Paper - Sensory nerves in the skin of human fetuses of 8 to 14 weeks of menstrual age correlated with functional capability

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Hogg ID. Sensory nerves and associated structures in the skin of human fetuses of 8 to 14 weeks of menstrual age correlated with functional capability. (1941) J. Comp. Neural.

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This historic paper published in 1941 by Hogg describes the development of sensory nerve endings in the fetal skin. Our understanding of integumentary neural development has improved since this historic human study.


Also by this author: Hogg ID. The embryological development of the commissura posterior in the human spinal cord. (1945) J Comp. Neural. : 255-281.
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Sensory Nerves and Associated Structures in the Skin of Human Fetuses of 8 to 14 Weeks of Menstrual Age Correlated with Functional Capability

Ira Dwight Hogg

Departmennt of Anatomy, School of Medicine, Uniiversity of Pittsburgh, Pennsylvania

Eleven Figures

  • Supported by grants from the Penrose Fund of the American Philosophical Society, from the Carnegie Corporation of New York and from the University of Pittsburgh.
  • Technical assistance has been rendered by Miss Catherine Dillon, Miss Beryl Dimmick and Reinhardt Rosenberg. figures 1, 2, 3, 4, 7, 10 and 11 were drawn from photomicrographs and retouched by microscopic examination of the original specimens by Mrs. Sue Watson Marshall. Publication no. 8, Physiological and morphological studies on human prenatal development.

Introduction

Very little has been Written about the structure of the peripheral nervous system in very young human fetuses or about its recognized physiological capabilities. Tello (’17, ’23) studied the development of the peripheral nervous system in mouse embryos and fetuses but made no‘ mentionlof having tested his material to determine the physiological capabilities of the animals" before they were killed. Other investigators, whose works are referred to in subsequent paragraphs, have studied the development of behavior in mammalian forms but have not reported on the state of development of the peripheral nervous system in sufficient detail so that their observations can be compared with those of Tello. Because of this lack of knowledge of what is significant concerning the physiological activity involved in an early nervous response, several phases of the structures of tlie fetal skin have been considered in this paper, some of which may prove to be irrelevant to the subject when more is known about the physiological activity of each part.


The subject of fetal behavior has been attracting a great deal of attention during the last 20 years but the first major work was published by Preyer in 1885. A portion of this work was translated into English by Coghill and Legner (Prayer, ’37). After studying fetal behavior in many forms of animals including man, Preyer predicted that it would some day be discovered that the first human movements were spontaneous, the result of endogenous excitement of the central nervous system, and that they would appear during the fifth or sixth week of menstrual age. He gave as his reason the fact that the umbilical cord is twisted first at about this age. Yanase (’07) reported an observation of an isolated twitch of the arm in a human embryo 22 mm. long, or about 8 Weeks of menstrual age, which he believed to be a spontaneous movement of the kind Preyer had predicted. He attributed the movement to endogenous stimulation and remarked that if he had been able to observe the embryo under more favorable conditions before its circulation had been disturbed, he might have seen more movement or othertypes of movement. That other forms of vertebrate embryos react first to endogenous stimulation has been repeatedly attested (Tracy, ’25; Swenson, ’28, ’29; Angulo, ’32; VVindle and his students, ’31, ’35, ’40). Doubt as to the endogenous nature of these stimuli has been expressed by Carmichael (’34) and Barcroft and Barron (’39 b).


Minkowski (’20 a, ’20 b, ’20 c, ’21, ’22, ’23, ’25, ’28, ’38) has reported a long series of observations made on living human embryos and fetuses in which he obtained responses to various types of stimuli, as well as spontaneous movements. He proved that the central mechanism responsible for fetal movements until late in fetal life is restricted to the spinal cord and medulla oblongata (Minkowski, ’22). Coghill (’29), Carmichael (’33), and Coronios (’33) summarize MinkoWski’s reports. Observations by other investigators on the human fetus and many other forms of embryos and fetuses are in very close agreement regarding the types of stimuli to which fetuses first respond both as to the order of appearance and the distribution of reflexogenous areas? In the human and most other forms the first recognized responses to external stimulation of the sensory nervous system can be evoked by stroking the area of the face which is supplied by the maxillary division of the trigeminal nerve (Hooker, ’39; Barcroft and Barron, ’39 a, ’39 b). At almost the same time the area in man supplied by the mandibular division of the trigeminal nerve becomes reflexogenous. In the human fetus no responses from the field of distribution of the ophthalmic division have been reported until about the thirteenth week. At that time the reflexes are local, similar to those described by Barcroft and Barron (’39 a, ’39 b) for sheep fetuses older than 55 days. For younger sheep fetuses they report general responses from the ophthalmic nerve similar to those obtained from the maxillary nerve.


In the human embryo the first definite responses have been obtained at about 8% weeks of menstrual age. The reflexogenous areas increase, slowly at first but more rapidly after the eleventh week, until the whole body becomes sensitive between the thirteenth and the fourteenth week. During that period the type of response changes from simple avoiding movements of the trunk to nearly all of the recognized specific somatic reflexes (Minkowski, ’28; Hooker, ’36). Neither respiration nor any of its associated reflexes has been observed at this stage of development but swallowing occurs when the lips of a 14-week fetus are stimulated (Hooker, ’36, ’39). At relatively the same age similar reflexes have been reported in the sheep (Barcroft and Barron, ’39 b).


‘In this article, the term “reflexogenous” is frequently used. This word does not appear in dictionaries of the English language. It is used here as an adjective to designate an area in which the peripheral nervous system has reached a state of maturity sufficient to become reflexogenic, i.e., capable of responding to a given type of stimulation by producing a motor response or reflex action.


Hooker (’36) called attention to the fact that little was known as to the state of development of the cutaneous nerves which were responsible for the observed responses to light cutaneous stimuli. A search of the literature has revealed that very little attention has been paid to the development of sense organs at such an early stage and no attempt has been made to correlate the type of endings in the skin with their functional capabilities at the time that reflexes are known to be first elicitable. The most careful investigation of the development of sense organs in the skin of man that has been found was reported by Martinez Pérez and A. P. Rodriguez Pérez in 1932. The youngest stages of sense organs that they reported as apparently being capable of receiving stimuli were found in the hands and feet of 6—month—old fetuses. The endings at this time were Very immature when compared with those in the adult. They consisted of free nerve endings between the epithelial cells. Each branching terminal was supplied with one or more dise~like expansions between adjacent epithelial cells similar to those endings known as the touch corpuscles of Merkel. These nerve endings were recognized as belonging to a type described by Martinez Pérez (’31) for the adult “intersudoral nerve plexuses.” A study of these endings in older fetuses revealed them as being primitive endings which terminated freely between the epithelial cells at first. Later collaterals from these fibers either grew back into the corium or branched from the fibers below the epithelium, but near the basement membrane, and grew up into the papillae of the corium to form a Very complex system of free endings close to the basement membrane, between the ducts of the sudoriparous glands. They could find no trace of encapsulated nerve endings until 4 or 5 weeks after these primitive endings appeared.


