Several years ago I corresponded with a parent (let’s call him Jim) who was interested in our findings of disturbed cortical organization in the brains of autistic individuals. The cerebral cortex is made of repeating circuits, called minicolumns, that depending on how they are connected provide for the emergence of higher functions like judgment, face recognition, and language. In our research we had discovered that these units were more numerous and malformed in autistic individuals. The finding made sense to Jim, but he still had some qualms about the same. He had consulted about them with a member of the MIND institute who stated categorically that minicolumns did not exist and the findings were therefore invalid.
It is interesting that I have given numerous lectures, including plenary presentations, and this concern or criticism has never been brought to my attention. I am presently editing a book on minicolumns to be published by Springer. The book is based on a conference that I chaired and among 15 invited speakers, 3 were members of the National Academy of Sciences. At present the validity of the minicolumnar construct can’t be denied and has been validated by numerous investigators using a variety of techniques. There are now numerous articles from the anthropological literature that attest as to how changes in this structure account for some of the evolutionary gains of our species. I think the most important work in this regard has been done by Oleg Favorov and more recently still by Ioan Opris. Among other things there is now direct proof that the emergence of working memory stems directly from the function of minicolumns. Working memory refers to the property of the brain by which it can transiently hold on to information in order to manipulate the same. It is essential for our ability to imitate, communicate via gestures or empathize with others.
The turn around in thinking about minicolumns is a throwback to Schopenhauer’s pessimistic view about human nature. Schoenhauer claimed that certain findings, important ones, will be denied vehemently at first but, later on, when they are proven correct, the same critics will claim that the findings were well known all along. Just to say that criticisms change and shift rather than get corrected. The overall result is almost like trying to hit a moving target. Researchers have their own pet ideas and rarely read anything from the medical literature that may contradict the same. A Google search as to «what is the cause of autism» brought me close to 55 million hits. One example, high on the list of possibilities, is how the immune system attacks the brain «thus» causing autism. We have to stretch our own credibility to accept for granted this supposition. There are many missing steps between an autoimmune reaction and «thus» causing autism.
I think that the proliferation of causative theories for autism is based on the fact that different authors have not been forced to explain observed and corroborated findings when discussing their ideas. Among some credible information is the fact that the brains of autistic individuals experience growth during early postnatal years that far surpasses that of neurotypicals. Microscopically there is ample evidence of migratory disturbances (of primitive neurons) and focal cortical malformations. Evidence from neuroimaging and electrophysiology attest to disturbances in the connectivity of the cerebral cortex. These findings serve to explain the presence of seizures and sensory abnormalities in autism. They have also suggested the possibility of medical interventions (e.g., rTMS). How would an autoimmune disorder explain the previous findings? Maybe it could, but thus far proposing authors have not even attempted to do so.
I would say that before authors propose any theories on causation that they should try to explain how their ideas explain (or are related) to observed abnormalities.
References
I just published a review article in the journal Brain entitled: Prefrontal cortical minicolumn: from executive control to disrupted cognitive processing (doi:10.1093/brain/awt359). The same is a rather technical explanation as to how minicolumns are involved in higher cognitive functions, and how their function is disturbed in pathological states. Anyone interested in obtaining a copy can email me directly at m0casa02@louisville.edu
Cortical Chauvinism 
Hello, if you remember me, my name is Yuval Levental. I contacted you over the summer asking what you discover with regard to research on autism. I recently graduated with a bachelor’s degree in electrical engineering from Michigan State University.
Meanwhile, I theorized that in some cases of autism, the main problem is a lack of dopamine in the brain. This is because many autistics are irritatable and frequently distracted, which are two symptoms of low dopamine. I decided to run a personal experiment of my own based on this theory to see if I could become more NT. It’s not a scientific experiment at all, the way I carried it out, but it had positive results for me. Think about it as an entertaining story. I will now email you a brief overview the experiment.
I would also like a copy of your paper, please and thank you.
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I will wait for you email detailing your story. I will certainly send you a copy of the article as I get to my office tomorrow. Nice to know that you finished your degree. Congratulations.
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Hi Manuel Cassanova –
I kind of think that our set of mysteries is large enough for both sets of findings to have a place in the puzzle. I’m not trying to defend someone saying that microcolumns don’t exist, but there is so much evidence of immune participation in cognitive disorders that it makes no sense to assume that because no one has propposed a unifying theory of how it can explain every observation in autism, that it comprises people not listening.
We have to stretch our own credibility to accept for granted this supposition. There are many missing steps between an autoimmune reaction and “thus” causing autism.
I wouldn’t exactly accept it for granted, but have you taken a look at the breadth of the maternal auto antibody work in this regard?
