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).
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.
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).
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.
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.