Their criterion for functional capacity for a nerve ending seems to have been close resemblance to a recognized adult form of ending. Judging the physiological capacity of nerve endings in the light of fetal responses, one is led to the conclusion that resemblance to an adult form is not a valid criterion of functional capacity. It has been well estabished that fetuses respond to light cutaneous stimuli applied to the skin long before they have reached the ages ascribed by Pérez and Pérez (’32). Inasmuch as human fetal responses to light cutaneous stimuli pass from the simplest reflexes at about 8% weeks to nearly all recognized cutaneous reflexes by 14 weeks, it has been thought advisable to limit the present investigation to the structure of the nerve terminals and accessory structures during and just previous to that age span.

Materials and Methods

In order to investigate the nervous mechanism responsible for the early reactions of fetuses more fully than Minkowski was able to do, the Department of Anatomy at the School of Medicine of the University of Pittsburgh began the collection of a series of human fetuses and embryos in 1932 (Hooker, ’36). These were fixed as soon after death as possible in fixatives which were suitablefor use with various methods of silver impregnation. The following table gives the more important data concerning each of the embryos and fetuses whose physiological reactions had been tested prior to fixation and which form the basis for this study. Fetus no.'O was 11ot physiologically tested before fixation, but was studied in this investigation. Not all of these specimens are equally suitable for the study of nerve terminals because of the erratic results of silver methods. However, by comparing embryos and fetuses of approximately the same age a very high percentage of the observations made on the best preparations can be corroborated by the other material.

Observations

Chalnges in the epithelium and basement membrane Pinkus (’10) noted that the epithelium is thicker over the ventral surface of the human embryo than it is over the dorsal surface. This is true during the premotile stage (nos. 12 and 0, table 1) as well as in older fetuses, but in these two the difference is principally a matter of the relative dimensions of the basal cells, for the epithelium is uniformly two cells

Table 1

1 C§3§‘£§' wmonr Aliitiiiglr MOTHJTY VISIBILITY F1;.'£)L_'s LENGTH IN MENSTRUAL Sgrgglf or NERVE (srr-rmo GRAMS AGE IN TERMINALS HEIGHT) wens Fa-ce Hand Foot mm.


12 22 8 _ _ _ 1 Fair 0 22 8 _ _ _. 3 Good 4 25 8% + __ __ 1 Fair 22 26 8% _ _ _. 2 Fair Dead? 19 26.5 . . . 8%: + _ _ 1 Poor 29 28 2.25 84} + _ _ 4 Poor 33 32 3.2 9 + _. .._ 3 Good 23 33 9% + _ ._ 5 Fair 16 35 9% -1- _. _ 1 Poor 18 36 . . . . 9% .+ ._ _ 2 Fair 34 40 6.3 10 + _ __ 3 Good 26 48.5 8.8 11 + + _ 2 Fair 8 54 . . . . 11% _ ._ _ 1 Poor Auaes. 39 61.5 17.7 12 + + + 3 Good 38 63.5 18.7 12 + + + 3 Good 45 75 27 .2 13 + + + 3 Good 37 85.5 38.6 14 + + + 3 Good 25 as 38.8 14 + + + 3 Good 40 87 45.3 14 + + + 3 Fair Stains used: 1 Pyridine silver (Ranson). Erythrosin and toluidine blue. Activated protargol (Bodian).


b50D[\') Cajal silver. 5 Hematoxylin and Lichtgriin.

As a result of these studies a suggestion is oifer-ed to investigators that in taking measurements of embryos and fetuses to determine the relative menstrual or gestation age the weight of the embryos as well as the length should be taken into consideration. Ultimate differences in stature may begin to be manifested in very young individuals. For example, compare the C—R lengths of nos. 25, 37' and 40 with their weights. It will be noted that no. 25 has the greatest sitting height although no. 40 is 6.5 gm. heavier. The weights of nos. 25 and 37 are almost the same although no. 25 was 2.5 mm. longer in crown rump length. In state of development of hair follicles and papillary ridges in the epithelium of the hands and the feet, nos. 25 and 37 are almost identical although no. 40 is considerably more mature. Evidently no. 40 is several days older than either no. 25 or no. 37. thick on both dorsal and ventral surfaces and the periderm is squamous in each instance. Cell measurements on no. 0 indicate that after fixation the ratio of height of basal cells on the dorsal and ventral surfaces is approximately as 6 is to 10. Moreover, the volume of a basal cell is approximately the same on each surface (400 p3). The transverse diameters are consequently almost the reciprocal of the vertical diameters or approximately in the ratio of 8 to 6. In 10 n sections this difference seems to be over—emphasized because of the greater number of nuclei visible in a given linear distance along the epithelium where the epithelial cells are taller (Ventral surface) and consequently smaller in their transverse diameters.


In these two embryos (nos. 12 and O) the thickness of the epithelium, noted above, is somewhat further increased in those areas supplied by the three branches of the trigeminal nerve and also in the touch balls of the hands. In these areas the basal cells are even more numerous than on the rest of the ventral surface and relatively taller. In these areas some cells appear between the basal cells and the periderm, but there are not enough to form a continuous intermediate layer of cells. In these two embryos the epithelium does not rest on a well—defined basal membrane, although there are some argyro— phil fibers between the bases of the epithelial cells. In embryo no. 0 the argyrophil fibers seem to be of the nature of young tonofibrils and probably their inner ends can be considered as entering into the formation of a basement membrane. These fibrils appear to be best developed where the epithelium is thickest.


In fetuses from 8%; to 9 weeks of age (nos. 4, 19, 22, 29), just after motor responses to cutaneous stimulation begin to occur, the epithelium in areas which have become reflexogenous is always three or more cells thick, considering the periderm as one layer of cells. In this respect this observation agrees with those of Tello (’23) on the embryonic and fetal mouse. In most of the non-reflexogenous areas the epithelium is not over two cells thick. There are exceptions to this general observation, however, particularly in the calvicular and pectoral regions and in the neighborhood of the ear, where the epithelium is several cells thick although the areas are still unresponsive to stimuli.


During the first week of motility, the epithelium covering a given reflexogenous area is of uniform thickness. Its junction with the subjacent mesenchyme forms an even line which conforms to the contour of the surface of that part of the body. There is generally a distinct line of demarcation between the epithelium and the subjacent mesenchyme, but whether or not there is a definite basement membrane such as is found in older fetuses and mature skin is difficult to determine by silver methods. In no. 22, a 26 mm. embryo which was stained with erythrosin and toluidin blue, the beginning of a basement membrane can be seen as a pink line below the areas of thickened epithelium on the face. Pinkus (’10) has described what he considered to be the beginning of a basement membrane in 30 mm. embryos. I have recognized it under areas in which the epithelium is three or more layers thick in fetuses over 30 mm. in length (nos. 33, 23, 16, 18) and in all older fetuses. The reason for stressing the presence of the basement membrane is its apparently intimate relationship to the growing nerve tips soon after responses to cutaneous stimulation begin.


During the tenth week (table 1; nos. 33, 23, 16, 18, 34) the difference in thickness of the epithelium covering the dorsal and ventral surfaces of the fetus becomes Very distinct. At this time even the basal layer of the epithelium over the dorsal surface becomes very thin or squamous, the two layers of cells forming an extremely thin covering for the mesen~ chyme. During this Week there are patches of epithelium which appear to die. The nuclei of such cells become pyknotic and the cells are loosened from the underlying mesenchyme. At the margins of these areas the growing cells of the surrounding epithelium are rounded off and seem to be pushing their way under the cells with the pyknotic nuclei. At a line running along the sides of the embryo where the thin epithelium of the dorsal surface meets the thicker epithelium of the ventral surface, the thin cells often extend beneath the thicker cells for two or three cell diameters. There is no zone of gradual transition from thick to thin epithelium.