There are multiple studies that show increased prevalence of brain auto antibodies in mothers of children with autism; i.e.,
http://www.ncbi.nlm.nih.gov/pubmed/18078998
http://www.ncbi.nlm.nih.gov/pubmed/18093664
http://www.ncbi.nlm.nih.gov/pubmed/24389156
http://www.ncbi.nlm.nih.gov/pubmed/24022729
http://www.ncbi.nlm.nih.gov/pubmed/23958959
http://www.ncbi.nlm.nih.gov/pubmed/23838888
http://www.ncbi.nlm.nih.gov/pubmed/22833194
Those studies include cohorts from Europe and the US as well as define relationships with well established genetic risk factors wherein the allele of interest (MET-C) is immunoregulatory and the allele represents underexpression.
This study in particular shows that auto antibodies in the are in fact associated with enlarged brains in the child:
http://www.ncbi.nlm.nih.gov/pubmed/23395715
There are rodent studies utilizing igg transfer from mothers with brain auto antibodies with consequent behavioral changes:
http://www.ncbi.nlm.nih.gov/pubmed/22951357
http://www.ncbi.nlm.nih.gov/pubmed/19362378
There are also two primate studies wherein IgG from mothers positive for brain auto antibodies were injected into pregnant rhesus monkeys with the treatment groups showing highly significant changes in behaviors. The second study also showed that the treatment group had enlarged brain volume.
http://www.ncbi.nlm.nih.gov/pubmed/18262386
http://www.nature.com/tp/journal/v3/n7/full/tp201347a.html
Are you honestly of the belief that because these findings are strictly correlational because the authors make no case to explain observations from your area of expertise?
Do the primate models give us any insight into the direction of causality in this relationship? Could you make a supposition as to how having a child with altered minicolumn structures could result in an altered IgG profile in the mother that was then capable of causing behavioral disturbances and brain enlargement in primates?
You might also be interested in some of the research indicating the glial population of the brain are critical participants in tuning of the synaptic network.
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Thank you for the email, your interest, and the thoroughness of your comment. Obviously you are well read in the matter. Overall the results of many immunological studies in autism suffer from serious limitations. The stickiness of the tissue for any given antibody not only depends on the presence of the antigen, it also depends on the preagonal and agonal condition(s) of the patients. The larger the postmortem interval, as an example, the more likely it will stain with anything. This is one of the reasons why populations need to be closely matched when making comparisons. This has not been the case for many of the cited studies.
Although there appears to be a link initially in-between some immunological studies and postmortem findings of gliosis, this is not the case. Some of the more recent studies were conducted with samples derived from different patient populations and processed in different manner by different laboratories. This may have accounted for the difference in findings. How did such studies get published or even received so much publicity is beyond my comprehension.
The article that probably started this all was that of Vargas et al. I reviewed the series in the study. About one third of the cases available from the Autism Tissue Program had drowned (some «near» drowning cases) and the rest had suffered a clear hypoxic insult which made them different from controls. The presence of gliosis within the white matter in these cases reflected an ischemia-reperfusion injury, that is, the findings are those expected when taking into account how the patients died- otherwise they had nothing to do with autism.
If you want I can provide the galley proofs of a recent review of the literature that bears on these issues. My email is m0casa02@louisville.edu
Thanks again for your comment.
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Hi PD,
‘The MET promoter variant rs1858830 allele “C”, found at increased rates in autism, is associated with neuronal growth and development, but also is involved in immune function and gastrointestinal repair . The fact that this genetic variant is present in 47% of the general population gives credence to the assertion that there is an environmental component to the development of autism’.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507704/
All of these may represent risk of small effect that contribute to the disruption of early brain development.but individually are unlikely to ‘cause’ autism. Autism is a multifactorial disorder and searching for a single causal mechanism hasn’t born fruit.
I have persented a ‘unifying’ theory of asutism that can explaim most of the obervations in autism. You may disagree buit I do respect your opinion.
Haz clic para acceder a 1379116999.pdf
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Hi Manuel Casanova –
For what it is worth, none of the studies I provided above utilized post mortem samples. They included populations from Italy, Spain, and the US and included several hundred or possibly a thousand mothers of children with autism.
http://archpsyc.jamanetwork.com/article.aspx?articleid=1393597
Utilized an in vivo mechanism to observe altered glial phenotypes in adults with autism.
http://www.ncbi.nlm.nih.gov/pubmed/18378158
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607626/
both reported differential gene expression with findings consistent with a heightened immune response in the autism population, so we don’t really need to worry about problems with antigen staining problems. I’m sure you would be better versed in understanding if the expression profile are consistent with reperfusion injury or not.
I kind of felt that the fact that different methodologies are coming up with similar themes can give us insight into the question if a particular set of findings are artifacts.
