Without any doubt, among many scientific gains of Volodymyr Betz, the discovery of the giant pyramidal neurons (also known as Betz cells) was the greatest and most significant achievement. So we dedicated this separate division of our web page to this prominent founding. We tried to illustrate it with informative microscopic images of Betz cells taken from different sources; for more illustrations, see "Gallery".
The giant pyramidal neurons are motor neurons of layer V of gray matter in the primary motor cortex. They are also called Betz cells after the famous Ukrainian physiologist and neuroanatomist Volodymyr Betz who discovered them and firstly described in 1874 (Betz, 1874). The giant pyramidal neurons are the largest cells in the central nervous system, sometimes reaching 100-120 ?m in diameter (Purves et al., 2008, pp. 432-434), and have thick myelin sheath. They are easily recognizable on stained sections, as they are approximately 20 times larger than other pyramidal cells. Betz cells are located in layer V and do not form a compact layer, but are rather isolated or arranged in small clusters (Meyer et al., 2014).
Figure 1. A. Betz cells in the Layer V of human primary motor cortex (Nissl stain; scale bar 40 mm). B. Parvalbumine-immunoreactive giant Betz cell, with intensely positive synapses contacting its soma (scale bar 40 mm). C. A giant Betz cell and medium-sized pyramidal neurons (asterisks) of layer V (Golgi method), a axon giving in intracortical collateral (scale bar - 5070 mm) (After Meyer et al., 2014).
Axons of Betz cells are directed downward, run into the pyramidal tract and connect with extrapyramidal system and subcortical nuclei. In the brainstem they cross and then connect with the anterior horn of the spinal cord on the contralateral side, and the longest axons reach the caudal segments of the spinal cord.
Apical dendrites of Betz cells reach the layer I of gray matter in the primary motor cortex. Apart from one apical dendrite typical for the pyramidal neurons, Betz cells have more primary dendritic shafts, which can branch out at almost any point from the soma (cell body) (Braak, 1976). These perisomatic (around the cell body) and basal dendrites project into all cortical layers, but most of their horizontal branches/arbors populate layers V and VI, some reaching down into the white matter (Meyer, 1987).
Somatosensory input from area 2 is relayed to Betz cells through corticocortical fibers from layers II and III of the motor cortex.
Figure 2 Betz cells.
The number of Betz cells in the motor area in the cortex of each hemisphere of the human brain makes 25-35 thousands, representing about 10% of pyramidal cells (Rivara et al., 2003). Axons of these cells form 2-3% of lateral pyramidal pathways.
1. Fig. 3 Betz cells in dogs brain, alcohol-ammonium fixation, Ranson's method, 162 x.
Figure 3 shows a section from the cerebral motor cortex (Area 4), where the pyramidal cells of Betz are found. Note the large multipolar cell body (perikaryon) and the apical dendrite directed toward the surface of the cortex. Surrounding these nerve cell bodies are processes of neural and glial origin (neuropil). In the neuropil, innumerable synaptic contacts (not seen by this method) occur between nerve cells and their processes (Bergman et al.).
Initially, the functional significance of Betz cells was unknown and they did not gain much attention. But then the situation has changed: British neuroscientist and Nobel laureate Charles Scott Sherrington showed that destroying rich with the Betz cells regions in the dog brain causes neurodegenerative changes. Also, later it was found that damage of Betz cell leads to motor disorders such as amyotrophic lateral sclerosis.
The most prominent discovery of Volodymyr Betz is described very well in article by Sergiy Kushchayev, Vitaly Moskalenko and others, which was published in 2012 in the Brain journal (Kushchayev et al., 2012). Therefore, we quote here a part of it, especially as it contains quotations from the original works of Volodymyr Betz:
Betz's most significant contribution was to connect cerebral organization and function with specific, unique histological evidence. The sulcus of Rolando divides the cerebral surface into two parts; an anterior in which the large pyramidal nerve cells predominate. They are predominantly in the fourth cortical layer and are from 0.05 0.06mm wide and from 0.04 0.12mm long?. Undoubtedly these cells have all the attributes of so-called motor cells and definitely continue as cerebral nerve fibres (Betz, 1874, pp. 578 80, 595 9). Betz wrote that he discovered these cells, which he called giant pyramids, in Meynert's fourth cortical layer (i.e. next to the deepest layer) of the precentral gyrus. Since that time the layers have been refined, and today the Betz cells are defined as being found in the fifth cortical layer. As well as in the human precentral gyrus, Betz found these cells in the same location in dogs, chimpanzees, baboons, and other primates (Fig. 4) (Betz, 1874).
