The problem of “too many findings in autism”

A few months ago I had the opportunity to talk to my good friend Steve Edelson from the Autism Research Institute (ARI). The conversation revolved around what makes for a good finding in autism research. The conversation took place NOT because we believed that there was a scarcity of findings in autism research; rather, there appear to be too many! The plurality of findings is evident in almost all spheres of autism research, be it postmortem, neuroimaging, immunological, chemical laboratory values, etc.  So an important question for all of us is what makes for a good finding in research, that is, one that is capable of making a positive difference to individuals with autism? What should we pay attention to when reading the latest article in the field?

One of the first things to look for in an article is how the author(s) validate their findings. It is the obligation of the researcher or senior author, when describing his/her findings in an article, to try and provide “adequate” correlations to known findings. The word “adequate” is of importance as in today’s science anything can be used to provide fanciful explanations to known phenomena. Today’s explanations depend on the imagination of the researcher, not on science. It really all comes down to how many concatenated “ifs” you can add to an argument and retain a semblance of a scientific thought. As an example, I have never seen more stretching of scientific facts as in the case of researchers advocating for a primordial role for abnormalities of the cerebellum in explaining the core symptoms of autism (see http://bit.ly/1aGeUgk). I have to believe that a major problem propelling fanciful explanations to non-significant cerebellar findings has been funding considerations. In reality you have to sell your findings as credible in order to get funded. Also, many researchers are unable to think outside the box or feel confident in leaving their area of expertise. So, if their expertise is the cerebellum, they will primarily do research in this area and will never address any evidence to the contrary.

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Figure: Magnetic resonance imaging of the cerebellum (outlined in red) in a cross section of the brain.

Neurologists are the clinicians who localize organic abnormalities in the brains of patients. Given the clinical findings of autistic individuals (e.g. language, socialization, sensory issues), ask any Neurologist worth his salt to localize the offending lesion and he/she will say the cerebral cortex, not the cerebellum. The cerebral cortex should be considered the null hypothesis for research. If no findings were to be present in the cerebral cortex then considering other areas of the brain would be allowable. The problem for the cerebellar proponents is that there are significant and reproducible findings in the cerebral cortex capable of explaining the core findings of autism.

It is my opinion that the significance of a finding can be judged primarily by its explanatory and predictive powers. The predictive value of a finding simply means whether it illustrates things that had not been previously recognized. As an example, when I first described disturbances in the modular organization of the cerebral cortex of autistic individuals, I wrote an article describing possible correlations to what was then unknown findings. In essence, I stated that the minicolumnar abnormalities would provide for; 1) alterations in the blueprint of connectivity of the white matter, 2) that neuroimaging volumetric studies would describe the presence of increased brain volumes wherein the increase in white matter would surpass the increase in gray matter, and 3) abnormalities in the way information was “bound together” to provide cognitive wholes (so-called gamma binding abnormalities detected by EEG) (see http://bit.ly/11KrMEl). I also suggested later on a possible therapeutic intervention based on Transcranial Magnetic Stimulation (TMS). All of these predictions have been corroborated in subsequent studies.

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Figure: Mapping the white matter tracks have shown major differences in the brains of autistic individuals as compared to controls.

The explanatory power of a finding relates to their ability at explaining known facts. At present there seems to be many corroborated facts in autism: 1) the brains appear to be larger, on average, at least during certain times of development, 2) despite the large brains, the long projections joining both hemispheres (corpus callosum) appears to be smaller, 3) the presence of migrational abnormalities of neurons on their way to the cortex by both neuroimaging and autopsy examination, and 4) a significant percentage of autistic individuals show the same constellation of clinical findings: seizures, sensory abnormalities, and a generalized dyspraxia (problems with movement and coordination) (see https://corticalchauvinism.wordpress.com/2013/02/01/clumsiness-and-autism/). So the question for anyone publishing a new finding in autism is how well do they explain or relate to the known abnormalities?

Research using animal models offer more opportunity for criticisms.There are major differences between the brains of rodents and humans. This differences are seen not only in terms of volume, but also in the way cells are arranged (and for that matter the types of cells), the way the brain is parcellated, and the connectivity between different parts of the brain (see: http://bit.ly/SndHr1 ). In previous blogs I have stated that the significance of an animal model for autism should rely on a Turing test. I would suggest using a blinded examiner who would perform all sorts of behavioral tests in animals and then try to diagnose the condition it was meant to imitate. I doubt whether any single of the presently used animal models would pass such a test. In effect, animal models copy a limited range of behaviors but seldom a human condition.

5 responses to “The problem of “too many findings in autism”

  1. Thanks for this post.
    Could you please comment on Markram et al. (2007) and Rubenstein & Merzenich (2003)’ research? (Both are based on animal models.)

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  2. Hi Olga,

    Kamila Markram developed the intense world theory of autism based on the valproic rat model of autism. She has done a lot of basic laboratory work on the model suggesting hyperplasticity of neural circuits. The animal model has added significant information to basic science. The value as to autism remains dependent on how well does the model recapitulates the core pathology of the condition.As an aside Alla Salmina’s preliminary work is now showing that this animal model exhibits increased activity of progenitor cells as expressed in different gene markers. Rubentein and Merzenich article was a theoretical one and postulated a hypothesis of a bias in the excitation/inhibition of the cortex of autistic individuals. They quoted my work as part of their validation. I had a similar argument based on my own results which was published the same year: 112. Casanova MF, Buxhoeveden D, Gomez J: Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. The Neuroscientist, 9(6):496-507, 2003.

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  3. ‘Too Many Findings In Autism’ is by no means unique to autsm. It is the same problem that plagues all multifactorial disorders. The one finding that may apply is that any group who proposes a single causal mechanism for any multifactorial condition may be chasing fools gold.

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  4. Una vez mas gracias, para los que pretendemos investigar, sus apreciaciones tienen para mi, un sentido docente. Tomo cada palabra de su análisis y seré mas cuidadoso, a la hora de presentar y argumentar mi proyecto.

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  5. “The neurotypicals trying to understand the autistics are like the neurotypicals trying to understand the apes”
    –Drew Mcpherson, author of “you may be insane and don’t even know it!”

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