Von Economo Neurons - Primate-Specific or Commonplace in the Mammalian Brain?

Abstract

The pioneering work by von Economo in 1925 on the cytoarchitectonics of the cerebral cortex revealed a specialized and unique cell type in the adult human fronto-insular (FI) and anterior cingulate cortex (ACC). In modern studies, these neurons are termed von Economo neurons (VENs). In his work, von Economo described them as stick, rod or corkscrew cells because of their extremely elongated and relatively thin cell body clearly distinguishable from common oval or spindle-shaped infragranular principal neurons. Before von Economo, in 1899 Cajal depicted the unique somato-dendritic morphology of such cells with extremely elongated soma in the FI. However, although VENs are increasingly investigated, Cajal's observation is still mainly being neglected. On Golgi staining in humans, VENs have a thick and long basal trunk with horizontally oriented terminal branching (basilar skirt) from where the axon arises. They are clearly distinguishable from a spectrum of modified pyramidal neurons found in infragranular layers, including oval or spindle-shaped principal neurons. Spindle-shaped cells with highly elongated cell body were also observed in the ACC of great apes, but despite similarities in soma shape, their dendritic and axonal morphology has still not been described in sufficient detail. Studies identifying VENs in non-human species are predominantly done on Nissl or anti-NeuN staining. In most of these studies, the dendritic and axonal morphology of the analyzed cells was not demonstrated and many of the cells found on Nissl or anti-NeuN staining had a cell body shape characteristic for common oval or spindle-shaped cells. Here we present an extensive literature overview on VENs, which demonstrates that human VENs are specialized elongated principal cells with unique somato-dendritic morphology found abundantly in the FI and ACC of the human brain. More research is needed to properly evaluate the presence of such specialized cells in other primates and non-primate species.

Keywords: anterior cingulate cortex; cerebral cortex; frontoinsular cortex; human; primate brain; pyramidal neuron; von Economo neurons.

FIGURE 1

Golgi staining of the FI in a 1-month-old human girl. Note the von Economo neurons (VENs) marked by the letters C and D, and the very distant axon origin of these cells. Image acquired from Cajal (1899).

FIGURE 2

Comparison of VENs and common modified pyramidal neurons (MPN) in the fronto-insular (FI), anterior cingulate cortex (ACC), and PFC on Golgi and Nissl staining. Axons on Golgi staining are marked by “a”. The magnification for all microphotographs is indicated by the 50 μm scale bar in the lower right corner. (A) Drawing of a VEN in the FI of a 1-month-old human, Golgi staining. Image modified from Cajal (1899). Note the distant axon origin and the brush-like terminal branching of the prominent basal dendrite. (B) Microphotograph showing a cluster of VENs in the FI of an adult human, Nissl staining. Image modified from von Economo and Koskinas (1925). (C) Microphotograph of a VEN in the ACC of an adult human, Golgi staining. Image modified from Banovac et al. (2019). Note the distant axon origin and the brush-like terminal branching of the prominent basal dendrite. (D) Microphotograph showing a cluster of VENs in the ACC of an adult human, Nissl staining. Image modified from von Economo and Koskinas (1925). (E) Microphotograph of a common MPN with a spindle-shaped cell body found throughout the PFC, Golgi staining. Image modified from Banovac et al. (2019). Note the axon origin close to the cell body and the lack of the brush-like terminal branching typical for VENs. (F) Microphotograph showing several common MPNs with a spindle-shaped cell body found throughout the PFC, Nissl staining. Image modified from Banovac et al. (2019).

FIGURE 3

Camera lucida reconstructions of common modified pyramidal neurons in the PFC. The axons on spindle-shaped neurons are marked by “a”. Note that the axon of common modified pyramidal neurons arises either from the cell body or extremely close to the cell body, unlike the distant axon origin found in VENs. Also note that common modified pyramidal neurons lack the brush-like terminal branching typical for VENs. Image modified from Petanjek and Kostović (1994b).

FIGURE 4

(A) Drawing showing spindle cells (Spindelzellen) of layer VI and morphological variants as seen on Nissl staining. (B) Drawing showing VENs (Stab- und Korkzieherzellen) of layer Vb found in the FI and ACC as seen on Nissl staining. Images modified from von Economo and Koskinas (1925).

FIGURE 5

(A) Microphotograph of the dome of the gyrus transversus insulae (Area frontoinsularis – FJ), Nissl staining. (B) Microphotograph of the dome of the gyrus limbicus, regio anterior; frontally and dorsally from the genu corporis callosi (Area cingularis anterior – LA₂), Nissl staining. The enlarged panels show VENs in layer Vb of the FI and ACC as well as other spindle-shaped cells (Spindelzellen) and cells of ambiguous somatic morphology. Note that on Nissl staining, even in the FI and ACC, it is difficult to classify certain cells as either VENs or common modified pyramidal neurons (spindle cells, Spindelzellen). Also note the clusters of VENs in both regions as well as the relative predominance of VENs in the FI compared to the ACC. Images modified from von Economo and Koskinas (1925).

FIGURE 6

Historical timeline of the most relevant research and review papers on VENs in healthy/neurotypical brains.

FIGURE 7

Neurolucida 3D reconstructions of VENs and common modified pyramidal neurons (MPN) found in the human cerebral cortex. The axon origin is marked by “a” and the axon is traced in red. Note the differences in axon origin between VENs and common MPNs as well as the brush-like terminal branching of the basal dendrite in VENs that is not present in common MPNs. Image modified from Banovac et al. (2019).

FIGURE 8

Drawing showing VENs as seen on Bielschowsky silver staining. Note the peculiar depiction of the axon arising laterally from the cell body, differing from all other studies that demonstrated the axon origin of VENs. Image acquired from von Economo (1926).