What Causes the Major Symptoms of Autism (Part 1)?

A pedagogic aspect of a pathologist’s job is trying to explain symptoms based on autopsy findings.  This follows a long tradition in medicine where a professor does dissections while asking questions to participating students.  Occasionally, in order to elicit the opinion of other authorities, the more perplexing or challenging cases are presented to a larger group of faculty members in a more formal setting.  The latter effort is called a clinicopathological conference (CPC).

The same year in which I described a deficit in the organization of the cerebral cortex  of autistic individuals (i.e., abnormal minicolumns) (Casanova et al, 2002a) we published a follow-up article describing possible clinicopathological correlations.  Discoveries usually gain significance based on their explanatory powers.  In our case we wanted to explain not only how known symptoms of autism were generated, but also to predict important aspects of its pathophysiology.  In essence, by knowing the pathology (what is wrong in the brain) we could not only talk about the known symptoms but also try to predict aspects of the condition never previously addressed within the medical literature.

In this particular blog I will talk about how minicolumnar abnormalities can procreate symptoms related to cortical hyperexcitability.  I will leave for the future a discussion in which I draw an analogy between the abdominal symptoms of some autistic patients and a migraine equivalent. Besides cortical hyperexcitability,  the analogy to migraine based on similarities in their natural history, provoking agents, high levels of serotonin in the blood, biopsy results, and ability to treat both with certain diets.  This analogy has been published only as a hypothesis (Casanova, 2008). In addition, other blogs will describe how the same minicolumnar abnormalities may also provide for changes in both the brain’s blueprint of connectivity as well as its capacity to bind together different elements of cognition.  These are all ideas stemming from  studies in my laboratory and as such remain subject to further experimentation and verification.

As I have previously alluded in previous blogs, an abnormality in the peripheral surround of minicolumns (the so-called “shower curtain of inhibition”) allows for the leaking of signals, that is, information that was supposed to be processed by a single minicolumn now suffuses into adjacent minicolumns.   If unchecked, stimulating minicolumns lacking in surround inhibition will themselves recruit adjacent minicolumns and continue their spread in an avalanche of stimulation that in some cases will be manifested as a seizure. Approximately one third of autistic individuals have suffered at least 2 seizures by the time they get to puberty.  The percentage of autistic individuals with an abnormal EEG is considerably higher, about two thirds. In the end hyperexcitability disrupts the normal process of information processing within the cerebral cortex (see figure below).

neuronal activity

Neurons react to stimuli (e.g., a square wave) by firing more often not by increasing the amplitude of their spike.  In the normal scenario the neuron is never silent, and even without apparent stimuli will fire occasionally thus  providing a background level of activity. In the hyperexcitable cortex neurons will fire more without appropriate stimulation.  In the pathological case (e.g., autism), the amount of firing is such that it makes it difficult to differentiate signal from noise.

The following are several paragraphs describing what happens when the nervous system is overstimulated and taxed in its abilities to cope with the environment. The paragraphs were taken from JJ Ratey Shadow Syndromes, 1997. The parallel to autism in Ratey’s description should be apparent.

“What researchers found was that in fact stimulus overload is devastating to the brain’s- to the self’s- capacity to maintain itself.  Entirely normal people who are severely overloaded, especially by unpredictable and uncontrollable stimuli, can show impaired functioning, raised physiological stress, internal chaos. Impulsive actions, and a “lower level of adaptation: to life’s challenges.”

“Because research shows that prolonged states of sensory overload (or noise) are actually traumatizing, we can conclude that patients suffering from severe mental disorders are actually being traumatized by their own brains.”

“Noise affects this top level, causing a person afflicted to fall back to a more primitive, “lower” level of brain functioning that corresponds to the social strategies of the adolescent or child. (Or lower still…where we respond reflexively instead of thoughtfully.”

“Finally, beyond both of these difficulties, intense physiological arousal also impairs reasoning ability, a phenomenon psychiatrists describe as becoming concrete. Once we have become concrete, we take things at face value; we are no longer responding to the subtle clues  and subtext of social interactions…But what happens when people become concrete is that they have no way of gauging the depth, the possible subtexts, of any particular exchange.”

The lack of peripheral or lateral surround to minicolumns has been recently corroborated by electrophysiological means (Keita et al., 2011). Mark Tommerdahl has been able to implement an ingenious diagnostic screening device based on our concept of lack of surround inhibition (see figure below).

Sensory Testin

Cortical activity in test animals measured as light absorbance from terminal fields in their cortex. Distance is measured from the center of their terminal fields. By varying the frequency of a stimulus we are able to make the area of peripheral inhibition to kick in or start functioning.

