Sensory Problems in Autism: Origins and Possible Intervention by Manuel Casanova, MD

Participant: Elias Tembenis Seizures Think Tank
Minicolumns are basic architectonic and physiological elements identified in all regions of the neocortex and in all mammalian species thus far evaluated. The minicolumnar circuit is an evolutionarily and ontogenetically conserved template adapted in the various cortical areas according to their specific developmental and functional requirements. The minicolumnar core comprises radially oriented arrays of pyramidal projection neurons (pyramidal cell arrays). At the core and periphery of the minicolumn combinations of Gamma Amino Butyric Acid (GABA) interneurons provide for a diversity of signaling properties that serve to dynamically modulate pyramidal cell inputs and outputs that perform area and task-specific information processing needs. Recently, computer image analysis studies by our group have reported abnormalities in the pyramidal cell arrays (minicolumns) of autistic patients. These studies have shown reduced horizontal spacing between pyramidal cell arrays and diminished neuropil space at the periphery of the minicolumn. This observation, a deficit of columnar surround inhibition, has now been corroborated by studies probing tactile resolution and habituation to stimuli in autism. Lack of minicolumnar surround inhibition provides for signal amplification and an overall increase in noise. The resultant inability to differentially process simultaneous sources of information provides for a deficit in selective attention, which in autism permeates all sensory modalities. In this model, a reduction in the peripheral neuropil space would result in smaller minicolumns which would coalesce into discrete, isolated islands of coordinated excitatory activity. These islands could serve as potential ictal (seizure) foci. Moreover, their autonomous activity would hinder the binding of associated cortical areas, arguably promoting focus on particulars as opposed to general features. Inhibitory cell elements at the periphery of the minicolumn have a bitufted axonal system that span several layers perpendicular to the pial surface. Our basic hypothesis is that the geometrically exact orientation of these cells and their location at the periphery of the minicolumn (inhibitory surround) makes them the appropriate candidate for induction to magnetic field applied parallel to the cortex. The principle of electromagnetic induction proposes that a changing magnetic field induces the flow of electric current in a nearby conductor. Maximal induction is proposed for conductors at 90 degrees to the magnetic field. Preliminary results using slow Transcranial Magnetic Stimulation over the dorsolateral prefrontal cortex (DLPFC) of autistic patients (an attempt to strengthen the inhibitory surround of minicolumns) have shown promising results. Due to the connectivity of this brain region we expect the intervention to generalize to other cortical areas.

Manuel Casanova, MD made his residency training in neurology and then spent 3 years doing a fellowship in neuropathology at The Johns Hopkins Hospital. During his stay at the Johns Hopkins Hospital, Dr. Casanova was in charge of Pediatric Neuropathology, a fact which kindled his interest in developmental disorders of the brain. His clinical experience was enhanced by appointments as either a consultant or staff neuropathologist at Sinai Hospital (Maryland), the North Charles Hospital and the D.C. General Hospital. Dr. Casanova has had over twenty years of experience in the neurosciences. Although trained in the classical methods of neurology and neuropathology, his interest has gradually shifted towards the study of abnormalities of cortical circuitry. His research has focused on the cell minicolumn, a vertical conglomerate of 80 to 100 neurons having a common latency of response to stimulation. Using computerized imaging analysis he has established the anatomical validity of the cell minicolumn. More recently Dr. Casanova has reported interhemispheric differences in the morphometry of minicolumns that could provide for the speciation of hominids. Localized in Broadmann area 22 - part of Wernicke's language region - the morphometric difference may play a role both in the development of language and in its disorders. His most recent studies have looked for the presence of abnormalities of minicolumnar organization and lateralization in the brains of patients who exhibit language disturbances, including autism, Asperger's syndrome, and dyslexia. He has summarized his work on minicolumns and provided an overview of the field in recent reviews of the literature appearing in Brain and Brain, Behavior and Evolution. Dr. Casanova holds the Gottfried and Gisela Kolb Endowed Chair in Psychiatry, Associate Chair for Research, University of Louisville Department of Psychiatry.