Paper - The development of the cerebral cortex
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See also by this author - Mellus EL. A contribution to the study of the cerebral cortex in man. (1911) Anat. Rec. 5: 473-482.
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The Development of the Cerebral Cortex
E. Lindon Mellus
From the Anatomical Laboratory of the Johns Hopkins University (1912)
During the course of an investigation (still incomplete) of the so-called ‘motor area’ in man (anterior central convolution of the cerebral cortex) I had occasion to examine sections from that area in the brain of an eight months foetus. To my surprise I found the corona radiata of both central convolutions thickly sown with what appeared to be migrating cells. These cells were in various stages of development, the large majority resembling the neuroblasts just leaving the matrix in earlier stages, but many were well advanced in development, the nucleus having a distinct nucleolus and being enveloped by a considerable cell body. This cell body was either round or ovoid. Many of the latter form had a distinct apical process at one or the other extremity, this being sometimes directed toward the cortex, at other times away from it as if the nucleus were being propelled so rapidly that the enveloping protoplasm was inclined to drag behind. The long diameter of the ovoid cells seemed always to indicate the direction of the movement, some of those quite near the cortex of the fissure walls having apparently turned toward the cortex and in such the long diameter was at an acute or almost right angle to that of those more toward the center of the corona radiata. The granules or undeveloped nuclei scattered through the corona radiata were of two sorts, and sizes. The smaller about 5 micra in diameter stained deeply and showed no nucleolus, the others about 10 micra in diameter were faintly stained and contained two or more dark spots. At first I was inclined to look upon the smaller of these two granules as spongioblasts and the paler as neuroblasts, but I found as many of the latter as the former in the first (molecular) layer of the cortex. In this portion of the cortex I find the line of demarkation between the first or molecular and the second (external granular layer of Meynert) very striking, composed almost entirely of small round deeply stained granules. This line is less pronounced on the crest of the convolution than within the fissure, both on the walls of the fissures and at the base. The stain is most intense at the base of the fissure and becomes gradually paler as we approach the surface of the brain. The sharp definition of this line seems to be due partly to the deeper stain taken by these small granules and partly to their being very closely packed. But on the crest of the convolution the stain of the same cells is distinctly fainter.
The appearance of so many cells in the white matter at this late stage of intra-uterine life naturally led to further investigation. The available material was by no means perfect. It consisted of a somewhat fragmentary brain from which the brain stem and the basal ganglia had been removed, and the least injured portion of the ventricle was the occipital end. The matrix surroun.ding the posterior horn of the lateral ventricle was in the greatest activity, throwing off neuroblasts in enormous numbers (fig. 1). There was still present between the ventricle and the cortex the layer of neuroblasts called by His the ‘Ubergangschicht.’ Between this and the cortex the corona radfata was full of partly developed cells and naked nuclei apparently streaming towards the cortex in more or less radial lines. From the matrix broad streams of nuclei led more or less direc_tly to the ‘Ubergangschicht.’ These streams were not everywhere radially directed, but for a certain distance ran parallel to the wall of the ventricle. In cross section the formation of the ‘Ubergangschicht’ was distinctly outlined, completely surrounding the ventricle except in that portion contiguous to the calcarine fissure, where the matrix more nearly approached the resting stage. Here the cortex of the calcarine fissure in its entire extent was much more deeply stained than _the cortex on the external surface of the convolutions an.d the ‘Ubergangschicht’ was not present. At each extremity of the long narrow slit representing the posterior horn of the lateral ventricle the broad band of deeply stained nuclei is a prominent object in the section clearly visible to the naked eye.
From the outer edges of this band radially directed streams of nuclei could be followed into the hiatus of each contiguous convolution. Sagittal sections through the occipital operculum showed similar conditions, the ventricle surrounded by this broad band of deeply stained nuclei from the external borders of which streams of cells radiated toward the surrounding cortex.
Fig. 1 Transverse section of occipital lobe of the brain of an eight-months human embryo. Enlarged 2 X. C, calcarine fissure; V, posterior horn of lateral ventricle.
A frontal section through the temporal region about midway between the frontal and occipital pole showed the matrix surrounding the ventricle t-o be in a state of great activity. The ‘Ubergangschicht’ is here distinctly stratified and the four layers described by His as developing between the third and fourth month can be easily seen. The white matter between the closely packed collection of nouroblasts and the cortex is thickly strewn with migrating cells.