Sensory Testing2

Spatial localization under two conditions of adapting stimulus duration. Varying the frequency of a tactile stimuli does not propitiate the kick in of the peripheral inhibitory surround because the same is defective in autistic individuals.

Cortical hyperxcitability may provide a suitable explanation for the sensory problems reported by many autistic individuals. In an interview with Tony Atwood, Temple Grandin (2008) when asked where the federal government should spend their research money answered: “…I would spend it on…really figuring out what causes all the sensory problems. I realize it’s not the core deficit in autism, but it something that makes it extremely difficult for persons with autism to function.”

Both excitatory and inhibitory neurons display spontaneous activity so that synaptic inputs modulate their firing rate around a baseline rate. A lack or deficiency of inhibition (e.g., a diminished number of interneurons, abnormal surround inhibition to minicolumns) may help depolarize existing neurons below the trigger point of their action potential.  In this scenario otherwise weak signals add up resulting in spikes of activity.  This phenomenon, called stochastic resonance, makes reference to the transmission of a weak signal in the presence of noise. Stochastic resonance may provide an explanation to the high prevalence of sensory problems and their resultant behaviors that  handicap many autistic patients.


Casanova MF, Buxhoeveden D, Switala A, Roy E:  Minicolumnar pathology in autism.  Neurology, 58:428-432, 2002.

Casanova MF, Buxhoeveden DP, Brown C: Clinical and macroscopic correlates of minicolumnar pathology in autism.  J Child Neurol, 17:692-695, 2002.

Casanova MF. The minicolumnopathy of autism: a link between migraine and gastrointestinal symptoms.  Medical Hypothesis, 70:73-80, 2008.

Keita L, Mottron L, Dawson M, Bertone A. Atypical lateral connectivity: a neural basis for altered visuospatial processing in autism. Bio Psychiatry 1; 70(9):806-11, 2011.

14 responses to “What Causes the Major Symptoms of Autism (Part 1)?

  1. Are developmental lesions different from adult lesions. Also, I think Eric Courchesne, if I did not misunderstand him said that all of your postmortem findings of minicoloumnar pathology were on adult brains and this was a limitation, since postmortem findings on limited samples of 3 year old autistic brains were different. But I don’t remember the exact specifics. Would the minicolumnar pathology exist in a 3 year old autustic brain or would their brain change as adults?


  2. Developmental lesions are those that occur during the formation of the brain, e.g. malformations of the cortex, migrational abnormalities of neurons (also called heterotopias). Lesions in the adult brain are different. Among other things, lesions in the adult brain may elicit a profound reaction from cells involved in repair mechanisms (such as astrocytes).
    We have sampled a broad population of patients in regards to age range. Our series has 2 four year-old patients. We have found that with aging some of the minicolumnar abnormalities tend to improve (unpublished observations).
    Thank you for the comment and for remaining a follower of the blog. I am impressed by the fact that you seem so widely read. Hopefully we will meet at a future conference.


  3. We did meet at a conference in Long Beach a few years ago, but you might not remember who I was because you were not familiar with me then. I’ve read a little here and there, I wish I had far more expertise so maybe i could figure out what was wrong with myself, but I guess I can’t expect to know if you and other neuroscience experts don’t know. hopefully we will meet up again someday


  4. I do remember the meeting and I remember you. I was probably concentrating on the fact that I had to give two lectures, one in English and the other in Spanish. The Rubins were wonderful hosts and it was nice to meet their daughter, Sue. Nice renewing our friendship.


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  10. If sensory overload is a central issue in autism, one would have to assume that this problem could be caused not just by deficits in the internal filters, tuners, organizers, but also by a real overloads. This would be the case in garnd prematures who are overwhelmed by all kinds stimuli for long periods, stimuli which are very diferent from those they would have normally had in the womb. Yet there has been little atention paid to this except i believe in some papers in the sixties/senventies.


  11. Good observation. I am not sure that the problem has been paid close attention, but extreme prematurity, as you already known, is a risk factor for autism. Thank you for the comment.


  12. Hi, Manny
    I so agree with you about sensory overload being one of the main (if not the main) problems (and one of the main causes – if we follow a cascade theory) in autism
    What do you think about the Intense World syndrome hypothesis (Markram et al. 2007)?


    • Hi Olga,

      I discussed the same with Henry before it was published. he saw commonalities to our minicolumnar findings, having closely adjacent modules. He has quoted the findings as evidence in favor of the hyperconnectivity observed in the valproic acid model. I think the main weakness in the intense world syndrome is that it is based on an animal model that may not necessarily be representative of autism in humans.


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