Fig. 4 (A) Betz's original microscope slides showing the brilliant carmine staining from Betz's technique.
(B) A modern photomicrograph of one of Betz's slides reveals the pyramidal cells of the cortex. Although not as revealing as staining techniques might be today, Betz was nevertheless able to interpret the cells and their processes. This is the first time Betz's sections have been published in colour. Photographs courtesy of the Volodymyr Betz Museum at the Department of Anatomy, Bogomolets National Medical University, Kyiv, Ukraine.
His discovery of giant pyramidal neurons in the fifth layer of the primary motor cortex, correlated to and elaborated by insight into cortical function, was formulated in the landmark article Anatomischer Nachweis Gehirncentra (Betz, 1874). Betz's descriptions of the processes of pyramidal cells began to explain Ehrenberg's findings that fibres in brain white matter were continuous with those of the spinal cord and those from the periphery (the terms cells, dendrites and precentral were added by the authors to make the quote more comprehendible): Each of them (cells) has two main processes, and 7 to 15 secondary protoplasmatic processes (dendrites) which in turn branch out into smaller ones. At its origin, one of the main processes is thick, as is the case in the pyramidal cells of the cortex. It then tapers as it proceeds to the periphery of the cortex and, in its course, gives off branches. The other process, however, is thin; it starts in the nucleus of the cell, and proceeds directly into the axis cylinder, which becomes thicker after a short distance and acquires a nerve sheath; it thus undoubtedly continues as a nerve. The cells of this anterior cortical region do not form a continuous layer but rather are imbedded as nests of one, two, three, or more cells. These nests are from 0.3-07?mm. distant from each other. In such a nest one may find at times as many as five cells of different sizes and of the dimensions stated above. Furthermore, these cells are sparser in the lower half of the anterior central (precentral) convolution but more plentiful and closer together in its upper end and in the part on the medial surface of the hemisphere (Betz, 1874, pp. 578 80, 595 9; Clarke and O'Malley, 1996).
With his usual attention to methodological detail, Betz sought to identify the characteristics of his giant pyramid cells and their processes in young and old human brain specimens: In young individuals and in an eleven-year-old brain I found fewer nests; the cells were smaller and also had fewer protoplasmic processes. In very old brains (seventy years old and slightly younger) these cells acquire a seemingly special nucleus, which consists of yellow granules that are resistant to carmine dye. In children and young individuals these cells have a uniform protoplasm which can be evenly stained with carmine and in which no derangement can be shown. These cells are more numerous and apparently large in the right hemisphere than in the left?. These giant pyramids occur in the stated areas in every human brain, in the idiot, in the chimpanzee, in the gray, brown, small Persian Pavian, and in the green monkey (Betz, 1950b, p. 225; Clarke and O'Malley, 1996).
Perhaps most importantly for the functional significance of the pyramidal cells, Betz linked them not only to the results of Fritsch and Hitzig, but investigated their existence in the same species in which Fritsch and Hitzig had done their work: Such consistency in the region where these cells can be found, manifested as a very definitive cortical layer, as well as in a specific cerebral convolution, prompted me to devote my attention to that particular part of the animal brain, mainly the dog's, in which Fritsch and Hitzig achieved such brilliant physiological results, i.e. the lobe which borders the cruciate sulcus. I now found such cells of the same shape and in exactly the same position in nests in the dog, precisely in the lobe just mentioned. So in the dog, as well as in man, they are imbedded in the fourth cortical layer and occur only in this lobe and in the anterior half of the posterior (postcentral) convolution bordering it. In the dog, they are somewhat smaller, but nevertheless are the largest in its entire nervous system. They also possess two large and many small processes, and the inner process runs into a genuine nerve filament. In the area where they are found there are also many axis cylinders visible in the white substance, which run in the same direction as in the human. Undoubtedly these cells have all the attributes of the so-called motor cells and very definitely continue as cerebral nerve fibres (Betz, 1874, pp. 578 80, 595 9; Clarke and O'Malley, 1996).