Dorsal to this line of juncture of thick and thin epithelium the sheet of prismatic epithelial cells is generally detached from the underlying squamous cells and curls away from the body of the embryo. The free edge is generally from six to ten cell diameters from the last attached cell.


During the tenth week the basement membrane probably spreads over the whole body although it is not recognizable everywhere under normal conditions. However, in areas where the epithelium has been removed accidentally, the underlying mesenchyme maintains its smooth surface and a silver precipitate in this surface produces a dark line along the border. Structurally it appears to be a homogeneous membrane, for in those parts where the epithelium is thin, neither fibers nor cytoplasmic processes are visible in it.


In the palm of the hand of no. 418 (9% weeks) the epithelium is more than two cells thick on the touch balls at the ends of the fingers, at the distal ends of the metacarpals, and in placodes, one of which lies over the proximal third of each metacarpal. This observation agrees with Broman’s observations of palmar elevations which he termed “primitive sense organs” (Broman, ’20). However, in the sectioned material, the placodes do not project distinctly above the surface of the surrounding skin as might be inferred from Broman’s description. A cutaneous branch of one or more nerves runs toward the epithelium in each of these areas, but there is no particularly intimate relationship between the nerve fibers and the thickened epithelium; i.e., sometimes the nerve fiber runs toward the center of‘ the thickened area but just as often it courses toward one edge. These fibers have not yet established a very close relationship to the epithelium. The reciprocal relationship between nerve fibers and epithelium, pointed out by Cajal (’19), is not in evidence in this embryo.


Evidence of a reciprocal relationship between nerve fibers and other tissues has been presented by many investigators, among whom are Cajal (’19, ’28), Tello (’17, ’23), and Boeke (’40). Such a reciprocal influence is perhaps more noticeable during the degeneration of nerve fibers and during the subsequent regeneration and establishment of sense organs, than it is during embryonic development. However, many times there is a suggestion of some such influence during fetal life. This reciprocal relationship was first emphasized by Cajal (’19). At that time, he expressed his growing conviction that nerve fibers are attracted to areas where cells are proliferating rapidly. After nerve fibers enter such an area there is frequently a rearrangement of the cellular elements in response to the presence of the nerves. The general subject of neurotropism is reviewed by Cajal (’28, VOL 1, pp. 388-392), but he specifically mentions the tissues which attract nerve fibers under the title, “Principle of innervation by steps,” on page 387.


In no. 34 (10 weeks) the epithelium over the entire palm is thickening but still there are areas over the cutaneous branches where it is thicker than between the branches. The basement membrane in the palm contains many fine fibrils which are chiefly cytoplasmic processes from cells of the mesenchyme. This embryo, better than any other of the series, shows the changes that occur in the epithelium of the hand just preceding the time when responses to cutaneous stimulation can be elicited (Hooker, ’38). In this embryo, Cajal’s reciprocal relationship between nerve and epithelium does seem to be indicated.


The epithelium over the dorsum of no. 34 is squamous as it is in the other younger embryos in this series during the tenth Week.


In no. 26, which is approximately 11 weeks of menstrual age, the epithelium all around the body is becoming thicker. Over the posterior part of the body the increase in thickness consists chiefly of the transformation of the basal layer of epithelial cells from the squamous type to a cuboidal type of cell. The epithelium is still relatively much thinner on the dorsal surface of the body than it is on the ventral. In no. 39 (12 weeks) the epithelium over the dorsum of the body is of about the same thickness as that on the ventral surface. In most regions of the body, it is about four cells thick. In some regions the cells are all polyhedral and in others where the skin seems to be under more tension, such as the outer surfaces of the arms, most of the cells are squamous. There are certain regions, such as the external ear and some parts of the face, especially where hair follicles are forming, where the epithelium is more than four cells thick.


In no. 39 (12 weeks) the walls of contiguous epithelial cells are still in contact. There are no signs of intercellular spaces or intercellular bridges that can be recognized as such. However, there are many black granules in the membranes between cells and some of these granules have coalesced to form short rods. These dots may represent early stages of the intercellular bridges or tonofibrils. Between the basal ends of the cells in the basal layer some fine fibrils lie between the cells and extend into the basement membrane. These I believe to be young tonofibrils. They are largely oriented parallel to the base of the epithelial sheet instead of being perpendicular to it as has been described for mature epithelium by Del Rio—Hortega (’17).


In this series the skin has been prepared only from the face, hands, and feet of fetuses older than 12 weeks. In these regions, the epithelium continues to increase in thickness with increasing age. The basement membrane becomes somewhat more definite during this period and is probably as well defined by 14 weeks as it ever will be.


In the feet, the development lags slightly behind that in the hands. In no. 34 -(10 weeks) the epithelium of the sole is relatively thin except along the lateral margin of the arch of the foot. Toward the middle of the metatarsal area the epithelium begins to thicken on the medial side and the extent of this thickening increases as the area approaches the distal ends of the metatarsals. Over the touch balls at the distal ends of the metatarsals, the epithelium is thickened considerably. As in the hand, there is some indication of a reciprocal relationship between the presence of nerve fibers which terminate near the basement membrane and the thickness of the epithelium nearby, thicker epithelium being associated with nearness of the nerve, but there are exceptions to this relationship. The reciprocal relationship between epithelium and nerve fibers, pointed out by Cajal (’19), may play a role here, but the epithelium is still too immature to manifest this relationship to any marked degree.


In fetuses nos. 38 and 39 (12 weeks) the epithelium of the feet is four cells thick over most of the plantar surface and over the anlagen of the nails on the dorsal surface of the toes. In all of this area the cells of the basal layer have become cylindrical, being about twice as tall as they are broad. The basement membrane is well developed and receives many cytoplasmic processes from the mesenchymal cells but no true connective tissue fibers are visible. The epithelium and basement membrane are beginning to show slight undulations as if the papillary ridges are beginning to form.


At 14 weeks (no. 40), the epithelium on the soles of the feet shows very definite folds which correspond to the papillary ridges. The epithelium is about six layers of cells thick over most of this region. The basal layer is composed of tall cells, the nuclei of which are staggered as one finds them in pseudostratified epithelium, but instead of a slender filament each cell has a relatively broad cytoplasmic process which reaches to the basement membrane. The cells of this layer form a quite definite germinative layer. Occasional tiny intercellular spaces can be seen between some of these cells, but in this fetus no intercellular bridges have been recognized. They do occur and are plainly visible in better preparations from other 14-week fetuses (nos. 25 and 37).


At the outer margin of the germinative layer somewhat squamous cells may be observed, here and there, which show granules in the cytoplasmic expansions which resemble those found in the stratum granulosum. The number of granules is so small that in most sections they are not recognizable in all cells of this layer but in tangential sections from the finger tips of no. 37 they are seen to form a continuous sheet. The nuclei of these cells still show traces of the nucleolus and occasionally a chromatin knot. They are not as pyknotic as the nuclei of the more superficial cells. The cytoplasm of these cells which lie more superficially is vacuolated and they have the general appearance of cells belonging to the stratum lueidum.


