Somato‐dendritic morphology and axon origin site specify von Economo neurons as a subclass of modified pyramidal neurons in the human anterior cingulate cortex

Von Economo neurons ( VEN s) are modified pyramidal neurons characterized by an extremely elongated rod‐shaped 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, VEN s have been reported in the ACC of apes and the FI of macaque monkeys. The first description of the somato‐dendritic morphology of VEN s 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 VEN s 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 VEN s. VEN s have a distinct somato‐dendritic morphology that allows their clear distinction from other modified pyramidal neurons. We established that VEN s have a perpendicularly oriented, stick‐shaped core part consisting of the cell body and two thick extensions – an apical and basal stem. The perpendicular length of the core part was 150–250 μm and the thickness was 10–21 μm. 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 brush‐like 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 VEN s 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 VEN s could be divided into two groups based on total dendritic length – small VEN s with a peak total dendritic length of 1500–2500 μm and large VEN s with a peak total dendritic length of 5000–6000 μm. Comparative morphological analysis of VEN s and other oval and fusiform modified pyramidal neurons showed that on Nissl sections small VEN s might be difficult to identify, and that oval and fusiform neurons could be misidentified as VEN s. 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 data show that the numerous recent reports on the presence of VEN s 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 foundation for further comprehensive morphological and functional studies on VEN s between different species.