Anyway, I think the bigger problem with the underlying argument that immune activation cannot account for development of neurological disorders is the wealth of data implicating the neuroimmune environment and peripheral immune system in a range of cognitive or classicial ‘brain’ disorders; schizophrenia, depression, bipolar disorder, epilepsy and autism. There is too much data to bother trying to link, but if all of those types of findings are spurious then there are a *lot* of people getting it wrong in the same way.
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Thanks again for your comments. I only stand to learn from such an exchange of ideas.
The increase avidity of antigens to bind as a function of preagonal conditions was meant to emphasize the importance of closely matching patient populations for comorbidities. My own pet peeve in this regard is epilepsy and in many cases cryptic EEG abnormalities that may not have expressed themselves as seizures. As more attention is paid to them immune abnormalities including autoantibodies appear to be more and more common in patients with seizures. Other problems is the way the data is presented. I don;t believe I am alone in this (see for example http://www.forbes.com/sites/emilywillingham/2013/07/28/moms-are-your-autoantibodies-causing-autism/)
I did my share of bench top research in this field with positive findings. Some of the results were published in a journal and later in a book chapter: Mott M, Fernandez-Bortran R, Casanova MF. Neuroinflammation in the pathogenesis of Autism Spectrum Disorders: converging evidence for systemic and central nervous system immune interaction. Brain Research Journal, 3(2): 1-31, 2011. Right now I am sitting on a wealth of «positive» data related to different trials and interventions using immune markers as outcome measures.
We bought our commercial kits and quantified by blots our protein expression. One of the peculiar things, in terms of methodology, in this type of work, is that everything needed to be done in triplicate- otherwise spurious findings are extremely common. Also, relating the specificity of the findings by using histological sections is seldom pursued. The end results is that findings abnormal levels/expression of antibodies and cytokines in autistic individuals is not difficult. Trying to explain their meaning, specially when they seemingly lack explanatory powers for many other observed phenomenon is more difficult.
One researcher in the field actually stated that she did not believe in neuropathology. She went on to say that any available neuropathological observation, if valid, would have to explain «her» findings. I think it is quite the opposite, core findings need to explain neuropathology. At present I know that there are many positive findings in regards to autoantibodies, cytokines, and oxidative markers. However, I believe the same confer the individuals with a susceptibility towards some type of exogenous insult (I usually talk about this under the proviso of a Triple Hit Hypothesis).
Again, thank you for your comments.
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Hi Manuel Casanova –
I was under the impression that any of the studies that used port mortem brains in the autism population suffered from a very constrained set of available tissue, making appropriate matching of cases difficult. I can see, however, how the type of structural changes (I think) that minicolumns represent would not be subject to the types of chemical changes that might occur as a function of manner of death.
Right now I am sitting on a wealth of “positive” data related to different trials and interventions using immune markers as outcome measures.
Sweet! If I remember correctly, you had an abstract poster at the 2011/2012 IMFAR meeting on the neuroimmune environment that still hasn’t made it to press. Make with the data!
The end results is that findings abnormal levels/expression of antibodies and cytokines in autistic individuals is not difficult.
I hope I’m not being obtuse here, but if we had methodological problems at blot time, wouldn’t you run the same risk with the control group and wind up with noise?
Trying to explain their meaning, specially when they seemingly lack explanatory powers for many other observed phenomenon is more difficult.
Hehe.
However, I believe the same confer the individuals with a susceptibility towards some type of exogenous insult (I usually talk about this under the proviso of a Triple Hit Hypothesis).
I am personally a fan of the multi hit hypothesis. I wrote a post along the lines of multiple hits and glial priming that you may find interesting, inane, or somewhere in between.
http://passionlessdrone.wordpress.com/2012/10/26/a-brief-overview-of-glial-priming-how-it-probably-applies-to-some-cases-of-autism-and-worrisome-speculation-on-a-model-of-a-low-penetrant-effect/
Again, thank you for your comments
You are being very kind responding to the layman jerk on the Internet. Thanks.
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Hi,
Thank you again for your constructive comments.
It is difficult to match postmortem tissue, especially when numbers are few (that is not the case in other conditions such as Alzheimer’s). That may be the reason why many researchers have not done so, creating a good number of controversial results. You are completely correct that minicolumnar morphometry may not be subject to many of these constraints.
