Several years ago Eric London received an achievement award from the International Meeting for Autism Research (IMFAR). The achievement was meant to recognize his work as the founder of the National Autism Research Alliance (NAAR) and one of the organizers of the first IMFAR meeting. The theme of his speech was the importance of postmortem research and how funding agencies were drifting away from this type of research and focusing more into genetics and studies on animal models of autism. In this year’s IMFAR out of the many hundreds of presentations only 2 or 3 qualified as neuropathological studies. Probably the most significant of these presentations was provided by Jerzy Weigel from the Brain Institute at Staten Island. Otherwise there were numerous mentions of animal models for autism for which some authorities believe we now have over 200 (for more information read my blog entitled: Of Mice and Men located at http://bit.ly/1PzFe77).
Jerzy Weigel is one of the few researchers in the field of autism research who has received training in neuropathology and presently works in an institute devoted to postmortem work. Many other researcher who have made studies and reported results on postmortem work have scant knowledge of the perils and confounds involved in this type of work and are responsible for many contradictory findings now present in the literature.
AT IMFAR2016 Jerzy presented work done on a collection of specimens called the Brain Atlas project. Specimens in this collection were collected and processed in a very meticulous fashion. Brains were embedded in celloidin (a pure form of nitrocellulose) in order to strengthen the consistency of the tissue and allow cutting the same. Celloidin has the added advantage of using very little heat during tissue processing and diminishing the amount of shrinkage the brain undergoes during its processing. The gentler procedure allows for less distortions and for more accurate cell counts. Whole brain hemispheres were cut with a specially designed cryotome and the sections collected into slides, a process that involved both science and art form.
Jerzy has been able to collect data from over a dozen brains of autistic individuals and a similar number of controls. Although the series is small this is more or less an average number for postmortem research. One of the strengths of this collection is that the brains have been serially sectioned into hundreds of slides. Jerzy’s latest observations focused on the corpus callosum. The latter is a bundle of projections that join both hemispheres of the brain. Many individuals with autism show abnormalities in this tract of white matter fibers. Lack of connections between the hemispheres during brain development forces each half of the brain to work independently giving rise to the possibility that some areas may develop novel functions. During evolution larger brains have developed along with thinner corpus callosum. The language area in the human brain is an example of how new properties or functions develop when we severe ties to homologous areas of the opposite hemisphere.
In this particular study Jerzy reported that a large portion of his autism specimens had abnormalities of the corpus callosum. What was striking about his report is that the corpus callosum abnormalities were quite different from those reported when this structure fails to develop. In some cases of autism the corpus callosum seemingly forms and then gets reabsorbed leaving behind a truncated arm within each hemisphere. There were no ragged edges to the truncated arms and the sliver of grey matter that covers the surface of this structure (called the indoseum griseum) was present but malformed. Also contrary to known developmental abnormalities of the corpus callous the radiation pattern of the convolutions in the middle of the brain was normal (from what I could see in photographs).
The reported abnormality is one that can easily be missed and attributed to artifacts either during neuroimaging screening or postmortem examination. Thousands of interested researchers have studied the brain describing a myriad of developmental abnormalities. Discovering anything new, that has escaped the scrutiny of previous researchers, is a major achievement. In Jerzy’s case, the finding is of added significance as it may help explain the cognitive profile of some autistic individuals as well as some of the splinter skills that they may exhibit. In essence the findings would help explain the emphasis of some patients on particulars and abnormalities in gestalt thinking. As one may conclude from this developmental abnormality, individuals affected could easily see the tree but loose sight of the forest.
Key Players in Autism:I. The Corpus Callosum http://bit.ly/25IvOhd
Interesting, but of course one of the problems with neuropathology research as opposed to animal models, genetics and fMRI is the scarcity of postmortem tissue, and the mishap in the autism speaks controlled brain bank added to that problem. This makes it infeasible to do a whole lot of research in this area.
Another problem that I think is possible that you did not mention in the post, is that autism is different from Parkinson’s, Huntington’s, Alzheimer’s etc. in that it is a developmental pathology and the normal devleoping brain keeps changing until adulthood. If I can find Wegiel’s study, might be interested in reading it. I’d be interested if he controlled for ages of the brains. I seem to remember the findings in a three year old autistic brain would be different than ones found in a 35 year old autistic brain, because in autism the brain seems to change, growing too much in fetal developmental, infancy and toddlerhood and then being abnormally heavy and then with synaptic pruning to shrink down to normal size.
I seem to remember one of the criticisms that Eric Courchesne leveled at your post mortem studies was that the majority of them were adults, so exactly what causes the problems in autism, minicolumn abnormalities, heterotopias, gliosis, etc. might not be valid unless you examine the brains of toddlers before it undergoes changes and finding postmortem tissue in 3 year olds would be even harder.
Also, there’s the question of the universality of the findings, since there are so many variations of autism and different cases might have different causes. This is probably one reason for a lot of different findings in MRI scans as opposed to postmortem tissues. MRI scans are skewed to higher functioning autistics for obvious reasons and most of the postmortem studies have been done on those with intellectual disabilities and might not apply to autistics without intellectual disabilities on the higher end.
I admit I’m far from an expert, so you can correct any points I’m mistaken about.
All of the points are well taken. Jerzy has not published the study, he presented it only as a poster at IMFAR2016. However, he did correct and matched the ASD and typically developing. The sparsity of tissue material does demand a fairly small age range to correct for possible confounds. In my own findings about minicolumns I reported smaller widths. Steven Chance reported larger widths. When he analyzed both his data and mine, we were both in perfect agreement. It seems that minicolumns maybe larger initially and then progressively diminish in size. ..I also agree with the point you made on MRIs.
I always wondered why control subjects are always typically developing comparison controls. It would make sense to me to have other control groups such as persons accurately diagnosed with schizophrenia, intellectual disability, learning disorders and/or seizures etc., but without strictly diagnosed autism. Are there differences or similarities?
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In our own studies on minicolumns we have used Typically Developing controls, Down syndrome, Rubella babies, tuberous sclerosis, and schizophrenia as comparison groups. We were trying to correct for possible confounds such as intellectual disability. Although not included in the corpus callosum study, Jerzy has used syndromic (chromosome 15) in previous studies. Like you I also believe that these comparisons are necessary. Now my wife when doing her genetic studies she will include cases of epilepsy and/or intellectual disability.
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