In the hand, the papillary ridges are very well developed in no. 40 in a small area of the palm between the thenar and hypothenar eminences. They are present, but much less well developed, in nos. 25 and 37. Over the rest of the palm they are very poorly developed or absent altogether. Those which are present are most numerous near the middle of the palm. On the volar surfaces of the fingers there are no papillary ridges except on the terminal touch balls. The best developed of these occur on the thumb in no. 40. In no. 25, the only well defined papillary ridges in the fingers are present in the nail beds. In no. 37, they can be seen in the little finger of one hand. This finger is sectioned almost at right angles to the papillary ridges. They may be present in the other fingers but in that case they lie so nearly in the plane of section that they are not noticeable.


The nail beds of the fingers are fairly well developed. The papillary ridges here are distinct, the nail roots have grown far down into the connective tissue and a very thin layer of cornified cells occurs on the surface to form the nail.


Changes in the mesenchyme In the younger fetuses of this series the mesenchymal cells show very little differentiation. The nuclei of the cells are large and oval in the deeper parts of the subepithelial tissue. Those of many of the undifferentiated mesenchymal cells greatly resemble those of the neurilemmal sheath cells of the nerve fibers and the nuclei of. both of these types, in turn, can easily be confused with those of endothelial cells.


The cytoplasmic processes of the mesenchymal cells reach out in all directions. Many of them have a very distinct centrosome somewhere in the cell body. The centrosome is frequently near the base of one of the larger processes.


Between the processes of the mesenchymal cells there are rather extensive spaces which contain no visible extracellular fibers.


Near the epithelium some of the mesenchymal cells are flattened out in such a manner that their nuclei appear to be very long and fnsiform (fig. 9). In older fetuses these cells become smaller and more closely resemble those of the more deeply lying tissue. Whether or not these cells give origin to most of the fibroblasts of the corium is not clearly demonstrated in this series.


Occasionally, among these cells near the epithelium, one can be seen which differs from the others by having argyrophil granules in its cytoplasm. Some of these appear to be attached to the termination of a nerve fiber (figs. 1 and 2). In such instances, they have the appearance of having been ameboid cells in the living state. The granule cell represented in

Abbreviations

B M, basement membrane F S, follicular sheath D C, dendritic cell or chromatophore H F, hair follicle EB, epithelial branch of a cutaneous NR, neural rete or superficial neural nerve plexus E P, epithelium l\' T, nerve terminal FN, follicular nerve

fig. 1 Skin from supraclavicular region of fetus no. 33 showing a granular cell, dendritic cell or chromatophore (D C). Two cytoplasmic processes extend from this cell toward the basement membrane (B M) but do not quite reach it. A third process extends from the opposite pole.


fig.2 Chromatophore in the skin of the foot of fetus no. 34 (D C). This chromatophore or dendritic cell is still in relation to a. nerve fiber (EB), but most of the granular cytoplasm is in the basement membrane or passing through it. The nerve fiber terminates at N T.


fig.3 Skin from the foot of fetus no. 34 showing a chromatophore (D 0) among the epithelial cells. Its nucleus is elongated and its cytoplasmic processes extend for a considerable distance among the epithelial cells.


fig. 4-. Skin from the eyelid of fetus no. 40. Here one of the chromatophores or dendritic cells (D C) is seen as it lies among the basal ends of the epithelial cells, close to the basement membrane (B M).

Figure 1 has a long filament of cytoplasm which extended obliquely down through the mesenchyme and lay along or surrounded the tip of a nerve fiber. The proximal portion of this process can be seen in the illustration. Such cells somewhat resemble leucocytes in association with nerve fibers, demonstrated in motion pictures by Speidel (’40). However, in figure 2, a similar cell is seen in the basement membrane and, in figures 3 and 4, cells which have apparently the same reaction with silver or gold chloride are seen among the epithelial cells. The latter two cells correspond to the descriptions of the so—called chromatophores (Cowdry, ’28), dendritic cells (Bloch, ’27), or cells of Langerhans.


These cells are extremely rare in most parts of the epithelium examined in this investigation but sometimes when one is found another is found in the vicinity. In the section from which figure 3 was made at second similar cell lay just beyond the edge of the field. Such a condition suggests the possibility of active multiplication of these cells after they enter the epithelium or of repeated invasion of the epithelium from a common source. No mitotic figures have been observed in them.


Figure 4 was made from the skin of the eyelid of no. 40. ln this region these cells are much more numerous than in any other region studied and in this particular fetus two or three could sometimes be seen in the same microscopic field.


During the twelfth week, fibroblasts begin to differentiate from the mesenchyme sufficiently to show the presence of fibers here and there. The intercellular spaces are filled with an indistinct meshwork of cell processes which refract light but which are hard to see when they are in proper focus. It seems that this meshwork may correspond in an indefinite degree to the syncytium described by Akkeringa (’30).


Very tortuous argyrophilic fibers lie in the walls of some of the young fibroblasts of nos. 38 and 39. They greatly resemble some of the finer neurofibrillae and their presence sometimes causes the cell process in which they lie to be twisted into a tiny spiral. In a photograph such processes greatly resemble the nerve fibers. One cell with such a fiber lies near the bottom of figure 10. These fibers seem to be transitory affairs for as the cells continue to divide and become smaller, as shown by comparing figures 10 and 11, the argyrophil fibers become smaller and less distinct and still seem to be limited to the expansions of the cell in which they lie.


During the fourteenth week the subepithelial mesenchyme or connective tissue begins to be differentiated as a eorium of the skin. The cells in a given area are much more numerous and smaller. figures 10 and 11 have the same magnification and a comparison of the two shows this change very well. During the 7-week span of embryonic and fetal life covered by this investigation, two nerve plexuses, an inner coarse meshed plexus and an outer fine meshed one, have been forming. There is some indication that the more superficial plexus of these fetuses corresponds to the deeper plexus of the eorium of adult skin. Blood vessels accompany the plexuses, the outer mesh being accompanied chiefly by vessels of capillary size. In all of the sections studied not one encapsulated nerve ending of any kind has been recognized.


