The human cerebral cortex is neither one nor many: neuronal distribution reveals two quantitatively different zones in the gray matter, three in the white matter, and explains local variations in cortical folding

Abstract

The human prefrontal cortex has been considered different in several aspects and relatively enlarged compared to the rest of the cortical areas. Here we determine whether the white and gray matter of the prefrontal portion of the human cerebral cortex have similar or different cellular compositions relative to the rest of the cortical regions by applying the Isotropic Fractionator to analyze the distribution of neurons along the entire anteroposterior axis of the cortex, and its relationship with the degree of gyrification, number of neurons under the cortical surface, and other parameters. The prefrontal region shares with the remainder of the cerebral cortex (except for occipital cortex) the same relationship between cortical volume and number of neurons. In contrast, both occipital and prefrontal areas vary from other cortical areas in their connectivity through the white matter, with a systematic reduction of cortical connectivity through the white matter and an increase of the mean axon caliber along the anteroposterior axis. These two parameters explain local differences in the distribution of neurons underneath the cortical surface. We also show that local variations in cortical folding are neither a function of local numbers of neurons nor of cortical thickness, but correlate with properties of the white matter, and are best explained by the folding of the white matter surface. Our results suggest that the human cerebral cortex is divided in two zones (occipital and non-occipital) that differ in how neurons are distributed across their gray matter volume and in three zones (prefrontal, occipital, and non-occipital) that differ in how neurons are connected through the white matter. Thus, the human prefrontal cortex has the largest fraction of neuronal connectivity through the white matter and the smallest average axonal caliber in the white matter within the cortex, although its neuronal composition fits the pattern found for other, non-occipital areas.

No relative expansion of the number of prefrontal neurons in primate and human evolution

“…Still, the V W /O W ratio is a useful parameter for comparing variations in average fiber caliber within an individual cortex, because the ratio is proportional to the average cross-sectional area of myelinated axons (15). Thus, the smaller V W /O W ratio in sections anterior to the callosum (and therefore defined as prefrontal) suggests that these sections contain fibers of smaller caliber, in line with the previous finding that callosal fibers are thinnest at the genu (9,16,17). This consonance supports the conclusion that cortex anterior to the callosum indeed defines comparable prefrontal cortical regions across primate species, including humans (4,(18)(19)(20)(21), even if these zones do not correspond to the entire associative areas in the frontal lobe.…”

“…Order of neurogenesis may indeed explain the generation of a larger number of neurons in the developing occipital region-although this order does not provide a mechanism to account for how these neurons are smaller and so occur at a greater neuronal density-but neurogenesis order does not explain the large neuronal densities also found in the frontal pole. It seems that other factors also determine the average size of cortical neurons and the fraction connected through the white matter in each cortical zone, as proposed previously (9,31). By recognizing that the A-P gradient of neuron generation time does not truly account for the variation in their sizes and densities, further study will be necessary to identify the different mechanisms by which the quantitative differences between the three regions observed here are formed, including the generation of the two neuronal density gradients found peaking in the prefrontal and occipital poles.…”

“…It seems from the controversy that any possible exceptionality of the white matter volume of the human prefrontal cortex must be small, because an exceptionality depends on the statistical analysis applied. Still, those studies were limited to the use of the only parameter available then, cortical volume, which we now know not to be a simple, direct reflection of numbers of neurons across cortical areas (8,9). If the human prefrontal cortex was preferentially expanded in evolution, then its gray matter should hold a relatively larger fraction of all cortical neurons.…”

“…Here we test these hypotheses by performing a systematic analysis of neuron distribution along the anteroposterior (A-P) axis of the cerebral cortex across eight primate species, including humans (9). We use the isotropic fractionator (10), a nonstereological method that yields results similar to those obtained with stereology (11), to analyze numbers of neurons and other cells in a systematic series of 2-mm coronal sections along the A-P axis of one cortical hemisphere of each species.…”

Cortical cell and neuron density estimates in one chimpanzee hemisphere

“…To examine whether the chimpanzee brain showed uniform cell and neuron packing densities across cortex (or a linear decrease in density beyond V1 from posterior to anterior), we examined densities in pieces of cortex across the anterior-to-posterior (A-P) dimension, using linear regression and curve estimation, testing multiple model functions. Recently, there have been a number of descriptions of neuron packing densities across the cortical sheet in monkeys and other mammals that revealed a trend from low packing densities to high neuron packing densities from anterior to posterior cortex (11,(30)(31)(32)(33). When we assessed how cell and neuron densities varied in the selected cortical regions across the A-P dimension, using generalized linear modeling with robust estimators, most cortical areas showed significant differences in estimated means of neuron and cell density (Fig.…”