Owing to imperfections in the material, the relations in the frontal lobes were not so clear but the number of migrating cells passing in the white matter was quite as great as in other parts of the brain. In addition to this there were numerous masses of nuclei here and there a distinctly yisible to the naked eye. The nuclei were thickly massed and resembled both the ‘Ubergangschicht’ and the streams seen passing from the ventricle in other parts of the brain.
A portion of the right hemisphere of a new-born child (stillborn) shows the same activity in the production of neuroblasts by the germinal cells in the walls of the ventricle. The stratification of the calcarine cortex is more marked than in the eight months brain but the ‘Ubergangschicht’ surrounding the ventricle in the occipital lobe is still distinct and at some points it consists of two layers separated by a pale layer. From the ‘Ubergangschicht’ several quite distinct streams of neuroblasts are directed toward the various convolutions and can be followed as such for some distance. The cells of the calcarine cortex were distinctly more developed in the new-born than in the eight months brain. While in the latter the solitary cells of Meynert were the only ones with a distinct cell body, in the former a majority of the cells of the calcarine cortex had developed distinct processes. I find it very difficult to arrive at any conclusion in regard to the comparative depth of the cortex in these two brains without more careful study, but in the new—born brain the cells in the calcarine cortex are certainly more numerous and more closely packed than in the same region in the eight months brain.
A frontal section through the Inidbrain just anterior to the temporal pole and passing through the anterior island shows a‘ band of closely packed neuroblasts passing in a broad sweep from the inferior horn of the lateral ventricle beneath the cross-cut bundles of the internal capsule, around the inferior and external margin of the lenticular nucleus, gradually growing narrower and less distinct as it passes upward and outward (fig. 2). This band of neuroblasts is quite easily seen by the naked eye in well stained sections. Outside this band is a broad pale zone following the same direction and continued upward around the external border of the lenticular nucleus nearly to the level of the superior horn of the lateral ventricle, separating the lenticular nucleus from the mass of the corona radiata which is contiguous to the cortex and which is thickly strewn with migrating neuroblasts. This pale zone is sharply defined externally by a more or less compact line of neuroblasts which in horizontal sections would probably represent a second layer of the ‘Ubergangschicht.’ The Wall of the ventricle covering the mesial surface of the caudate nucleus is actively producing neuroblasts, while the opposite Wall of the ventricles is much less active although not in a state of rest. In this brain the blood vessels are much engorged (probably due to asphyxiation) and many of those in the direct track of the migrating neuroblasts are surrounded by closely packed nuclei. This is quite suggestive of the way in which small objects ﬂoating down stream collect temporarily about an obstruction. This was not observed in the eight months brain and is possibly pathological, as all the blood vessels in the new-born brain were engorged.
fig. 2 Transverse section, right hemisphere, of a new-born child, just anterior to the temporal pole. Enlarged 2 X. 00., corpus callosum; CI/1., crosscut bundles of the anterior limb of the internal capsule; I ., island of Reil; LN., lenticular nucleus; NC’., caudate nucleus; SP., septum pellucidum.
Thus it appears that in man, even at the period of birth, all the constituent parts of the cerebral cortex are not only not in situ but that the birth of new units is still going actively on and that these elements are still moving from their place of origin in the ventricular Wall to their ultimate destination in that latest and highest development of the animal organism. The latest authoritative statement as to the development of the human cerebral cortex based upon personal investigation is to be found in the last work of His published in 1904. He says the germinal cells produce both neuroblasts and glia cells, but he also states that here and there We find developing elements where no germinal cells are present and he agrees with Shaper that they must there develop from undifferentiated cells. He also says the more crowded they become the more both neuroblasts and spongioblasts assume the drawn out form (pear-shaped) and they can only be dilferentiated by the visible connection of the spongioblasts with connective tissue, and the neuroblasts by the connection with a nerve fiber.
Essick in a recent paper on the development of the pontine and arcuate nuclei-describes the migration of cells from the roof of the fourth ventricle and the wall of the lateral recess, passing through the intervening tissues in closely packed streams. This behavior of the new elements seems to closely resemble that observed in the ‘slides obtained from the two brains described in this paper. In the case of the developing cortex, however, the closely packed cells streaming from the matrix maintained this peculiar formation only as far as the ‘Ubergangschicht’ and from here to the cortex the migration was continued in what might be called ‘single file,’ but it was apparently more direct.
