Tuesday, August 19, 2008

Autism at the Brain Level

Autism is a disorder characterized by impairments in social interaction, deficits in language use or development, and the appearance of repetitive or ritualized behaviors. It's important to note that the degree of disability of those affected by autism falls along a spectrum. On one end there's remarkably high functioning individuals like Daniel Tammet , on the other is an adult living in a world of frustration and misunderstanding because he can't communicate at all. This irregularity in behavior is mirrored in the pathology affecting the structures of the brain.

David Amaral et al. reviewed the current knowledge this disease in a paper published in the March edition of Trends in Neurosciences. Their review covers a field of study that is saturated with low sample sizes, divergent investigation techniques, and dissimilar cohorts.

Small sample sizes make it very hard to generalize to the autistic population as a whole. Disparate research methods, such as magnetic resonance imaging (MRI) and postmortem tissue analysis (counting the number of neurons, synapses, glia, etc.), do not at the same thing, and this makes it hard to form connections between the different studies. The papers surveyed for review were also frequently not conducted on subjects with the same clinical diagnoses. For instance, one MRI study was on high functioning individuals with no retardation or seizures while a postmortem was the exact opposite; this seemed to be the trend rather than the exception. None the less, it seems that the authors were able to make some sense of the chaos.

Total brain volume tests (measured by head circumference or MRI studies in young children) indicate a period of abnormal growth in the first year of life, in turn leading to an enlarged brain for the remainder of childhood. This, however, awaits validation by a more rigorous MRI study comparing brain volumes over several years.

It has been suggested that this abnormal growth may be larger in white matter—the area made up of long distance wiring of neurons and associated support cells. A few studies have shown this, but it is unclear if the disproportional size of white matter continues into adult brains. The grey matter's smaller increases in size, however, have been shown to persist in a few studies. Diffusion tensor imaging studies (a way of showing the length and direction axon bundles) hint at an increase in the white matter maturity of toddlers.

There have been several attempts at isolating these enlargements to certain regions; the most reliable area to see increases is the prefrontal cortex. However, this area of research seems particularly troubled by inconsistencies in experimental design, as the authors politely pointed out: "A perusal of this literature emphasizes the need for the field of developmental neuropathology to establish a systematic approach to evaluating abnormal brain development."

Postmortem studies on the cellular level have been limited in a similar way, with very small sample sizes and a lack of quantitative analysis. The best idea to come out of this line of investigation is a question posed by Casanova and his collaborators on the structure and organization of minicolumns in the cortex. A minicolumn is thought by many to be the individual functional unit of the brain. There is an excellent description of cortical columns in this article describing a team in Switzerland's attempts to model one. They are organized in the cortex in a manner similar to skyscrapers in a city, except this city would cover the world and be filled only with skyscrapers. Casanova suggested that these columns are abnormal in both quantity and width in the autistic brain. If minicolumns are indeed the functional units of the brain, abnormalities in their overall makeup would certainly cause problems.

There have also been abnormalities—distinct from those mentioned above—documented in specific brain areas. The two most easily identified regions are the cerebellum and the amygdala.

A very consistent finding of postmortem studies of the autistic cerebellum is a decreased density of Purkinje cells, especially in the outer cortex of the hemispheres. These cells make up the majority of the cerebellum, which necessary in coordinating complex movements. The authors note that this is at odds with some MRI research showing an enlarged cerebellum in autistics, but this is largely due to significant differences (high functioning vs. not, etc) between the patients studied.

During the period of abnormal growth discussed earlier, the amygdala also seems to increase in size and this may continue into late childhood. Increased amygdala size is correlated with many things, among them anxiety and impaired social skills. Further abnormalities exist when autistic boys hit puberty, where the amygdalar growth typically seen in teenage boys is nonexistent. Studies on older males have shown either no difference or smaller amygdalar volumes than controls.

After reading this review, it is obvious that the research into the biological basis of autism is in serious need of organization. The lack of continuity between methods and the differences in patients studied only adds to the difficulty in understanding the pathology of autism. The situation seems similar to that which has plagued research into other disorders like schizophrenia and anxiety/depression for years. Autism research could clearly benefit from some sort of a collaborative framework or organizing body.

Even with the shortfalls of the current state of research, there are a few areas of consonant findings that I can sum up here. During the first year of life, there is a period of abnormal enlargement in the brains of autistic boys. Both white and grey matter is increased, but white matter much more so. It is not clear that this enlargement continues through childhood. In this same time period, the amygdala is enlarged disproportionally but does not increase in size during puberty, as is normal. It is also likely that autistics will have a decreased number of Purkinje cells in the cerebellum.

These findings are no small achievement, and are helpful in developing animal models of the disorder for research. For instance, the lab I volunteer in recently did a study comparing the evoked dopamine release in the prefrontal cortex of mice that have decreased Purkinje cell counts (Lurcher mice chimeras) versus wild type mice. These Lurcher chimeras display repetitive stereotyped behaviors that are similar to those seen in autism.

The mouse model isn't perfect—and never will be—but research to further define the disease on a human level is absolutely necessary in guiding us at the basic stages.


Amaral et al. Trends in Neurosciences. 31(3) 137-145



Teloch said...

Hi! I'm a author of a neuroscience blog neurotyk.net - so same topic, different language ;) I want to ask You about your header image. It is fantastic! I was looking for my header that kind of picture, connected with brain cells, but I couldn't find anything free and good looking ;) Can I ask you where did you find this graphic? It was free to use?

Great site!

Ryan Morehead said...

I don't remember specifically, it was a British site with a bunch of neuro images. At the time I was looking for a desktop background.

I did a little searching and it turns out the image was originally created by Graham Johnson, a freelance animator.

Here's a link to the entire image: http://www.sciencemag.org/sciext/vis2005/show/images/slide1_large.jpg

It's probably not free to use, but I'm not sure.

Kim Hunter said...

Good stuff.