346.5 Minicolumnar Model of Somatosensory Perceptual Abnormalities In AutismOleg V. Favorov, Omar Awan, Mark Tommerdahl

Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, NC 27599

CONCLUSION

The developed minicolumnar model of the somatosensory cortical network

offers a mechanistic link between the primary autistic deficit in inhibitory

synaptic transmission and the consequent abnormalities in cortical

minicolumnar structure and functioning and their manifestation at the

perceptual level.

INTRODUCTION

Minicolumns, which are radially grouped cords of neurons 30-50 µm in

diameter, are a basic unit of cerebral cortical anatomical and

functional organization.

One notable feature of autistic cerebral cortex is the abnormal structure of its

minicolumns (Casanova, The Neuroscientist 12:435-441, 2006). The functional

significance of these minicolumnar abnormalities for autism has not been

established yet much beyond indications of reduced inhibitory interactions

among minicolumns. Increased ratio of excitation to inhibition in the cortex has

been proposed to be the common pathway for causing autism (Rubinstein and

Merzenich, Genes Brain and Behavior 2:255-267, 2003).

Favorov and Kelly (Cereb. Cortex 4:408-442, 1994) minicolumnar model of the

somatosensory cortex offers an opportunity to quantitatively explore how

excitation/inhibition imbalance in the minicolumnar network can lead to the

development of tactile perceptual abnormalities characteristic of autism.

FIGURE 1. Progression of receptive field centers in the radial and

tangential directions of the somatosensory cortex.

FIGURE 2. Optical response of the somatosensory cortex to a

vibrotactile stimulus, revealing minicolumnar patterns of activation.

D: model response.

METHODS

The original Favorov-Kelly model was a model of a single cortical

macrocolumn comprising a hexagonally-arranged set of 61 minicolumns. Its

design is based on the anatomy and physiology of the primary

somatosensory cortex of non-human primates.

FIGURE 3. Each minicolumn consists of 4 cells: an input spiny-stellate cell (which

receives thalamic input and distributes it to all other cells of the same minicolumn and, to

a lesser degree, to other nearby minicolumns), an intrinsic double-bouquet cell (which

inhibits adjacent minicolumns), an output pyramidal cell, and inhibitory basket cell.

Cortical cells are modeled as electric circuits with parallel, variable

excitatory, inhibitory, and afterhyperpolarization conductances.

Connections from the thalamic cells to minicolumns are plastic; they are

allowed to self-organize in accordance with a Hebbian rule during a

developmental period in which the network is driven by skin stimuli.

Minicolumns acquire through self-organization a complex, richly detailed

pattern of thalamic connections.

The original model was expanded to a circular-shaped field of 37

macrocolumns. Each macrocolumn has the same thalamic-spiny-stellate

connectional pattern, but shifted somatotopically across the thalamic field.

Excitatory “pyramidal” and inhibitory “basket” cells are randomly

interconnected; pyramidal cells across all 37 macrocolumns, basket cells

only within macrocolumns.

STIMULUS LOCALIZATION STUDY

Somatosensory cortical response to a local vibrotactile stimulus undergoes

gradual, but prominent funneling with continuous stimulus application, from

an initially widespread response of a large cortical territory to eventually very

focused response limited to just a small group of macrocolumns.

FIGURE 4. Five

successive time frames

show how the spatial

pattern of optical response

of the somatosensory

cortex becomes

progressively more

spatially focused in the

presence of continuing

stimulation.

Correspondingly, healthy human subjects also gradually improve their

ability to localize a point vibrotactile stimulus during its continuous

application. Subjects with autism, however, do not improve their stimulus

localization ability with longer stimulus exposures (Tommerdahl et al.,

Brain Res. 1154:116-123, 2007).

FIGURE 5. In control subjects, pre-

exposure of a skin region to a 5 sec flutter

stimulus results in a major improvement in their

ability to localize stimuli delivered to that same

skin region. Stimulus-localization performance

of autistic subjects is better than that of the

control subjects when the adapting stimulus is

only 0.5 sec long, but this performance does not

improve with longer, 5 sec duration adapting

stimuli.

The model reproduces the neural and psychophysical findings – under

reduced-inhibition conditions the modeled network localizes short-duration

stimuli better than the “normal” network, but does not improve its localization

capabilities with longer stimulus durations.

FIGURE 6. Response of the

modeled cortical region to the first 80

msec and 1000 msec of stimulation.

FIGURE 7. Average activity of

minicolumns as a function of their

distance from the center of the

responding cortical region. Broken line

- first 80 msec of stimulation, solid line

- after 1 sec of stimulation.

FIGURE 8. Average RF profile

of modeled cortical neurons.

Subjects were asked to detect the temporal

order of two sequentially delivered vibrotactile

stimuli applied to two fingertips, engaging

different sets of macrocolumns in SI, linked

however by long-range horizontal connections.

Weak background in-phase vibrotactile

stimulation of the two skin sites appears to

synchronize the periodic firings of neurons in the

macrocolumns driven from the two skin sites,

which interferes with normal subjects’

performance on the TOJ test. Subjects with

autism, however, are insensitive to this

background in-phase vibration (Tommerdahl et

al., Behav. Brain Funct. 4:19, 2008).

TEMPORAL ORDER JUDGEMENT STUDY

Figure 10. Top panel – response of the model cortex to two sequential pulse

stimuli under the normal and reduced-inhibition condition. Bottom panel –

response of the model cortex to two sequential pulse stimuli superimposed on

flutter vibration.

The reduced-inhibition minicolumnar model reproduces the experimentally

observed differences between healthy and autistic subjects in this temporal

order judgment task.