The question arises, and it is a most important one, whether all these nuclei proceeding from the matrix represent both neuroblasts and spongioblasts or whether they are spongioblasts alone. His considered the distinctive characteristic of the neuroblast in the younger embryo to be the darker stain taken by the cell at the end from which the nerve process arises. But he distinctly states that in the middle of the third month this is no longer to be depended on. He agrees that the cortical layer exclusively, or very nearly exclusively, now holds nerve cells, but in the inner zone of the intervening layer the tangentially directed cell bodies should be considered glia cells.
In the first or external layer of the cortex (the molecular layer of Meynert) the few scattered nuclei present may be safely looked upon as spongioblasts. At least if any neuroblasts are present they are so few in number they may safely be ignored, But between the nuclei here present and the naked nuclei swarming in the different layers of the cortex, even at birth, I can detect no characteristic differences. Some of the nuclei in the broad streams going out from the matrix and in the ‘Ubergangschicht’ have partly developed cell bodies and distinct protoplasmic processes, but the great majority are naked nuclei and correspond in every Way to the majority of those already arranged in the cortical layers. Some are doubtless spongioblasts, but it is hardly possible that they represent more than a small percentage. It seems quite evident that many neuroblasts reach the cortex where they arrange themselves in their ultimate position before they have developed any protoplasmic processes or possess any demonstrable cell bodies. His suggests that the protoplasmic process may serve as a locomotor apparatus, but the majority of the nuclei are clearly able to reach their goal without it. He speaks of the route followed by the cells in their migration from the matrix to the cortex as always radial, and in this respect differing from that taken by the neuroblasts of the spinal cord and the medulla oblongata. This is apparently true in the earlier stages and would apply up to the end of the fourth month of foetal life, at which stage he thought the migration was completed. But as the brain develops, the space between the matrix and the cortex becomes filled with new growths and the nuclei can no longer pursue the purely radial direction.
I have not been able to find any satisfactory explanation of the formation of the ‘Ubergangschicht.’ With the exception of the elaustrum, for which it appears to form the anlage, it is only a transitory formation, although distinct traces of it persist at birth and perhaps longer. Preparations from the occipital lobe in the eight months brain have been described. In those preparations (fig. 1) the ‘Ubcrgangsehicht’ is still present as a layer of closely packed nuclei almost completely surrounding the ventricle but separated from the matrix by a pale layercontaining only scattered nuclei. Several streams of nuclei lead from the matrix to the ‘Ubergangschicht’, but instead of taking a radial direction they run for some distance along the wall of the ventricle and parallel to it, and then leaving the ventricular wall join with other streams to form this closely packed layer. From the external border of the ‘Ubergangschicht’ its component parts appear to be migrating in a radial direction towards the cortex. Why nuclei destined to take part in the formation of the cerebral cortex should collect in a distinctly formed band which apparently persists through many months of intra-uterine life before proceeding on their further journey is a question even harder to answer than that of the propulsive force which carries them to their appointed destination. His states that the formation of the cortex goes on not only during the entire third but also the greater part of the fourth month. I. do not find any statement of his that the process is complete at that time, but it is generally understood that such was his belief. All authorities seem to agree in fixing the time of the completion of the migration of the neuroblasts somewhere about the end of the third or fourth month of foetal life. According to Jackson the volume of the central nervous system at the third month is about 7 cc. and at birth 376 cc. In the interval between these periods the volume of the central nervous system has increased more than fifty—three fold and the cerebral cortex has nearly doubled in thickness not withstanding the proportional increase in the superficial area due to the development of fissures and convolutions. By this the superficial area must be made more than double that of the plane surface.
In the recently published Work by Keibel and Mall Streeter states that the “migration is most active during the third month and continues well into the fourth.” In the English edition he says “at this period” (end of the fourth month) “the wandering of the cortical neuroblasts is completed.” In the German edition the statement ‘um dieser Zeit’ is not quite so definite. He ‘says further “The ependyma does not appear as active as hereto fore although it apparently is still giving off spongioblasts that are to form the-neuroglial elements of the White substance. The cortical or pyramidal layer has taken up all its Wandering neuroblasts from the deeper layers and is sharply marked off from the sulojacent intermediate layer.” He assumes that all the new elements given off by the matrix after the end of the fourth month are spongioblasts, although His expressly states it is impossible at this stage to distinguish between spongioblasts and neuroblasts in the primitive granular form. The question may arise here as to Whether or not the matrix may not again become active after passing into the so-called restin.g stage. This might explain Why What appears to be its great activity in later stages has been overlooked.