A story in this regard was a researcher who stood corrected when he applied for tissue as his suggested method would not provide for valid results. He nevertheless did the study and published the results (and never mentioned any of the criticisms inherent in his methodology). In another case I was the primary reviewer for a study that was rejected. The paper was later published in another journal after having removed the information that was initially a cause for concern. My favorite story comes from notes gathered from the Autism Tissue Program:
“…it was very disappointing to discover that the majority of the brain samples showed extensive degradation and that no meaningful conclusions could be drawn from the experiments. If we had not decided to perform the autoradiography and the hemalum staining after the Western blot experiments, we would have not been aware that we were working with degraded tissue samples. Several research groups received the same brain samples that we got and because they did not perform brain sections, they did not realize the problem with the tissue quality and went on to publish their findings.” Catalina Betancur and Salah El Mestikawy, Université Pierre et Marie Curie, Paris France (Jane Pickett, ATP Report, 2010).
«Right now I am sitting on a wealth of “positive” data related to different trials and interventions using immune markers as outcome measures». We have some good data using a profile of immune markers that predict in our small population who would have good results to both our electrophysiological (e.g., TMS, neurofeedback) and medical interventions.
«Sweet! If I remember correctly, you had an abstract poster at the 2011/2012 IMFAR meeting on the neuroimmune environment that still hasn’t made it to press.» In part, that has to do with the fact that I work at the University of Louisville and can collaborate with only a couple of people that I myself trained. I think that in other major academic institutions all of our results would have by now been published because so many other people share the same interest. At present I usually do a major portion of the bench top work and in the end have to write the manuscripts. Meghan Mott, my PhD student doing the immunology work, already moved to another institution (NIH). Now I find myself targeting and prioritizing what to do.
«we had methodological problems at blot time, wouldn’t you run the same risk with the control group and wind up with noise?» If the populations were matched correctly, there could be a systematic error differentiating patients and controls. Also many of the methods are somewhat capricious, making commercial companies «recommend? they be done in triplicate. This «recommendation» is not always followed.
«I am personally a fan of the multi hit hypothesis.» I have read some of your posts including insightful remarks about the morphology of microglia (resting vs. activates). You know a lot more about neuroscience, have been more critical in your literature review, and have offered more insightful views about the autism literature than many of my professional colleagues.
As I said, I only stand to learn from your comments.
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Are those alternative hypothesis necessarily exclusive? Are not they indicating precisely the complexity of the matter in autism? Is there a focal point of origin (i.e., para-ventricular organs) or perhaps many other routes of initiation? Is not worth of scientific effort to look a cases of significant recovery of children in the spectrum, access al pertinent information from the parents, and then work backwards to the early phenotypical manifestations of the disorder to propose specific paths ? Thank you all participants for the insights.
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Yes, alternative hypothesis tend to be mutually exclusive. Also the null hypothesis is usually the most parsimonious explanation to a particular phenomenon. Just to say that regardless of clinical heterogeneity we should first look for a common mechanism, one that would help explain both idiopathic and syndromic cases. That is where heterochronic division of periventricular germinal cells may play a major role in autism. If you are interested in this regard I have an upcoming article discussing this and would readily make it available when published, if so desired. Also the literature is reviewed in the Handbook of Autism (just published this month, Fred Volkmar editor) chapter on neuropathology.
As an aside, besides periventricular germinal celas those of the rhombic lip may be involved as a way of explaining brainstem and cerebellar abnormalities.
Thank you for your comments.
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I would love to read the article. Many thanks for your kindness.
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My email is m0casa02@louisville.edu. Please contact me and I will respond with a copy of the manuscript. I will be in my office late in the morning or early afternoon.
Thanks again for your interest.
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Dear Dr. Manni, just one question that appears intriguing to me (forgive me if it does not appear relevant to your work, or merely tangential). The work of Dr. Tennant (I am sure you are familiar with) implies the presence of low voltage in cells that are not functioning properly, and to that effect he has devised an apparatus that allegedly donate electrons to said cells in need of «recharging,» is this type of work in any way related to DBS, and similar approaches to regulate the electric activity of the brain?
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I am not sure that it is. I do not understand some of the attempts at recharging cells by giving alkaline water? It is hard to follow the logic and I do not believe there is any proof for the same..
TMS use a very strong magnetic field (of the order of 1 -3 Tesla) similar to an MRI machine. It is capable of providing a magnetic field with effects in the brain, depolaring large networks of neurons. TMS has a track record of research of close to 100 years (the early research was in regards to phosphenes from the visual and retinal cortex). It works by using Faraday’s law of electromagnetic induction, something known by high school students.
Thanks!
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Dear Dr. Casanova,
Can you please send me the article you refer to at end of this wrote-up?
«I just published a review article in the journal Brain entitled: Prefrontal cortical minicolumn: from executive control to disrupted cognitive processing (doi:10.1093/brain/awt359).»
Thank you, Prasanna
Best regards, Prasanna
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Hi Prasanna,
Thank you for your interest in our research. I have sent you a copy of the requested article to your email. Hopefully you will enjoy the same.
Best regards,
Manuel
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