Hair follicles When responses can be elicited for the first time in the human embryo there are no well developed hair follicles present. The first follicles to appear are for the superciliary hairs. Pinkus (’10) states that he found some in one embryo at about 8% weeks. None have been recognized in fetus no. 4, but hair follicles are beginning to appear in the superciliary region in nos. 19, 22 and 29. However, no nerve fibers from the ophthalmic nerve have been traced to them until much later. Sometime during the tenth week, hair follicles begin to appear on the upper lips (nos. 18 and 34). At first they develop slowly. At the close of the eleventh week (nos. 26 and 8), they still consist of epithelial thickenings subjacent to which there has been a moderate proliferation of mesen— chyme cells. By the twelfth week, the follicles of the eyebrow have grown to the depth of about % mm. below the surface (nos. 38 and 39). By this time fibers from the ophthalmic nerve have grown into the connective tissue sheaths of many of the superciliary follicles. Generally the nerve fiber approaches the follicle with the capillary which will. supply the papilla but, instead of terminating in the papilla, the nerve passes diagonally upward through the follicular sheaths. Usually it continues toward the surface, leaves the outer root sheath and terminates close to the basement membrane of the epithelium just outside the edge of the follicle, or passes on to become a part of the most superficial nerve plexus. Such fibers as I have seen are nearly straight and generally unbranched, but are expanded in their course through the sheath of the follicle (fig. 8). A similar relationship is found between nerve fibers and hair follicles in the superciliary region, zygomatic region, and upper lip in 13- to 14-week fetuses (nos. 45, 25, 37 and 40). In the maxillary region, the hair follicles are about half as long at the twelfth week as they are in the superciliary region. Many nerve fibers are growing toward the papillae of the follicles but few, if any, have come into intimate relationship with the follicles as have those found in the superciliary region. The maxillary follicles are distributed in two groups at this time. One group is on the upper lip. These are the longer. The other group may be termed an infraorbital group, although the follicles lie near the anterior border of the masseter muscle. They are less mature than those on the upper lip, but more mature than those on the lower lip. The fig.5 Hair follicle and cutaneous nerve in the supereiliary region of fetus no. 34. A nerve fiber (E B) approaches the epithelium between follicles and another fiber (N R) joins a capillary which passes toward the base of the hair follicle (HF). This fiber could not be traced among the cells of the follicular papilla. This follicle represents the most mature ones to be found at 10 weeks.


fig.6 Nerve fiber (E B) and young hair follicle (1-1 F) from upper lip of fetus no. 39. This illustration shows one of the younger follicles and a good illustration of the epitlxeliul branch of a. cutaneous nerve. The nerve fiber could be followed a little closer to the basement membrane than the illustration shows but did not seem to pierce it. The hair follicle had no visible innervation.

Figures 5 and 6 latter are very young follicles, the most mature ones in this group being like the follicle in figure 6. Nerve fibers have not reached them at 12 weeks. Consequently, the hairs, or their follicles, cannot be responsible for the reception of stimuli until the twelfth week and then only in very restricted areas such as the eyebrows with possibly a Very small number of follicles in the upper lip.


During the thirteenth and fourteenth weeks a great change occurs in the number of follicles which receive a nerve fiber, like the one illustrated in figure 8. Almost all of the older follicles receive such a fiber. Occasionally a follicle can be found in which this wide band of nerve fibers sends out collateral branches which lie in intimate relation to one or more of the cells of the sheath of the follicle. Many other younger follicles receive fibers, as in figure 5 (NR).


Free terminals to the epithelium, represented in figures 5 and 6, become more difficult to find with increasing age. \Vhether they become incorporated in younger hair follicles or are more widely separated by increase in area of the surface has not been determined at this time.


Distribution of terminals 111 embryos of the premotile age, 16 to 25 mm. crown—rump length (nos. 12 and O) cutaneous nerve fibers have grown from the peripheral nerves along the paths of their main cutaneous branches. Some of these, particularly in the face, over the shoulder, in the axilla, and in the thigh, have approached close to the epithelium. According to Broman (’20) rudimentary sense organs can be found at this time in the axilla and groin.


The relationship of fibers to the epithelium is very much the same in each of the regions named above. In general, it can be said that the fibers which are more intimately sociated with the epithelium are on the ventral surface of the body and the proximal fiexor portions of the extremities. There is a decidedly less abundant distribution of nerve fibers to the dorsal surface of the body and the extensor surface of the extremities during this interval and for some time after motility begins.


According to those who have investigated the appearance of motility in man (p. 373), reflex responses to light cutaneous stimulation can first be obtained from the area supplied by the maxillary division of the trigeminal nerve. Almost _‘a._ ‘F, . Q29 fig.7 One of the most mature follicles on the upper lip of fetus no. 39. The neurofibrillae of the epithelial branch of this nerve (E B) terminate suddenly in the middle of the section. A row of nuclei which may belong to neurilemmal sheath cells extends beyond the neurofibrillae. The follicular branch (FN) can be seen passing among the cells of the follicular sheath to disappear behind the epithelial cells of the follicle (H F).


simultaneously the area supplied by the mandibular division becomes responsive. These precede reflexes originating in the ophthalmic division by several weeks. In this respect man differs quite markedly from the sheep according to the findings of Barcroft and Barron (’39 b). The next area of response in man is the palm of the hand (Hooker, ’38) and the fourth area is the sole of the foot (Hooker, ’39). At a still later date the rest of the body becomes sensitive, but the exact order of the expanding sensitivity has not been worked out.


The above order of appearance of reflexogenous areas is not in harmony with the distribution of the earliest cutaneous nerves as described in the first paragraph of this section. The structure observed would lead one to assume that responses should be obtained from the shoulder, axilla, and thigh almost as soon as from the face. However, the earliest appearance of cutaneous nerve fibers is somewhat misleading, for as the embryo grows older many of the fibers which appear to be in relatively intimate relationship to the epithelium continue to form plexuses in the mesenchyme instead of entering the epithelium to become fixed in a given area. Such a condition of unfixed growth continues for most nerve fibers until some time after the period covered in this investigation. In the meantime some fibers supplying the palms of the hands and soles of the feet have time to reach the site of their ultimate distribution and become functional before responses can be elicited from areas which apparently were about to be in— nervated much earlier.


I)cscripti(m of me/we tcawmnals At 84; Weeks, when the .first responses can be elicited by cutaneous stimulation, the cutaneous nerves of the maxillary reflexogenous area terminate in the mesenchyme below the basement membrane, or what corresponds to the basement membrane (nos. 4, 19, 22, table 1). A. small number of fibers come much closer to the epithelium than the majority do. In no. 4, there are two fibers from the mandibular nerve and one from the maxillary nerve which were followed to a position about 5 u below the bases of the epithelial cells where they run parallel to the surface for a short distance. All of these fibers are on the right side of the face. None on the left side are closer than 18 u from the bases of the epithelial cells. They appear to be undifferentiated, growing tips. Older fetuses show a similar relationship for the next week or two. During this time and for a long time thereafter, many of the fibers grow in the dermis to form a complex plexus, the finer meshes of which lie just below the epithelium, the individual strands often consisting of a single fiber (fig. 9). An almost identical condition has been described for the 1 cm. rat embryo by Cajal (’19, fig. 5). The only relationship of any of these fibers which seems to be different from that of any other growing fiber is that occasionally one is in very intimate association with the body of a peculiar type of granular cell, which was described in the section on changes in the mesenchyme.


As fetuses increase in age the terminals of some of the cutaneous nerves grow closer to the epithelial cells. By the eleventh week some of the fibers supplying the face reach the basement membrane but do not seem to pierce it (fig. 9). During this time the refiexogenous area has spread to include the areas of both the maxillary and mandibular divisions of the trigeminal nerve and of the palms of the hands. In all of these areas the epithelium has been proliferating at an increased speed so that it is from three to several cells in thickness.


In embryos of 25 mm. to 50 mm. C-R length, before the nerve fibers pierce the basement membrane, either some fibers which enter into fairly intimate relations with the epithelium are not capable of being stimulated or they have not yet established functional connections in the central nervous system, for twigs of nerves have been found which enter into as intimate relations with the epithelium in areas from which no responses have been reported by any of the investigators as have been observed in the refiexogenous areas. Such non-responsive areas are: The area in front of the ear supplied by the great auricular nerve, the area over the shoulder and clavicle supplied by the supraelavicular nerves, the axilla, and the upper part of the thigh.

