In previous posts I have mentioned our findings of abnormal minicolumns in the brains of autistic individuals.  The minicolumn is an elemental modular unit of the cortex serving as an architectonic template according to which are arranged representative cellular elements as well as their connections. A chain of excitatory neurons (called pyramidal cells) with their projections (axonal and dendritic bundles) constitutes its core, extending radially through the layers of the cerebral cortex. Around the periphery of this core is neuropil (a cell-body sparse region) containing synaptic elements integrating translaminar connections among different levels of the minicolumn. The peripheral neuropil also contains inhibitory interneurons (prominently radially-oriented GABAergic double-bouquet cells) providing a “sheath” of inhibitory activity.

The first panel recreates the position within a minicolumn of cells and their projections,  The second panel is meant to illustrate the compartmentalization of the minicolumn: the core comprised of excitatory cells and the peripheral neuropil space with inhibitory elements.  The last panel  illustrates results from a study where the normalized width of the whole minicolumn (CW) and its peripheral neuropil space (NS) were measured.  A redution of the peripheral neuropil space accounts for most of the findings.  RDR is a measurement of relative cell dispersion.

The basic minicolumnar circuit is distributed iteratively throughout neocortex, incorporated into a nested hierarchy of modular units. Cortical microstructure exhibits variability intra- and interareally, across hemispheres within a given brain, as well as among individuals within and across species with regard to cell size, density, number, and size of neuronal projections (i.e., axonal and dendritic bundles). Nevertheless, the basic organization of microcircuitry is maintained throughout the cortex in all individuals and species.

Our findings in autism showed that minicolumns were smaller with most of the reduction being based at the periphery of this modular structure. The abnormality resides within the peripheral neuropil space, which as already stated is the home of inhibitory elements for the minicolumn.  It is interesting to note that the brains of autistic individuals are normal or above normal in volume.  This means that a reduction in size for this modular structure over a linear length, translates into more minicolumns. The paradox is that although a given brain from an autistic individual may have more minicolumns, a good thing, they nevertheless appear to be structured differently to those of neurotypicals.

A famous neuroanatomist from Budapest, John or Janos Szentagothai, once called the peripheral neuropil space of minicolumns a “shower curtain of inhibition”.  The presence of inhibitory cells within this compartment serves, in part, to keep information processing within the core of the minicolumn.  A defect in this compartment allows for stimuli to overflow to adjacent areas and recruit other minicolumns.  The resultant avalanche of stimulation would, under certain circumstances, provide for seizures.

Initially I thought that we could take advantage of or postmortem  findings for therapeutic purposes by increasing the inhibitory tone of cells within the peripheral neuropil space, e.g., using such things as anticonvulsants or benzodiazepines. However, these drugs are not selective for inhibitory elements located within the peripheral neuropil space.  Using these agents could indiscriminantly dampen the activity of all cells within the cerebral cortex.  The result would provide for amelioration of some autistic symptoms but also for formidable side effects. Nevertheless there are case reports within the literature of improvement in autistic behaviors in children treated with anticonvulsants for seizures as in the case of tuberous sclerosis.

The figure shows the presence of some of the inhibitory cells that are found within the periphery of the cell minicolumn.  These cells (stained by immunocytochemistry) stand out because of their exquisite geometrical orientation with the surface of the brain.

How can we take advantage of the exquisite geometrical orientation of some inhibitory cells within the peripheral neuropil space? The idea came to me that we could apply Faraday’s law to this problem. Faraday’s law proposes the induction of a voltage in a conductor when exposed to a varying magnetic field. If we exposed the cortex to a varying magnetic field, we could preferentially induce conduction across the vertically arranged inhibitory elements of the peripheral neuropil space of minicolumns (see figure above).

(A) Poor spatial contrast across minicolumns as postulated in the brain’s of autistic individuals.  Minicolumn 2 receives input but is not capable of adequate inhibition of surrounding columns for optimal contrast. (B) TMS activation of intracortical inhibitory neurons within minicolumn 2 leads to enhanced surround inhibition and better spatial contrast.  This leads to a greater discriminatory capacity for the involved cortical unit.

Initially, I tried unsuccessfully to convince several other neuroscientists who had a track record  in TMS to perform the studies. I even went around the country and provided Grand Rounds introducing the idea with little interest as a result.  It took me several years before venturing myself to perform the first clinical trial.  However, the results have been unquestionably positive.  We have some 6-7 publications on the subject, have tested 100-200 patients, have found little in terms of side effects, and the results are being reproduced by other groups around the world.

One of the problems we had to overcome initially was where within the cerebral cortex of affected individuals should we use the technique (TMS)?  Given limitations with the equipment it would be impossible  to simultaneously stimulate all of the brain. Fortunately, we had already done a topographical or mapping study of minicolumnar abnormalities in autism.  Time and time again most of the abnormalities were found within the prefrontal cortex.  In the end, we selected an area within the brain called the dorsolateral prefrontal cortex (DLPC).  This area of the brain has the almost unique attribute of being connected to all the rest of the brain.  I therefore decided to follow what I called a «cascading» principle. The idea is that «fixing» one area of the brain would promote the well being of other brain regions to which it was heavily interconnected.  In essence, we were counting with the plasticity of the brain to fix itself. I was motivate in this regard by the natural history of the condition wherein  improvements with aging are seen in many autistic individuals (some even losing their diagnosis).  TMS would only serve to expedite the healing process (or neuroplasticity) of the brain itself.

Although we have had positive results by using TMS the overall trials have been conducted so as to apply what we have learned from the one before; babysteps. In future blogs we will talk about optimizing the use of TMS.

References:

1. Sokhadze E, El-Baz A, Singh S, Mathai G, Sears L, Casanova MF. Effects of low frequency transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related potentials during processing of illusory figures in autism. JADD 39(4): 619-634, 2009.
2. Sokhadze, E.,   Baruth, J., El-Baz, A., Ramaswamy, R., Sears, L., Casanova, M.  Transcranial magnetic stimulation study of gamma induction in response to illusory figures in patients with autism spectrum disorders. Journal of Neurotherapy, 13(4), 271-272, 2009.
3. Sokhadze E, Baruth J, Tasman A, Mansoor M,  Ramswamy R, Sears L, Mathai G, El-Baz A, Casanova MF. Low frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related measures of novelty processing in autism.  Applied Psychophysiology and Biofeedback, 35:147-161, 2010.
4. Baruth JM, Casanova M, El-Baz A, Sears L, Sokhadze E. Low-frequency repetitive transcranial magnetic stimulation (rTMS) modulates evoked-gamma frequency oscillations in autism spectrum disorder (ASD). Journal of Neurotherapy, 14(3): 179-194, 2010.
5. Baruth J, Sokhadze E. El-Baz A, Mathai G, Sears L, Casanova MF. Transcaranial Magentic Stimulation as a Treatment for Autism. Siri K and Lyons T (eds). Cutting Edge Therapies for Autism, Skyhorse Publishing: New York, ch. 63, pp. 388-397, 2010.
6. Baruth JM, Williams EL, Sokhadze E, El-Baz A, Sears L, Casanova MF. Beneficial effects of repetitive Transcranial Magnetic Stimulation (rTMS) on behavioral outcome measures in autism spectrum disorder. Autism Science Digest, 1: 52-57, 2011.