A statistically based density map method for identification and quantification of regional differences in microcolumnarity in the monkey brain.

We present a statistical density map method derived from condensed matter physics to quantify microcolumns, the fundamental computational unit of the cerebral cortex. This method provides measures for microcolumnar strength, width, spacing, length, and periodicity. We applied this method to Nissl-stained 30 microm thick frozen sections from areas 46, TE, and TL of rhesus monkey brains, areas that differ visually in microcolumnarity and are associated with different cognitive functions. Our results indicate that microcolumns in these areas are similar in width, spacing, and periodicity, but are stronger (possess a higher neuronal density) in area TE, as compared to areas TL and 46. We modeled the effect of section orientation on microcolumnar spacing and demonstrated that this method provides an adequate estimate of spacing. We also modeled disruption of microcolumnarity by performing simulations that randomly displace neurons and demonstrated that displacements of only one neuronal diameter effectively eliminate microcolumnar organization. These results indicate that our density map method is sensitive enough to detect and quantify subtle differences in microcolumnar organization that may occur in the context of development, aging, and neuropathology, as well as between areas and species.

Age-related reduction in microcolumnar structure in area 46 of the rhesus monkey correlates with behavioral decline.

Many age-related declines in cognitive function are attributed to the prefrontal cortex, area 46 being especially critical. Yet in normal aging, studies indicate that neurons are not lost in area 46, suggesting that impairments result from more subtle processes. One cortical feature that is functionally important, but that has not been examined in normal aging because of a lack of efficient quantitative methods, is the vertical arrangement of neurons into microcolumns, a fundamental computational unit of the cortex. By using a density-map method derived from condensed-matter physics, we quantified microcolumns in area 46 of seven young and seven aged rhesus monkeys that had been cognitively tested. This analysis demonstrated that there is no age-related reduction in total neuronal density or in microcolumn width, length, or periodicity. There was, however, a statistically significant decrease in the strength of microcolumns, indicating microcolumnar disorganization. This reduction in strength was significantly correlated with age-related cognitive decline on tests of spatial working memory and recognition memory independent of the effect of age. Modeling demonstrated that random neuron displacements of approximately 30% of a neuronal diameter (<3 mum) produced the observed reduction in strength. Hence, it is possible that, with changes in dendrites and myelinated axons, subtle displacements of neurons occur that alter microcolumnar structure and correlate with age-induced dysfunction. Therefore, quantitative measurement of microcolumnar structure may provide a sensitive morphological method to assay microcolumnar function in aging and other conditions.