During the twelfth week (nos; 8, 38, 39) the soles of the feet become reflexogenous. Here, too, the epithelium is undergoing; rapid proliferation (fig. 10). This is also the age at which the nerve fibers definitely make contact with the epithelial cells. In the reflexogenous areas of the face the fibers which are in contact with the epithelium have just pierced the basement membrane and have spread out along the bases of the nearest epithelial cells to form crude discs which resemble touch eorpuseles of Merkel except that they are at the bottom of the basal cells of the epithelium instead of being between the cells of the germinal layer. This expansion is probably only temporary and may be a large cone of growth. Each fiber of this nature has only one such disc at its terminal (fig. 10). Such fibers occur in the areas free from follicles and between follicles when the latter are present (nos. 38, 39, figs. 5 and 6). Not every fiber which approaches the epithelium has pierced the basement membrane. Terminals which do pierce it at 12 weeks are either rare or hard to recognize.


During the thirteenth and fourteenth weeks, the refiexogenous area is extended to include almost the whole of the body. A careful examination of the skin from the face and scalp reveals many nerve fibers which pierce the basement. membrane and reach the bases of the epithelial cells (nos. 25, 37, 40). Here they lie as very short, simple fibers which extend between the epithelial cells for about one-third the diameterof the basal cells (fig. 11). As in the .12 weeks fetuses these fibers twist about so much as they approach the epithelium that they generally have to be followed by focusing up and fig. 8 This figure shows the most mature nerve fiber in the superciliary region of fetus no. 39. The follicular nerve (F N) expands as it enters the sheath of the follicle and passes obliquely toward the surface among the cells of the follicular sheath (F S). As the fiber leaves the sheath it is gathered into a. more compact bundle which becomes a part of the nerve rete (N R) or superficial plexus. This fiber is almost as mature as any to be found in any of the 14 weeks fetuses.


Fig. 9 Free nerve ending from the skin of the face of fetus no. 33. This is a typical fiber of the most advanced stage of development of cutaneous nerves in human embryos up to 10 weeks of age. The terminals all end below the basement membrane (B M). down and photographic illustrations that show a great deal of their extent are almost impossible to obtain.


Many cutaneous nerves, especially in the hands and feet of fetuses of 11 weeks and older, are surrounded by an area in which the mesenchymal cells are larger, more mature and more loosely associated with each other than usual, giving the general appearance of localized edema. Sometimes the tissue in these areas is so loose that the intereellular spaces almost resemble the blind end of a lymph capillary. This condition is particularly noticeable along the deeper branches of the nerves of the hands and feet of fetuses of 11 to 13 weeks of menstrual age.


After papillary ridges begin to form 011 the palms and soles of the feet during the fourteenth week, those nerve fibers which reach the epithelium often enter it at its deepest portion, i.e., at the bottom of the epithelial fold between the papillary ridges of the corium. Such bundles of nerves are by no means as numerous as Perez and Pérez (’32) have described for 6- and 7-month fetuses. In fact, the only area in which the papillary ridges approach the state of development described by them is in the middle of the palm of no. 40.


Perez and Pérez found no trace of encapsulated endings in the skin of the hand or foot until toward the close of the seventh month. No signs of encapsulated endings have been recognized in the skin of the face, hands, or feet of fetuses of this series. All of the nerve terminals that have been seen at 14 weeks are either free endings which appear to be growing fiber tips in the mesenchyme, free endings on the sides of epithelial cells, or simple expansions in the sheaths of hair follicles.


Fig. 10 Cutaneous nerve ending (N T) on the basal cells of the epithelium of the face of fetus no. 38. This is an exceptionally good demonstration of the most advanced fibers to be found at 12 weeks. Such terminals are fairly numerous but specimens suitable for photographing are very rare. The nerve fibers shown in this drawing were taken from two arljacent sections.


Fig. 11 Epithelial branch (E B) of a cutaneous nerve from the hand of fetus no. 25., The fibers terminate as indicated (N T) at about the level of the nucleus of one of the basal cells of the epithelium.

The latter two types are found only in reflexogenous areas. The first type is often the only one found in areas which are known to have been reflexogenous. In the younger embryos they are closely associated with the basement membrane without any other distinguishing feature that has been recognized. In 11 weeks fetuses they are generally associated with the edematous appearance described above.


Those fibers which reach the epithelial cells correspond in appearance to the youngest fibers described by Perez and Perez. It is assumed that they really are younger stages of the same type of fiber described by them as “intersudoral plexuses.”

Discussion

In the third part of this paper, under the heading “observations,” the subjects considered have been dealt with chiefly from the point of view of objective description. Before proceeding to that part of the discussion which deals with the theoretical phase of the subject (some of it at present controversial) a very brief summary of certain phases of the observations on which the interpretations are based is given here.


With one exception (embryo 0) all of the embryos and fetuses used in this study were tested for motor responses. Two of those tested failed to give them. One of these was no. 12, which was probably too young to respond, and the other was no. 22 (table 1), which was probably anesthetized but which may have been dead.


Of the remaining fetuses, no. 8, which was undoubtedly anesthetized, failed to give responses from areas which were reflexogenous in other fetuses of the same size. It did respond to stimulation over the body and extremities with a strong hair. However, in this instance the response was a local contraction of the muscles, limited to the area stimulated, and was interpreted by Hooker as being direct stimulation of the muscles.


Histologically there are certain differentiations in the tissues and alterations in the relation of the nerve fibers to them which have been described in the section on observations and which will be discussed in the following paragraphs in an attempt to correlate them with the fetal activity exhibited or, where no correlation can be recognized, to point out the improbability of their taking part in the responses.


The histological findings in this study of the peripheral nerves indicate that in the skin of the human fetus at the time it becomes responsive to cutaneous stimulation there are no structures which are comparable to sensory endings found in the adult. When movement can first be elicited by the stroke of a hair across the lip and cheek of the fetus, very few nerve fibers have grown into the tissue which lies between the anlage of the mimetic musculature and the epithelium and most of these terminate relatively far, 40 to 50 p, below the epithelium. Occasionally a branch can be traced to within 5 or 6 u of the bases of the epithelial cells. Two such fibers were traced from the mandibular division of the trigeminal nerve and one from the maxillary branch in no. 4. All three lie near the angle of the mouth and all are found only on the right side of the face. The number of such fibers has not been recorded exactly for older fetuses but it increases somewhat and they are found on both sides of the face. A similar condition exists until well after the fields of both maxillary and mandibular divisions of the trigeminal nerves have become refiexogenous. During this time the main branches of the trigeminal nerve are forming a deep plexus with branches of the facial nerve. This plexus lies below and sometimes within the anlage of the mimetic musculature.


During this period the ophthalmic division of the trigeminal nerve has been spreading out below the epithelium of the eyelids and superciliary region, and hair follicles have appeared near the medial end of the superciliary fold. However, no response has been elicited from this region in any of the tested fetuses before the twelfth week. There are no nerves in intimate relation to the hair follicles before that time. At about that time local contraction of the orbicularis oculi muscle has been obtained upon stimulation of the superciliary region and eyelids (Hooker, ’36).