Considering cortical cytoarchitectonics in relation with physiological function, Betz recognized this organization in two areas: motor and sensory. Based upon the present findings, it may be asserted that there are two cerebral areas which may be designated as two centers, one motor and the other sensory (Betz, 1874, pp. 578 80, 595 9; Clarke and O'Malley, 1996). Betz described functional areas on histological grounds and thereby opened the way for study of the precise relationships between cells and cortical areas. His work laid the foundation for the modern doctrine of cytoarchitectonics based on macro- and microscopic studies of the cortex surface that enabled him to view the paths of nerve cells in the brain. By linking cytoarchitecture, neurophysiology, and cerebral localization, the discovery of pyramidal cells was a momentous event in philosophical and scientific approaches to the brain. Betz coupled his discovery with experiments on electrical stimulation of the motor centres of the brain. He not only studied the morphology of the pyramidal cells, but he also postulated their function by relating his findings to the best neurophysiological and phenomenological evidence of the day: Previous investigations of anatomists and histologists did not find proper anatomical background for explaining the results of Fritsch and Hitzig's experiments. In 1874, I published investigation of the human and monkey cortex where I showed a specific unknown before nervous cells discovered by me which I called, giant pyramides (Betz, 1950d, p. 229).
In his work Uber die feinere Struktur der Gehirnrinde des Menschen (On Details of the Cerebral Cortex Structure in Man) published in 1880, Betz provided an architectonic division of the brain cortex and arranged (the material) in topographical order. Clearly identifying five cortical layers, as opposed to the mere lines visible to Gennari and others in fresh unstained brains, Betz found evidence for structural specialization that he believed correlated with specific functions and described the giant pyramidal cells in more detail: The general structure of the human cortex is the following. It consists of five different layers, one after another from outer layer to inner one?. The fifth layer is a layer of special fusiform cells. This five-layer structure of the human cortex can be considered as a fundamental pattern. So far specific particularities of the cortex structure depending on the location were found only in a few areas. Meynert showed that the cortex around the fissurae calcarinae does not contain the third pyramidal layer, but it has two granular layers, divided by the layers of neural fibres?. And finally according to my investigations the cortex of the anterior central gyrus and paracentral lobuli contains the giant cells (giant pyramidal cells) that are localized as nests (Betz, 1950d, pp. 230 1).
The anteriorcentral gyrus, beginning from the upper border of the lower one-third of its length, demonstrates in the upward direction the following peculiarities. First, large cells (giant pyramidal cells) appear in this region in the superficial part of layer V; these cells appear as single units or pairs, and these pairs are localized at considerable distances from each other. Then, in the upward direction, these cells are grouped in clusters containing three or four units, and the spacing between these clusters decreases. In more upward parts, these clusters include greater numbers of the cells, at least four, but sometimes five or even seven. From the former site, i.e. the superficial part of layer V, these clusters enter layer III and are localized in the latter as an interconnected stratum, and single cells enter layer II and also layer IV and an upper part of layer V. In the paracentral lobe, this stratum is again divided into clusters, and, within the above lobe per se, these cells are localized either as layers, one above another, or as clusters occupying different positions (Betz, 1950d, p. 232).
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8. Rivara, C. B., Sherwood, C. C., Bouras, C, Hof, P. R. (2003). Stereologic characterization and spatial distribution patterns of Betz cells in the human primary motor cortex. The Anatomical Record. Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology, 270 (2): 137 51.