Von Economo neurons (VENs) are modified pyramidal neurons characterized by an extremely elongated rodshaped soma. They are abundant in layer V of the anterior cingulate cortex (ACC) and fronto-insular cortex (FI) of the human brain, and have long been described as a human-specific neuron type. Recently, VENs have been reported in the ACC of apes and the FI of macaque monkeys. The first description of the somato-dendritic morphology of VENs in the FI by Cajal in 1899 (Textura del Sistema Nervioso del Hombre y de los Vertebrados, Tomo II. Madrid: Nicolas Moya) strongly suggested that they were a unique neuron subtype with specific morphological features. It is surprising that a clarification of this extremely important observation has not yet been attempted, especially as possible misidentification of other oval or fusiform cells as VENs has become relevant in many recently published studies. Here, we analyzed sections of Brodmann area 24 (ACC) stained with rapid Golgi and Golgi-Cox in five adult human specimens, and confirmed Cajal's observations. In addition, we established a comprehensive morphological description of VENs. VENs have a distinct somato-dendritic morphology that allows their clear distinction from other modified pyramidal neurons. We established that VENs have a perpendicularly oriented, stick-shaped core part consisting of the cell body and two thick extensionsan apical and basal stem. The perpendicular length of the core part was 150-250 lm and the thickness was 10-21 lm. The core part was characterized by a lack of clear demarcation between the cell body and the two extensions. Numerous thin, spiny and horizontally oriented side dendrites arose from the cell body. The basal extension of the core part typically ended by giving numerous smaller dendrites with a brushlike branching pattern. The apical extension had a topology typical for apical dendrites of pyramidal neurons. The dendrites arising from the core part had a high dendritic spine density. The most distinct feature of VENs was the distant origin site of the axon, which arose from the ending of the basal extension, often having a common origin with a dendrite. Quantitative analysis found that VENs could be divided into two groups based on total dendritic lengthsmall VENs with a peak total dendritic length of 1500-2500 lm and large VENs with a peak total dendritic length of 5000-6000 lm. Comparative morphological analysis of VENs and other oval and fusiform modified pyramidal neurons showed that on Nissl sections small VENs might be difficult to identify, and that oval and fusiform neurons could be misidentified as VENs. Our analysis of Golgi slides of Brodmann area 9 from a total of 32 adult human subjects revealed only one cell resembling VEN morphology. Thus, our Journal of Anatomy data show that the numerous recent reports on the presence of VENs in non-primates in other layers and regions of the cortex need further confirmation by showing the dendritic and axonal morphology of these cells. In conclusion, our study provides a foundati...

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.

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Somatostatin cells are frequently described as a major population of GABAergic neurons in the cerebral cortex, however, a comprehensive analysis of their molecular expression, morphological features and laminar distribution has not yet been performed. In this study, we provided a detailed description of somatostatin neurons in the human prefrontal cortex, including their proportion in the total neuron population, laminar distribution, neurotransmitter phenotype as well as their molecular and morphological characteristics using immuno uorescence and RNAscope in situ hybridization. We found that somatostatin neurons comprise around 7% of neocortical neurons in the human Brodmann areas 9 and 14r, without signi cant difference between the two regions. Somatostatin cells were NeuN positive and synthesized vesicular GABA transporter and glutamate decarboxylase 1 and 2, con rming their neuronal nature and GABAergic phenotype. Somatostatin cells in the upper cortical layers were small, had a high expression of somatostatin mRNA, a relatively low expression of somatostatin peptide and coexpressed calbindin. In the lower cortical layers, somatostatin cells were larger with complex somatodendritic morphology, typically showed a lower expression of somatostatin mRNA and a high expression of somatostatin peptide, and co-expressed neuronal nitric oxide synthase (nNOS), but not calbindin. Somatostatin neurons in the white matter co-expressed MAP2. Based on their somato-dendritic morphology, cortical somatostatin neurons could be classi ed into at least ve subtypes. The somatostatin neurons of the human prefrontal cortex show remarkable morphological and molecular complexity with substantial differences compared to rodents, both of which imply a unique function in the human brain.