During the ninth Week a basement membrane can be observed under the thicker portions of the epithelium of the face. It also becomes visible under the thick epithelium of the plaeodes which form on the volar surfaces of the hands and plantar surfaces of the feet. The nerve fibers do not actually touch it for several days after movements can be elicited by gently stroking the skin but sometimes one or more fibers can be found which lie within 5 or 6 u of it.


During the tenth and eleventh weeks an increasing number of nerve fibers do come into contact with it in the face, but there is no marked change in the ability of the fetus to respond to light cutaneous stimuli. Changes which have been noted are: A11 increase in the extent of the area which is reflexogenous, greater ease in elicitation of responses (lowered threshold?), and more resistance to fatigue. The latter two changes may be correlated with the increase in the number of nerve fibers in the reflexogenous area.


Iaztcrprctaitions and conclusions The interpretation of the physiological activity of a nervous system which has end—organs seemingly so immature as those described but which, nevertheless, gives such positive evidence of being able to respond to light cutaneous stimulation presents a rather perplexing problem. Any conclusion which may be drawn has to be based on some assumption which is at present disputed. There is a group of investigators who have revived the theory of the reticular structure of connective tissues and of nerve fibers. Some of them look upon the relations between nerves and the cells among which they terminate as always being syncytial in nature (Boeke, ’32). This point of view has been discussed in detail by Akkeringa (’30). The reasons for the opposite View have been reviewed at length by Cajal (’34). Wliile certain findings in the material used in this investigation might be interpreted in support of each of the points of view, the bulk of the material tends more to corroborate Cajal’s conclusions than those of Akkeringa, i.e., that the nerve fibers have definite terminals and that the cells of the tissues are discrete.


According to Adrian (’32) deformation of a nerve terminal, ‘as by stretching, is generally necessary to initiate a nerve impulse in an adult. It may be possible for nerve fibers which are apparently as immature as those found in the skin of very young fetuses to be subjected to sufficient stretching, under the conditions imposed where responses were obtained, to stimulate them.


In this connection it is interesting to note that the basement membrane begins to appear in the face at about the time that this area becomes reflexogenous. Also, the epithelium is thicker over the reflexogenous area. The structure of the basement membrane is very indefinite at first and no fibers are Visible in it or in any of the cells in contact with it. However, it may be that it helps to reduce the elasticity of the epithelial sheet and that it can exert traction on the cytoplasmic processes from the subjacent mesenchymal cells which blend with it, when the surface is moved. Lateral traction, which occurs in all directions about a depressed point on the skin, may exert considerable tension on any nerve fibers which lie between the basement membrane and the bodies of mesenchymal cells having processes embedded in it, for an appreciable distance from the depressed point. In this way the basement membrane may play a passive role in increasing the area of effective movement in the skin, thus raising the effectiveness of a stimulus.


At about 12 weeks some of the nerve fibers peirce the basement membrane and come into contact with the epithelial cells (fig. 10). Also at this time some of the hair follicles begin to be invaded by nerve fibers (figs. 7 and 8). The method by which this is brought about seems to be as follows: A nerve fiber and a capillary grow obliquely toward the epithelium near or below a future hair follicle (fig. 5). The epithelial portion of the follicle grows down into the mesenchyme past the more superficial portion of the nerve. During this time the mesenchyme is condensed around the epithelial bud (fig. 6) and the blood vessel supplies that part which later becomes the papilla of the follicle. The mesenchyme which differentiates into the follicular sheaths completely surrounds a portion of the nerve. Later that portion of the fiber which is incorporated in the follicular sheath seems to swell slightly and the neurofibrillae become more widely separated (fig. 8). At a still later period collaterals begin to grow from the neurofibrillae which terminate on the cells of the sheath.


At about the time that the nerve fibers begin to be incorporated in the sheaths of the follicles, localized rather than generalized responses begin to occur when the skin of the region is stimulated but this time relationship appearsto l1ave no significance. The work of Angulo (’39) and others indicates that the mechanism responsible for this change in the type of response resides in the central nervous system instead of in the receptors. It is also at about this time that the hand and foot become reflexogenous and here, too, the type of response is generally local (Hooker ’s protocols).


Because of the tardiness of contact between nerve fibers and epithelial cells as compared to the appearance of motor responses to tactile stimulation, the conclusion that physical contact between epithelium and nerve fibers is not essential for stimulation of the latter seems evident.


Occasionally the presence of granular cells on or close to the basement membrane was noted. These cells exhibit in fixed preparations all of the forms characteristic of actively ameboid cells (figs. 1 and 2). Nothing is known of their activity in the living state but because of their relationship to the tips of nerve fibers and because of the recent trend among physiologists to View the activities of the nervous system as being based on the secretion of hormones, considerable attention has been devoted to them.


The granules of these cells are stained by Bodian’s activated protargol method in the same manner as the granules in other cells which lie within the epithelium (figs. 3 and 4) and which have no Visible connection with any nerve fiber. The number of these granule cells found in close association with nerve fibers is so small in any fetus studied as to make it highly improbable that they have any part in sense perception. However, because they sometimes seem to enter the epithelium before they lose connection with the nerve fiber (fig. 2) and because they resemble so closely those cells whic'h lie among the epithelial cells (interpreted as chromatophores, MaXimowBloom, ’38; Cowdry, ’28; or dendritic cells, as Bloch, ’27, preferred to call them) it seems that they may represent stages in the origin of the latter. Strength is lent to this interpretation by the experimental work of Dorris ( ’38) on the origin of chromatophores in the chick and by the observations of Jalowy (’35) on degenerating touch corpuscles of Merkel in the skin of the ape. J alowy states that during the degeneration of the nerve fiber to the corpuscle, the almost transparent cell on which the nerve fiber terminates sends out processes, acquires granules. resembling those seen in the chromatophores, and then degenerates.


Among the accessory organs of the skin which, because of their function in the adult, might serve as sense organs in embryos and fetuses of the ages under consideration are the hair follicles. In adult man the hair follicles of the body are supplied with nerves which respond to touch and, under certain conditions, to pain. A pressure sufficient to bend a hair on any part of the body, if applied quickly, will cause a sensation of touch, providing the nerve endings in the follicle are not fatigued. Because of this extreme sensitivity to touch, attention has been directed toward the possibility of the early innervation of hair follicles as a means of the reception of stimuli in very young embryos. Broman (’20) described rudimentary organs in the skin of embryos, some of which appear in human embryos as small as 10 mm. of crown-rump length. By the time they reach 25 mm., he found these organs on the arms, forearms, and face. He homologized them with tactile hairs found in lower mammals. Further emphasis has been laid on the possibility of follicles being the sense organs because of observations of fetal behavior made on animals other than man (Lane, ’17). Tello (’23) found the vibrissae of the albino mouse to be innervated at 8 mm., C—R length, and hair follicles over most of the body to be innervated at 18 mm. Also, he found free nerve endings in the epithelium of the mouse in considerable numbers at this time. These embryos were not tested to determine their ability to respond to cutaneous stimuli.