Probably at some period not long after birth the matrix is exhausted and no longer produces new elements. The indications are, that proceeding from the caudal end of the neural tube cerebralwards, the matrix is actively productive of new elements in successive stages; that is, as one segment becomes exhausted and goes into a state of rest the next contiguous segment becomes active, and so on until the last and highest segment takes up the work and gives birth to the cells that form the cerebral cortex. The development of many of these elements goes on rapidly during the migration to the cortex. His has estimated from careful measurements of the thickness of the cortical layer at various stages of embryonic life, that the period occupied by the migration of a cell from the matrix to the cortex must be at least half a day. This seems to ignore a possible delay in that ‘half way station’ the ‘Ubergangschicht.’ But Streeter may be right in what I take to be his assumption, that the ‘Ubergangschicht’ is largely made up of spongioblasts. If in the early stages, during the third and fourth months, a neuroblast can pass from the matrix to the cortex in half a day when the distance through the Zwischcnschicht is comparatively slight, the time occupied by the migration of an element some months later becomes complicated by distance and intervening obstructions. An indication of greater time occupied in the migration is the greater development of the cell body and processes to be seen in certain migrating cells still in the white matter in the eight months and new-born brain.
It is a very difficult matter, perhaps impossible, to say whether or not any given nerve—cell in the cortex, or elsewhere, is fully developed. We find in the cortex of every age cells large and small, and every gradation in size of the cell body between these, to say nothing of numerous granules with no cell body. The cell body and its processes probably develop under the demands of functional activity. No one can say that any cell body has reached the limit of its growth. Comparing the cells in the cortex of the new-born with those in the adult brain I conclude that no cell in the cerebral cortex is fully developed at birth. The increase in volume of a cortical cell during the development of the cell body, nerve fiber and processes varies greatly according to location and function.
It is the belief of the writer that all mental development has an anatomical basis. In a comparative study of the cellular structure of the so-called ‘Broca’s area“ in the brains of three individuals there was found a very appreciable difference in the thickness of the cortical layers in favor of the left hemisphere. It is almost impossible to say just where this difference lies. The counting of cells in a cortical area is extremely difficult, although by no means impossible. In many instances the count varies so considerably in contiguous areas of the same convolution, due sometimes to the presence of blood vessels and the doubtful nature of many of the cells that it is difficult to arrive at satisfactory eonclusions. As a rule, however, it appears that the deeper cortex has the greater number of cells. We would naturally suppose that a cortex increased in depth by increased functional activity would be due either to increase in the volume of the cells or separation of the cells by reason of an increase in the outgrowing or ingrovving processes; or both together. From careful and prolonged study of the motor area in the human cortex I am convinced that there are great variations in different individuals in the development of the largest elements~the so—called Bctz cells.
5 A contribution to the study of the cerebral cortex in man. Mellus, Anat. Rec., vol. 5, p. 473.
Much time and study has been expended in the effort to find an anatomical basis for intellectual development in brain Weight and in the comparative complexity of the convolutions. Such efforts have so far been Without result. Many millions of cells may vary greatly in development and the Weight of the brain be inappreciably affectedfi Estimates based on a careful count in different cortical areas of the adult human brain place the number of cells in a cubic millimeter of cortical substance at about 100,000. The total area of cortex in a brain Weighing 1360 grams is estimated by Donaldson at 2352 sq. cm. On that basis a cortex of 2.5 mm. average depth would contain nearly 6000 million cells while a cortex averaging 3 mm. in depth would contain more than 7000 million cells.
5 A note on the significance of the small volume of the nerve cell bodies in the cerebral cortex of man. H. II. Donaldson, Jour. Comp. Neur., vol. 9, 1899.
- Die Entwickelung des menschlichen Gehirns wahrendes ersten Monats. Wilhelm His. Leipsig, 1904.
- Essick CR. The development of the nuclei pontis and the nucleus arcuatus in man. (1912) Amer. J Anat. 13(1): -54.
- Jackson CM. On the prenatal growth of the human body and the relative growth of the various organs and parts. (1909) Amer. J Anat., 9(3): .
- Streeter GL. The Development of the Nervous System. (1912) chapter 14, vol. 2, in Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia.
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