may simply be an artifact of diagnostic techniques or improved health car for children - keep in mind that Asperger Syndrome only began to be recognized and actively diagnosed since the early 1990s.
Improved health care for those carrying genetic traits that in the past would have significantly impeded their ability to successfully mate, reproduce and raise offspring carrying those same traits may now often mitigate some disadvantages, allowing those affected to successfully reproduce.
However, since the population of even Western countries has generally doubled in the past ~40 years or so, the total number of people exhibiting ASD symptoms could also be expected to similarly increase. This general population increase, along with increased diagnoses, likely significantly contributes to the apparent growing number of autistic people.
There are also many theories of environmental contaminants that could also be affecting the number of individuals being diagnosed with ASD.
In summary, to the extent that ASD produces capabilities in individuals that improve their ability to produce successful progenitors in the current social environment in competition with those who do not exhibit ASD symptoms, it could offer an evolutionary benefits. Perhaps enhanced ability to focus on video game playing to the exclusion of social interaction may offer some long term evolutionary benefit...