Unfortunately, no data are known that can be used to correlate the physiological capabilities of mouse embryos with available data on rat and human embryos. Neither have there been any such complete anatomical studies made on any of the tested rat or human material as Tello made on the mouse. A rather brief study, made by the writer, of nerve endings in rat materi‘al of the same stages as the tested material indicates that the anatomical structure of nerve endings as given for the mouse by Tello corresponds very closely to that of the endings seen in the rat of somewhat greater size. The endings in a 10 mm. rat correspond fairly well to his illustration of the nerve endings in an 8 mm. mouse (Tello, ’23, fig. 4). His illustration (fig. 6 from the same article) of a follicle from a 9—10 mm. mouse embryo corresponds closely to the state of development found in the rat at the time motility begins, i.e., between 13 mm. and 14 mm.


Lane (’17) states that the vibrissae of a rat fetus are in~ nervated at the time it first responds to cutaneous stimuli in that region. Preparations of premotile rat embryos examined for comparison show innervation of some of the follicles of the vibrissae and, in personal conversation, Angulo and Windle have stated that they each have similar preparations. In addition to the innervation of the follicles in these premotile and just motile rat embryos, there are other nerve fibers which either are in Contact with the bases of some of the epithelial cells or are so close to them that, with silver impregnation, no separation can be observed. Consequently the hair follicles in these human fetuses have been studied with great care to determine whether they Could possibly initiate the observed responses. It will be noted in the description of the follicles that their innervation first appears at about the close of the twelfth week. Therefore, the hair follicles in human fetuses cannot be considered as receptors until the twelfth week. After that time they may receive stimuli.


The next structures to be considered are the placodes described by Broman (’20). Thickenings of the epithelium were found in the regions corresponding to the position of structures which he believed to be rudimentary sense organs. However, the data recorded for the human fetuses studied here show that only the face acted as a reflexogenous area until the close of the eleventh Week. During the time just preceding this age, the mesenchyme under the placodes on the fingers and toes becomes a loose meshwork in many instances. Such a condition was noted earliest in no. 29, of about 811; weeks, but is somewhat more pronounced in the 11 weeks fetuses. At this time the cytoplasmic processes from the mesenchymal cells under the epithelial placodes on the fingers and toes increase in diameter and many cells have at least one process which reaches the basement membrane. Most of the sensory nerve fibers to these areas terminate in this rather loose mesenchyme.


In the fixed material the epithelial placodes do not seem to project above the surrounding areas to the same extent as was described by Broman in the fresh specimens. It is probable that the interstices of the mesenchyme are turgid with tissue fluids in the living condition, so that light pressure on the surface would be transmitted readily to the underlying nerves, thereby increasing the sensitivity of the region in a manner somewhat analogous to that of an inflamed area in adult skin.


Among the various structures considered in this discussion which may be responsible for the transmission of stimuli to the cutaneous nerve fibers in very young fetuses, the most probable mechanism seems to be the nerve fibers lying between the basement membrane and the bodies of mesenchymal cells attached to it. Under such conditions, movements of the surface of the body may cause stresses to be set up in the tips of the nerve fibers which activate them, as Adrian (’32) has described for the adult.


During the thirteenth and fourteenth weeks of menstrual age some nerve fibers begin to come into contact with the epithelial cells. Such fibers possibly can be considered to be more nearly comparable to the structures found in the adult. However, they are not very numerous and it is very probable that much of the earlier mechanism remains active for a considerable time after the oldest stage considered in this investigation.


The distended appearance of the mesenchyme of the fingers and toes disappears during the thirteenth and fourteenth weeks and the corium of the skin begins to be visibly different from the looser subcutaneous tissue. This condition may not imply any decrease in the firmness of the subepithelial tissues. Indeed, the probability of transmission of movement of the surface to the nerve fibers below may be increased, because the mesenchymal cells have longer processes in or on which tortuous fibrillae appear and many more of the cutaneous nerve fibers lie between the bodies of these cells and the basement membrane.


It is very apparent from this investigation that the embryo or fetus must be considered as a whole, rather than merely as a growing nervous system, if its behavior is to be understood. To comprehend the growth of the nervous system in the human fetus, it must be remembered that there is a relative, as well as an absolute, rate of growth of its elements. The absolute increase in length of a nerve fiber is offset to a considerable degree by the separation of its cell of origin and its ultimate termination caused by the growth of the fetus as a whole. Furthermore, during the whole of this time the tip of the nerve may lie only 10 to 50 u from the site of its future end organ. The difference in the rates of growth of the nerve fibers and of the other parts of the body determines the time at which a nerve terminal can reach its ultimate destination. This observation has been very ably discussed by Cajal ( ’28, vol. 1). Apparently the factor of relative growth plays some role in determining the time at which certain areas of the skin may become reflexogenous, athough the weight of evidence-available indicates that the explanation of the changes in fetal behavior lies in the development of connections within the central nervous system.

Summary

  1. In order to determine the nature of the nerve endings present in the skin of human embryos and fetuses when the reflex responses to cutaneous stimulation are first developing, the skin has been examined in individuals from 8 to 14 weeks of menstrual age. These fetuses were prepared by the use of three silver methods, the most satisfactory of which has been that of Bodian using protargol. The skin from reflexogenous areas has been studied with great care and the principal cutaneous nerves have been followed in other parts of the body also.
  2. Cutaneous nerves are very immature when responses can first be elicited. Some nerve terminals in the reflexogenous areas are found in -the mesenchyme just below the epithelium but not in direct contact with it.
  3. Occasionally nerve fibers are found in contact with the bodies of granular cells which lie near or in contact with the epithelium. The number of observations of such cells is too small to be conclusive but cells with similar granules have been found below the basement membrane, piercing it, and above it, incontact with nerve fibers and separate from them. It is thought that possibly they represent stages in the formation of chromatophores.
  4. The epithelium in the reflexogenous areas is several cells thick, but no definite hair follicles are present at 8%} weeks and but few are innervated before 13 weeks.
  5. During the latter part of the period studied, the cutaneous nerves enter the spaces between the epithelial cells in considerable numbers but are limited to a zone near the bases of the cells in the basal layer. No encapsulated nerve endings have been seen. It is suggested that early excitation of the sensory nerves is probably dependent on deformation of the growing tips of the fibers by displacement of the surrounding tissue.

Literature Cited

ADRIAN, E. D. 1932 The mechanism of llervous action. Electrical studies of the neurone. Univ. of Pa. Press, Phila.

AKKERING-A, L. J. 1930 Die Lage der Neurofibrillen am peripheren Ende des Nervenbahn. J ahrb. Morph. und mikr. Anat., Abt. II, Zeitsch. f. rnikr. Anat. Forsch, Bd. 19, S. 183-270

ANGULO Y GONZALEZ, A. W. 1932 The prenatal development of behavior in the albino rat. J. Comp. Neur., vol. 55, pp. 395-442.

1939 Histogenesis of the monopolar neuroblast and the ventral longitudinal path in the albino rat. J. Comp. Neur., vol. 71, pp. 325-360.

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Cite this page: Hill, M.A. (2018, December 10) Embryology Paper - Sensory nerves in the skin of human fetuses of 8 to 14 weeks of menstrual age correlated with functional capability. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_Sensory_nerves_in_the_skin_of_human_fetuses_of_8_to_14_weeks_of_menstrual_age_correlated_with_functional_capability

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